Tormenta de citoquinas provocada por COVID-19

TORMENTA DE CITOQUINAS PROVOCADA POR COVID -19

En el frente de una crisis global: Prevenir y detener la propagación

Covid 19- debuta con pancreatitis en paciente puertorriqueño

Amiloidosis cardiaca: Evaluación, diagnóstico oportuno y tratamiento

El año de la telemedicina

UN AÑO A PRUEBA PARA LA MEDICINA Y LA SALUD PÚBLICA

2

Revista Puertorriqueña de Medicina y Salud Pública

S A L U D P Ú B L I C A | A N I V E R S A R I O #1 5

VACUNAS Y EL PRINCIPIO DE EQUIDAD mérica Latina y el Caribe no tienen la cantidad de vacunas contra la covid-19 que necesitan. Hasta este viernes, la región había recibido 37 millones de dosis, que deberá repartir entre 630 millones de personas. La cifra alcanza para administrar menos de 6 dosis por cada 100 habitantes: manteniendo un criterio de dos por persona, hoy la región puede inmunizar al 2,8% de su población.

En Estados Unidos, mientras tanto, casi uno de cada cuatro ciudadanos ya ha recibido la vacuna. Las desigualdades en el reparto global dibujan el mapa de las diferencias entre países ricos y pobres, como lo denunció en enero la Organización Mundial de la Salud.

El 87% de las dosis están manos de solo cuatro países: Brasil (15 millones), Chile (8,6 millones), México y Argentina (4 millones).

Coincide el organismo internacional que los cuatro países integran el grupo de las cinco mayores economías de la región, con la única ausencia de Colombia. Mientras que países como Cuba (que prepara su propia fórmula) y Honduras no han recibido ni una sola dosis. Otros apenas cuentan con unas pocas miles, como Paraguay (4.000), Ecuador (73.000) o El Salvador (20.000).

Las diferencias son evidentes.

La mayoría de los países de América Latina y el Caribe hoy dependen de Covax, el mecanismo conjunto de la OMS y la Iniciativa Mundial para las Vacunas y la Inmunización (GAVI) para repartir equitativamente 281 millones de dosis.

Revista Puertorriqueña de Medicina y Salud Pública

3

VENCLEXTA + GAZYVA® (obinutuzumab):

THE ONLY CHEMO-FREE REGIMEN

DESIGNED TO STOP AFTER 12 MONTHS IN 1L CLL1*

*The VEN+G regimen is designed to be completed after 12 months (twelve 28-day treatment cycles): GAZYVA is administered in Cycles 1-6 and VENCLEXTA is taken orally 400 mg/day from Cycle 3, Day 1, after the first cycle of GAZYVA and the 5-week VENCLEXTA dose ramp-up.

1L=first-line; CLL=chronic lymphocytic leukemia; VEN+G=VENCLEXTA + GAZYVA.

LEARN MORE AT VENCLEXTAHCP.COM Indication and Important Safety Information Indication • VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Important Safety Information Contraindication • Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome (TLS).

Tumor Lysis Syndrome • Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients with high tumor burden when treated with VENCLEXTA. • In patients with CLL who followed the current (5 week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL monotherapy studies. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure.

• VENCLEXTA poses a risk for TLS at initiation and during the ramp-up phase.

Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.

• Patients should be assessed for TLS risk, including evaluation of tumor burden and comorbidities, and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Reduced renal function further increases the risk.

Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases.

• Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors or P-gp inhibitors may increase the risk of TLS at initiation and during the ramp-up phase, and requires dose adjustment due to increases in VENCLEXTA exposure.

Neutropenia • In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients treated with VENCLEXTA in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients treated with VENCLEXTA in combination and monotherapy studies.

• Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF).

Infections • Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with VENCLEXTA. Monitor patients closely for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and higher infection.

Immunization • Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective.

Embryo-Fetal Toxicity • VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment.

Distributed and marketed by AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064 Marketed by Genentech USA, Inc., 1 DNA Way, South San Francisco, CA 94080-4990 ©2019 AbbVie Inc. and Genentech USA, Inc.

VEN+G REDUCED PATIENTS’ RISK OF PROGRESSION OR DEATH BY 67% VS GClb 1 (HR=0.33; 95% CI: 0.22–0.51; P<0.0001)

Progression-free survival per independent review committee1,2 Estimated PFS at 12 months†

Progression-free survival (%)

Estimated PFS at 24 months†

95% (95% CI: 92–98)

100

VEN+G DEMONSTRATED DURABLE PFS AFTER STOPPING TREATMENT AT 12 MONTHS1

89% (95% CI: 84–93)

91%

• After a median follow-up of 28 months (range: 0.1–36 months), there were 29 events in the VEN+G arm (14 progression and 15 death events) compared with 79 in the GClb arm (71 progression and 8 death events).‡ Median PFS was not reached in either arm1

VEN+G

(95% CI: 87–95)

64%

50

24-month follow-up, the estimated rate 89% • Atof PFS was 89% 2†

GClb

(95% CI: 57–70)

• At the time of the analysis, median OS had not been reached, with fewer than 10% of patients experiencing a death event (37 in total: 20 in the VEN+G arm and 17 in the GClb arm)1,3 12 MONTHS ON TREATMENT

0 0

3

6

9

TIME OFF TREATMENT 12

15

18

21

24

27

30

33

36

Time (months) Number of patients at risk VEN+G 216

200

195

195

192

187

181

178

148

85

23

6

GClb 216

200

195

189

183

164

151

140

108

67

20

9

Study design: CLL14 was a randomized (1:1), multicenter, open-label phase 3 study that evaluated the efficacy and safety of VEN+G versus GClb for previously untreated CLL in 432 patients with coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The primary endpoint was progressionfree survival (PFS).§

HR estimate is based on Cox proportional hazards model stratified by Binet stage and geographic region; P value is based on log-rank test stratified by the same factors.

Estimated 12- and 24-month PFS rates were not prespecified and were not tested for statistical significance. ‡ Number of events based on earliest event of disease progression or death due to any cause. Events due to progression may include deaths occurring post-progression. § On Day 1 all patients received intravenous GAZYVA at 1000 mg (the first dose could be split as 100 mg and 900 mg on Days 1 and 2, respectively). GAZYVA 1000 mg was then administered on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent cycle, for a total of 6 cycles. Patients in the VEN+G arm began the 5-week VENCLEXTA ramp-up schedule on Day 22 of Cycle 1 and received VENCLEXTA 400 mg once daily from Cycle 3, Day 1 until the last day of Cycle 12. Patients randomized to the GClb arm received 0.5 mg/kg oral chlorambucil on Day 1 and Day 15 of Cycles 1 to 12. Each cycle was 28 days. †

VEN+G DEMONSTRATED DURABLE PFS AFTER STOPPING TREATMENT AT 12 MONTHS1

12

MONTHS

• The VEN+G regimen is completed in 12 months (twelve 28-day treatment cycles) • VENCLEXTA 400 mg/day is taken orally from Cycle 3, Day 1, after the first cycle of GAZYVA and the 5-week VENCLEXTA dose ramp-upǁ After the first treatment cycle of GAZYVA and before the VENCLEXTA dose ramp-up, patients’ ALC was reduced by 98% (from a median count of 55 x 109 cells/L at baseline to a median count of 1.27 x 109 cells/L at Day 15).4 Median lymphocyte counts are descriptive in nature and not powered for any type of comparison. Per the trial protocol, tumor burden was assessed based on ALC and lymph node size. The effect of the first GAZYVA treatment cycle on lymph node size was not evaluated. Changes in TLS risk status based on ALC reduction were at the discretion of the trial investigators.

ǁ

GClb=GAZYVA + chlorambucil; HR=hazard ratio; CI=confidence interval; OS=overall survival; ALC=absolute lymphocyte count; TLS=tumor lysis syndrome.

Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone • In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions • In patients with CLL receiving combination therapy with obinutuzumab, serious adverse reactions were most often due to febrile neutropenia and pneumonia (5% each). The most common adverse reactions (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%).

• In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (≥5%) was pneumonia (9%). The most common adverse reactions (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), cough (22%), and nausea (21%).

• In patients with CLL/SLL receiving monotherapy, the most frequent serious adverse reactions (≥5%) were pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). The most common adverse reactions (≥20%) of any grade were neutropenia (50%), diarrhea (43%), nausea (42%), upper respiratory tract infection (36%), anemia (33%), fatigue (32%), thrombocytopenia (29%), musculoskeletal pain (29%), edema (22%), and cough (22%).

Drug Interactions • Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Adjust VENCLEXTA dosage and closely monitor patients for signs of VENCLEXTA toxicities. Resume the VENCLEXTA dosage that was used prior to concomitant use of a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.

• Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A. • Avoid concomitant use of strong or moderate CYP3A inducers.

• Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA. • Monitor international normalized ratio (INR) closely in patients receiving warfarin.

Lactation • Advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA. Females and Males of Reproductive Potential • Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose.

• Based on findings in animals, male fertility may be compromised by treatment with VENCLEXTA. Hepatic Impairment • Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more closely for signs of toxicity. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

References: 1. VENCLEXTA Prescribing Information. 2. Data on file, AbbVie Inc. ABVRRTI68008.

3. Data on file, AbbVie Inc. ABVRRTI68083. 4. Data on file, AbbVie Inc. ABVRRTI68219.

VENCLEXTA® is a registered trademark of AbbVie Inc. GAZYVA® is a registered trademark of Genentech, Inc.

Please see Brief Summary of full Prescribing Information on the following pages.

US-VENC-190373/August 2019

Printed in USA

DO NOT RE-SIZE US-VENC-190373

VENCLEXTA® (venetoclax tablets) INDICATIONS AND USAGE Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Acute Myeloid Leukemia VENCLEXTA is indicated in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

This indication is approved under accelerated approval based on response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

CONTRAINDICATIONS Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during the ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions].

WARNINGS AND PRECAUTIONS Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients with high tumor burden when treated with VENCLEXTA [see Adverse Reactions].

In patients with CLL who followed the current (5 week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL monotherapy studies. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2 to 3 week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure [see Adverse Reactions].

VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.

The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. Reduced renal function further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases [see Use in Specific Populations].

Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up phase and requires VENCLEXTA dose adjustment [see Drug Interactions].

Neutropenia In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients treated with VENCLEXTA in combination and monotherapy studies (see Tables 2, 4, 6). Febrile neutropenia occurred in 4% to 6% of patients treated with VENCLEXTA in combination and monotherapy studies [see Adverse Reactions].

In patients with AML, baseline neutrophil counts worsened in 97% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles of therapy.

Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF).

Infections Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with VENCLEXTA [see Adverse Reactions]. Monitor patients closely for signs and symptoms of infection and treat promptly.

Withhold VENCLEXTA for Grade 3 and higher infection.

Immunization Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations may be less effective.

Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman.

In an embryo-fetal study conducted in mice, administration of venetoclax to pregnant animals at exposures equivalent to that observed in patients at a dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. There are no adequate and well-controlled studies in pregnant women using VENCLEXTA. Advise females of reproductive potential to avoid pregnancy during treatment. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while taking VENCLEXTA, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Tumor Lysis Syndrome [see Warnings and Precautions] • Neutropenia [see Warnings and Precautions] • Infections [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

03-B947 Venclexta PB-7.5 x 10.5(3).indd 1

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Clinical Trial Experience with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma CLL14 The safety of VENCLEXTA in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) was evaluated in a randomized, open-label, actively controlled trial in patients with previously untreated CLL. Patients randomized to the VEN+G arm were treated with VENCLEXTA and obinutuzumab in combination for six cycles, then with VENCLEXTA as monotherapy for an additional six cycles. Patients initiated the first dose of the 5 week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and once completed, continued VENCLEXTA 400 mg once daily for a total of 12 cycles. The trial required a total Cumulative Illness Rating Scale (CIRS) >6 or CLcr <70 mL/min, hepatic transaminases and total bilirubin ≤2 times upper limit of normal, and excluded patients with any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system.

A total of 426 patients were treated (212 with VEN+G, 214 with GClb).

The median duration of exposure to VENCLEXTA was 10.5 months (range: 0 to 13.5 months). The median number of cycles was 6 for obinutuzumab and 12 for chlorambucil.

In the VEN+G arm, fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection. Serious adverse reactions were reported in 49% of patients in the VEN+G arm, most often due to febrile neutropenia and pneumonia (5% each).

In the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%.

In the VEN+G arm, neutropenia led to dose interruption of VENCLEXTA in 41% of patients, reduction in 13%, and discontinuation in 2%.

Table 1 and Table 2 present adverse reactions and laboratory abnormalities identified in the CLL14 trial, respectively. The most common (≥15%) adverse reactions observed with VEN+G were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

Table 1. Common (≥10%) Adverse Reactions in Patients Treated with VEN+G

Grade 4 laboratory abnormalities developing in ≥2% of patients treated with VEN+G include neutropenia (32%), leukopenia and lymphopenia (10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia (2%).

MURANO The safety of VENCLEXTA in combination with rituximab (VEN+R) versus bendamustine in combination with rituximab (B+R), was evaluated in an open-label randomized study, in patients with CLL who had received at least one prior therapy.

Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily in combination with rituximab for 6 cycles followed by single agent VENCLEXTA for a total of 24 months after ramp-up. Patients randomized to B+R received 6 cycles (28 days per cycle) for a total of 6 months.

At the time of analysis, the median duration of exposure was 22 months in the VEN+R arm compared with 6 months in the B+R arm.

In the VEN+R arm, fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab were reported in 2% (4/194) of patients.

Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%).

In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%.

In the B+R arm, adverse reactions led to treatment discontinuation in 10% of patients, dose reduction in 15%, and dose interruption in 40%.

In the VEN+R arm, neutropenia led to dose interruption of VENCLEXTA in 46% of patients and discontinuation in 3%, and thrombocytopenia led to discontinuation in 3% of patients.

Table 3 and Table 4 present adverse reactions and laboratory abnormalities, respectively, identified in the MURANO trial. The MURANO trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for VEN+R as compared with B+R, for any specific adverse reaction or laboratory abnormality.

Table 3. Common (≥10%) Adverse Reactions Reported with ≥5% Higher All-Grade or ≥2% Higher Grade ≥3 Incidence in Patients Treated with VEN+R Compared with B+R

VENCLEXTA + Obinutuzumab + Obinutuzumab Chlorambucil (N = 212) (N = 214) Adverse Reaction by Body System All All Grade ≥3 ≥3 Grades Grades Grade % % % % Blood & lymphatic system disorders 60 56 62 52 Neutropeniaa 17 8 20 7 Anemiaa Gastrointestinal disorders Diarrhea 28 4 15 1 Nausea 19 0 22 1 Constipation 13 0 9 0 Vomiting 10 1 8 1 General disorders and administration site conditions a 21 2 23 1 Fatigue Infections and Infestations Upper respiratory 17 1 17 1 tract infectiona aIncludes multiple adverse reaction terms.

Other clinically important adverse reactions (all Grades) reported in <10% of patients treated with VEN+G are presented below: Blood & lymphatic system disorders: febrile neutropenia (6%) Infection and infestations (all include multiple adverse reaction terms): pneumonia (9%), urinary tract infection (6%), sepsis (4%) Metabolism and nutrition disorder: tumor lysis syndrome (1%) During treatment with single agent VENCLEXTA after completion of VEN+G combination treatment, the most common all grade adverse reaction (≥10% patients) reported was neutropenia (26%). The most common grade ≥3 adverse reactions (≥2% patients) were neutropenia (23%), and anemia (2%).

Table 2. New or Worsening Clinically Important Laboratory Abnormalities Occurring at ≥10% in Patients Treated with VEN+G

VENCLEXTA + Rituximab Followed by Single Agent Bendamustine + VENCLEXTA Rituximab (N = 194) (N = 188) All All Grade ≥3 Grade ≥3 Adverse Reaction by Grades Grades (%) (%) Body System (%) (%) Blood & lymphatic system disorders 65 62 50 44 Neutropeniaa Gastrointestinal disorders Diarrhea 40 3 17 1 Infections & infestations Upper respiratory 39 2 23 2 tract infectiona Lower respiratory 18 2 10 2 a tract infection Musculoskeletal and connective tissue disorders 19 1 13 0 Musculoskeletal paina Metabolism and nutrition disorders Tumor lysis 3 3 1 1 syndrome aIncludes multiple adverse reaction terms.

Other adverse reactions (all grades) reported in ≥10% of patients in the VEN+R arm in MURANO, and other important adverse reactions are presented below: Blood & lymphatic system disorders: anemia (16%), thrombocytopenia (15%), febrile neutropenia (4%) Gastrointestinal disorders: nausea (21%), constipation (14%), abdominal pain (13%), mucositis (10%), vomiting (8%) Respiratory disorders: cough (22%) General disorders and administration site conditions: fatigue (22%), pyrexia (15%) Skin disorders: rash (13%) Nervous system and psychiatric disorders: headache (11%), insomnia (11%) Infections & infestations: pneumonia (10%), sepsis (1%) During treatment with single agent VENCLEXTA after completion of VEN+R combination treatment, the most common all grade adverse reactions (≥10% patients) reported were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%). The most common Grade 3 or 4 adverse reactions (≥2% patients) were neutropenia (12%) and anemia (3%).

Laboratory Abnormalities Table 4 describes common treatment-emergent laboratory abnormalities identified in the MURANO trial.

Table 4. Common (≥10%) New or Worsening Laboratory Abnormalities Occurring at ≥5% (Any Grade) or ≥2% (Grade 3 or 4) Higher Incidence with VEN+R Compared with B+R

Laboratory Abnormalitya

VENCLEXTA + Obinutuzumab + Obinutuzumab Chlorambucil (N = 212) (N = 214) All All 3 or 4 Grades Grade 3 or 4 Grades Grade (%) (%) (%) (%)

Hematology Leukopenia 90 46 89 41 Lymphopenia 87 57 87 51 Neutropenia 83 63 79 56 Thrombocytopenia 68 28 71 26 Anemia 53 15 46 11 Chemistry Blood creatinine 80 6 74 2 increased Hypocalcemia 67 9 58 4 Hyperkalemia 41 4 35 3 Hyperuricemia 38 38 38 38 aIncludes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown.

Laboratory Abnormality Hematology Leukopenia Lymphopenia Neutropenia

VENCLEXTA + Rituximab N=194 Grade 3 All or 4 Gradesa (%) (%) 89 87 86

46 56 64

Bendamustine + Rituximab N=188 All Grade 3 Gradesa or 4 (%) (%) 81 79 84

35 55 59

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Laboratory Abnormality

VENCLEXTA + Rituximab N=194 Grade 3 All or 4 Gradesa (%) (%)

Bendamustine + Rituximab N=188 All Grade 3 Gradesa or 4 (%) (%)

Chemistry Hypocalcemia 62 5 51 2 Hypophosphatemia 57 14 35 4 AST/SGOT 46 2 31 3 increased Hyperuricemia 36 36 33 33 Alkaline phosphatase 35 1 20 1 increased Hyperbilirubinemia 33 4 26 3 Hyponatremia 30 6 20 3 Hypokalemia 29 6 18 3 Hyperkalemia 24 3 19 2 Hypernatremia 24 1 13 0 Hypoglycemia 16 2 7 0 aIncludes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown.

New Grade 4 laboratory abnormalities reported in ≥2% of patients treated with VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia (6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), hypoglycemia (2%), and hypermagnesemia (2%).

Monotherapy Studies (M13-982, M14-032, and M12-175) The safety of single agent VENCLEXTA at the 400 mg recommended daily dose following a dose ramp-up schedule is based on pooled data from three single-arm trials (M13-982, M14-032, and M12-175). In the pooled dataset, consisting of 352 patients with previously treated CLL or SLL, the median age was 66 years (range: 28 to 85 years), 93% were white, and 68% were male. The median number of prior therapies was 3 (range: 0 to 15). The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks.

Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most commonly (2 patients) from septic shock. Serious adverse reactions were reported in 52% of patients, with the most frequent (≥5%) being pneumonia (9%), febrile neutropenia (5%), and sepsis (5%).

Adverse reactions led to treatment discontinuation in 9% of patients, dose reduction in 13%, and dose interruption in 36%. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia. The most frequent adverse reaction (≥5%) leading to dose reductions or interruptions was neutropenia (8%).

Adverse reactions identified in these trials of single-agent VENCLEXTA are presented in Table 5.

Table 5. Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade ≥3) of Patients with Previously Treated CLL/SLL (VENCLEXTA Monotherapy)

Body System Blood and lymphatic system disorders

Gastrointestinal disorders

General disorders and administration site conditions

Infections and infestations Musculoskeletal and connective tissue disorders Nervous system disorders

Adverse Reaction Neutropeniaa Anemiaa Thrombocytopeniaa Lymphopeniaa Febrile neutropenia Diarrhea Nausea Abdominal paina Vomiting Constipation Mucositisa Fatiguea Edemaa Pyrexia Upper respiratory tract infectiona Pneumoniaa Lower respiratory tract infectiona Musculoskeletal paina

Any Grade Grade ≥3 (%) (%) N=352 N=352 50 45 33 18 29 20 11 7 6 6 43 3 42 1 18 3 16 1 16 <1 13 <1 32 4 22 2 18 <1 36

1

14

8

11

2

29

2

Arthralgia

12

<1

Headache Dizzinessa Cougha

18 14 22

<1 0 0

Respiratory, thoracic, and a 13 1 mediastinal disorders Dyspnea Skin and subcutaneous Rasha 18 <1 tissue disorders Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms.

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Laboratory Abnormalities Table 6 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline. The most common (>5%) Grade 4 laboratory abnormalities observed with VENCLEXTA monotherapy were hematologic laboratory abnormalities, including neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%).

Table 6. New or Worsening Laboratory Abnormalities with VENCLEXTA Monotherapy (≥40% Any Grade or ≥10% Grade 3 or 4) All Gradesa Grade 3 or 4 (%) (%) Laboratory Abnormality N=352 N=352 Hematology Leukopenia 89 42 Neutropenia 87 63 Lymphopenia 74 40 Anemia 71 26 Thrombocytopenia 64 31 Chemistry Hypocalcemia 87 12 Hyperglycemia 67 7 Hyperkalemia 59 5 AST increased 53 3 Hypoalbuminemia 49 2 Hypophosphatemia 45 11 Hyponatremia 40 9 aIncludes laboratory abnormalities that were new or worsening, or worsening from baseline unknown.

Important Adverse Reactions Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA. CLL14 The incidence of TLS was 1% (3/212) in patients treated with VEN+G [see Warnings and Precautions]. All three events of TLS resolved and did not lead to withdrawal from the study. Obinutuzumab administration was delayed in two cases in response to the TLS events.

MURANO In the open-label randomized phase 3 study, the incidence of TLS was 3% (6/194) in patients treated with VEN+R. After 77/389 patients were enrolled in the study, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures. All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days.

All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 4.

Monotherapy Studies (M13-982 and M14-032) In 168 patients with CLL treated according to recommendations, the rate of TLS was 2%. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L); or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm and/or ALC ≥25 x 109/L. All events resolved within 5 days. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias or sudden death and/or seizures was observed in these patients. All patients had CLcr ≥50 mL/min. Laboratory abnormalities relevant to TLS were hyperkalemia (17% all Grades, 1% Grade ≥3), hyperphosphatemia (14% all Grades, 2% Grade ≥3), hypocalcemia (16% all Grades, 2% Grade ≥3), and hyperuricemia (10% all Grades, <1% Grade ≥3).

In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting doses, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. After this experience, TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised.

Clinical Trial Experience with Acute Myeloid Leukemia The safety of VENCLEXTA (400 mg daily dose) in combination with azacitidine (n=67) or decitabine (n= 13) and VENCLEXTA (600 mg daily dose) in combination with low-dose cytarabine (n= 61) is based on two non-randomized trials of patients with newly-diagnosed AML. The median duration of exposure for patients taking VENCLEXTA in combination with azacitidine and decitabine was 6.5 months (range: 0.1 to 31.9 months) and 8.4 months (range: 0.5 to 22.3 months), respectively. The median duration of exposure for patients taking VENCLEXTA in combination with low dose cytarabine was 3.9 months (range: 0.2 to 29.2 months).

VENCLEXTA in Combination with Azacitidine or Decitabine Azacitidine The most common adverse reactions (≥30%) of any grade were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

Serious adverse reactions were reported in 75% of patients. The most frequent serious adverse reactions (≥5%) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal adverse drug reactions was 1.5% within 30 days of starting treatment. No reaction had an incidence of ≥2%.

Discontinuations due to adverse reactions occurred in 21% of patients.

The most frequent adverse reactions leading to drug discontinuation (≥2%) were febrile neutropenia and pneumonia (excluding fungal).

Dosage interruptions due to adverse reactions occurred in 61% of patients.

The most frequent adverse reactions leading to dose interruption (≥5%) were neutropenia, febrile neutropenia, and pneumonia (excluding fungal).

Dosage reductions due to adverse reactions occurred in 12% of patients.

The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia.

Decitabine The most common adverse reactions (≥30%) of any grade were febrile neutropenia, constipation, fatigue, thrombocytopenia, abdominal pain, dizziness, hemorrhage, nausea, pneumonia (excluding fungal), sepsis (excluding fungal), cough, diarrhea, neutropenia, back pain, hypotension, myalgia, oropharyngeal pain, peripheral edema, pyrexia, and rash.

Serious adverse reactions were reported in 85% of patients. The most frequent serious adverse reactions (≥5%) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis, and localized infection.

One (8%) fatal adverse drug reaction of bacteremia occurred within 30 days of starting treatment.

Discontinuations due to adverse reactions occurred in 38% of patients. The most frequent adverse reaction leading to drug discontinuation (≥5%) was pneumonia (excluding fungal).

Dosage interruptions due to adverse reactions occurred in 62% of patients.

The most frequent adverse reactions leading to dose interruption (≥5%) were febrile neutropenia, neutropenia, and pneumonia (excluding fungal).

Dosage reductions due to adverse reactions occurred in 15% of patients.

The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia.

Adverse reactions reported in patients with newly-diagnosed AML using VENCLEXTA in combination with azacitidine or decitabine are presented in Table 7.

Table 7. Adverse Reactions Reported in ≥30% (Any Grade) or ≥5% (Grade ≥3) of Patients with AML Treated with VENCLEXTA in Combination with Azacitidine or Decitabine

Body System

Adverse Reaction

VENCLEXTA in Combination with Decitabine Any Any Grade ≥3 Grade ≥3 Grade Grade (%) (%) (%) (%) N = 13 N = 67 N = 13 N = 67

VENCLEXTA in Combination with Azacitidine

Thrombo49 45 54 54 cytopeniaa 49 49 38 38 Neutropeniaa Febrile 36 36 69 69 neutropenia 30 30 15 15 Anemiaa Nausea 58 1 46 0 Diarrhea 54 3 38 8 Gastrointestinal Constipation 49 3 62 0 disorders a 40 0 23 0 Vomiting Abdominal 22 4 46 0 a pain Peripheral 46 1 31 0 edemaa General Fatiguea 36 7 62 15 disorders Pyrexia 21 3 31 0 and administration Cachexia 0 0 8 8 site Multiple organ conditions dysfunction 6 6 0 0 syndrome Pneumonia 27 25 46 31 (excluding fungal)a Sepsis 13 13 46 46 (excluding Infections and fungal)a infestations Urinary tract 16 6 23 0 infection Cellulitis 6 0 15 8 Localized 0 0 8 8 infection Musculoskeletal Back pain 15 0 31 0 and connective a 10 0 31 0 tissue disorders Myalgia Nervous system Dizzinessa 28 1 46 0 disorders Skin and subcutaneous Rasha 33 1 31 0 tissue disorders a 25 0 38 0 Cough Respiratory, Hypoxia 18 6 15 0 thoracic and mediastinal Oropharyngeal 9 0 31 0 disorders pain 46 7 46 0 Hemorrhagea Vascular 21 6 31 0 Hypotensiona disorders Hypertension 12 7 15 8 Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms.

Blood and lymphatic system disorders

Laboratory Abnormalities Table 8 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline.

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Table 8. New or Worsening Laboratory Abnormalities with VENCLEXTA Reported in ≥40% (Any Grade) or ≥10% (Grade 3 or 4) of Patients with AML Treated with VENCLEXTA in Combination with Azacitidine or Decitabine

Laboratory Abnormality

VENCLEXTA in Combination with Azacitidine Any Grade 3 Gradea or 4a (%) (%) N = 67 N = 67

VENCLEXTA in Combination with Decitabine Any Grade 3 Gradea or 4a (%) (%) N = 13 N = 13

Hematology Neutropenia 100 100 100 100 Leukopenia 100 98 100 100 Thrombocytopenia 91 78 83 83 Lymphopenia 88 73 100 92 Anemia 57 57 69 69 Chemistry Hyperglycemia 75 12 69 0 Hypocalcemia 58 7 85 0 Hypoalbuminemia 52 4 38 8 Hypokalemia 49 7 46 0 Hyponatremia 49 4 38 0 Hypophosphatemia 46 15 23 8 Hyperbilirubinemia 45 9 46 15 Hypomagnesemia 21 0 54 8 aIncludes laboratory abnormalities that were new or worsening, or worsening from baseline unknown.

VENCLEXTA in Combination with Low-Dose Cytarabine The most common adverse reactions (≥30%) of any grade were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

Serious adverse reactions were reported in 95% of patients. The most frequent serious adverse reactions (≥5%) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal adverse drug reactions was 4.9% within 30 days of starting treatment with no reaction having an incidence of ≥2%.

Discontinuations due to adverse reactions occurred in 33% of patients.

The most frequent adverse reactions leading to drug discontinuation (≥2%) were hemorrhage and sepsis (excluding fungal).

Dosage interruptions due to adverse reactions occurred in 52% of patients.

The most frequent adverse reactions leading to dose interruption (≥5%) were thrombocytopenia, neutropenia, and febrile neutropenia.

Dosage reductions due to adverse reactions occurred in 8% of patients.

The most frequent adverse reaction leading to dose reduction (≥2%) was thrombocytopenia.

Adverse reactions reported in patients with newly-diagnosed AML receiving VENCLEXTA in combination with low-dose cytarabine are presented in Table 9.

Table 9. Adverse Reactions Reported in ≥30% (Any Grade) or ≥5% (Grade ≥3) of Patients with AML Treated with VENCLEXTA in Combination with Low-Dose Cytarabine Any Grade Grade ≥3 (%) (%) N = 61 N = 61 59 59 Thrombocytopeniaa a 46 46 Blood and lymphatic system Neutropenia disorders Febrile neutropenia 46 44 26 26 Anemiaa Nausea 64 2 Gastrointestinal disorders Diarrhea 44 3 Constipation 33 0 General disorders and 44 10 administration site Fatiguea conditions 20 18 Sepsisa 18 16 Pneumoniaa Infections and infestations Device related 13 11 infection Urinary tract 8 7 infection Metabolic and nutritional Decreased 28 7 disorders appetitea Respiratory disorders Dyspneaa 31 3 49 15 Hemorrhagea 21 7 Hypotensiona Vascular disorders Hypertension 15 8 Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms.

Body System

Adverse Reaction

Laboratory Abnormalities Table 10 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline.

Table 10. New or Worsening Laboratory Abnormalities with VENCLEXTA Reported in ≥40% (Any Grade) or ≥10% (Grade 3 or 4) of Patients with AML Treated with VENCLEXTA in Combination with Low-Dose Cytarabine Laboratory Abnormality

All Gradesa Grade 3 or 4a (%) (%) N = 61 N = 61

Hematology Thrombocytopenia 100 96 Neutropenia 96 96 Leukopenia 96 96 Lymphopenia 93 66 Anemia 61 59 Chemistry Hyperglycemia 85 8 Hypocalcemia 79 16 Hyponatremia 62 11 Hyperbilirubinemia 57 3 Hypoalbuminemia 59 5 Hypokalemia 56 20 Hypophosphatemia 51 21 Hypomagnesemia 46 0 Blood creatinine increased 46 3 Blood bicarbonate decreased 41 0 aIncludes laboratory abnormalities that were new or worsening, or worsening from baseline unknown.

Tumor Lysis Syndrome Tumor lysis syndrome is an important risk when initiating treatment in patients with AML. The incidence of TLS was 3% (2/61) with VENCLEXTA in combination with low-dose cytarabine with implementation of dose ramp-up schedule in addition to standard prophylaxis and monitoring measures. All events were laboratory TLS, and all patients were able to reach the target dose.

DRUG INTERACTIONS Effects of Other Drugs on VENCLEXTA Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax Cmax and AUCinf, which may increase VENCLEXTA toxicities, including the risk of TLS [see Warnings and Precautions].

Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated [see Contraindications].

In patients with CLL/SLL taking a steady daily dosage (after ramp-up phase), consider alternative medications or adjust VENCLEXTA dosage and closely monitor for signs of VENCLEXTA toxicities.

In patients with AML, adjust VENCLEXTA dosage and closely monitor for signs of VENCLEXTA toxicities.

Resume the VENCLEXTA dosage that was used prior to concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.

Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A. Strong or Moderate CYP3A Inducers Concomitant use with a strong CYP3A inducer decreases venetoclax Cmax and AUCinf, which may decrease VENCLEXTA efficacy. Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers.

Effect of VENCLEXTA on Other Drugs Warfarin Concomitant use of VENCLEXTA increases warfarin Cmax and AUCinf, which may increase the risk of bleeding. Closely monitor international normalized ratio (INR) in patients using warfarin concomitantly with VENCLEXTA. P-gp Substrates Concomitant use of VENCLEXTA increases Cmax and AUCinf of P-gp substrates, which may increase toxicities of these substrates. Avoid concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no available data on VENCLEXTA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.

Based on toxicity observed in mice, VENCLEXTA may cause fetal harm when administered to pregnant women. In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at a human dose of 400 mg daily. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while taking VENCLEXTA, the patient should be apprised of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data Animal data In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human AUC exposure at a dose of 400 mg daily). No teratogenicity was observed in either the mouse or the rabbit.

Lactation Risk Summary There are no data on the presence of VENCLEXTA in human milk, the effects of VENCLEXTA on the breastfed child, or the effects of VENCLEXTA on milk production. Venetoclax was present in the milk when administered to lactating rats (see Data).

Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from VENCLEXTA is unknown, advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA. Data Animal Data Venetoclax was administered (single dose; 150 mg/kg oral) to lactating rats 8 to 10 days parturition. Venetoclax in milk was 1.6 times lower than in plasma. Parent drug (venetoclax) represented the majority of the total drug-related material in milk, with trace levels of three metabolites.

Females and Males of Reproductive Potential VENCLEXTA may cause fetal harm [see Warnings and Precautions and Use in Specific Populations].

Pregnancy Testing Conduct pregnancy testing in females of reproductive potential before initiation of VENCLEXTA [see Use in Specific Populations].

Contraception Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose [see Use in Specific Populations].

Infertility Based on findings in animals, male fertility may be compromised by treatment with VENCLEXTA. Pediatric Use Safety and effectiveness have not been established in pediatric patients.

In a juvenile toxicology study, mice were administered venetoclax at 10, 30, or 100 mg/kg/day by oral gavage from 7 to 60 days of age. Clinical signs of toxicity included decreased activity, dehydration, skin pallor, and hunched posture at ≥30 mg/kg/day. In addition, mortality and body weight effects occurred at 100 mg/kg/day. Other venetoclax-related effects were reversible decreases in lymphocytes at ≥10 mg/kg/day; a dose of 10 mg/kg/day is approximately 0.06 times the clinical dose of 400 mg on a mg/m2 basis for a 20 kg child.

Geriatric Use Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Of the 352 patients with previously treated CLL/SLL evaluated for safety from 3 open-label trials of VENCLEXTA monotherapy, 57% (201/352) were ≥65 years of age and 18% (62/352) were ≥75 years of age.

No clinically meaningful differences in safety and effectiveness were observed between older and younger patients in the combination and monotherapy studies.

Acute Myeloid Leukemia Of the 67 patients treated with VENCLEXTA in combination with azacitidine in the clinical trial, 96% were ≥65 years of age and 50% were ≥ 75 years of age. Of the 13 patients treated with VENCLEXTA in combination with decitabine in the clinical trial, 100% were ≥65 years of age and 26% were ≥ 75 years of age. Of the 61 patients treated with VENCLEXTA in combination with low-dose cytarabine, 97% were ≥65 years of age and 66% were ≥75 years of age.

The efficacy and safety data presented in the Adverse Reactions and Clinical Studies sections were obtained from these patients [see Adverse Reactions]. There are insufficient patient numbers to show differences in safety and effectiveness between geriatric and younger patients.

Renal Impairment Due to the increased risk of TLS, patients with reduced renal function (CLcr <80 mL/min, calculated by Cockcroft-Gault formula) require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA [see Warnings and Precautions].

No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr ≥ 30 mL/min). A recommended dose has not been determined for patients with severe renal impairment (CLcr < 30 mL/min) or patients on dialysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more closely for signs of toxicity.

OVERDOSAGE There is no specific antidote for VENCLEXTA. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities. Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.

Manufactured and Marketed by: AbbVie Inc. North Chicago, IL 60064 and Marketed by: Genentech USA, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 © 2019 AbbVie Inc. © 2019 Genentech, Inc. Ref: 03-B947 Revised: July, 2019 LAB-2815 MASTER

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PREVALENCIA DE HIPOGLICEMIA Y CALIDAD DE VIDA EN PACIENTES HISPANOS CON DIABETES MELLITUS TIPO 2

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EDITOR FUNDADOR Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD PRINCIPAL OFICIAL EJECUTIVO Pedro Carlos Lugo Hernández III, P.A PRESIDENTA Y FUNDADORA Glorybelle Hernández Figueroa, MBA VICEPRESIDENTA Y FUNDADORA Laila Paloma Lugo, MBA CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA, MARKETING Y SERVICIOS 360 Ivelisse Cortés,Yasmin Morell PERIODISTAS Belinda Burgos, Grenda Rivera, Mayra Acevedo, Luis Penchi ARTISTAS GRÁFICOS Natalia Zoé Rivera Torres, Nathaly Margarita Gómez Rodríguez DIRECTORA AUDIOVISUAL Fabiola Plaza REALIZADORA AUDIOVISIAL Salomé Mateus FOTOS Revista Medicina y Salud Pública DIRECCIÓN GENERAL Carlos Alexis Lugo Marrero DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente Para ventas y otros servicios pueden comunicarse al 787.848.3333, msp@editorialmundo.com o www.medicinaysaludpublica.com Revista Puertorriqueña de Medicina y Salud Pública ISSN 1937-8521 COMITÉ EDITORIAL CIENTÍFICO COMITÉ EDITORIAL Olga Rodríguez, MD - Decana Escuela de Medicina de Ponce (Puerto Rico), Vivian Green, LND, MS, PhD, Sub editora y fundadora (Puerto Rico), José Cordero, MD, MPH - Exdecano Escuela Graduada Salud Pública Recinto de Ciencias Médicas UPR (Puerto Rico), Ángeles Rodríguez, MD, MPH (Puerto Rico), Simón Carlo, MD (Puerto Rico), Bárbara Rosado, MD (Puerto Rico), Idhaliz Flores PhD (Puerto Rico), Jesús Cruz-Correa, MD, FACOG (Puerto Rico), Rafael Bredy, MD, LicMTo, MBE, MS (Puerto Rico), David Caseida, MD, FACOG, (Puerto Rico), José Capriles, MD, MHSA (Puerto Rico) Joaquín Laboy, MD, FACOG (Puerto Rico), Luis Adrian Rivera Pomales, MD, PEMBA, MPH, CMQ (Puerto Rico), Juan Fernández, MS, PhD (Puerto Rico), Nuria Sebate, MD (Puerto Rico), Pedro Amador, MD, MPH (Puerto Rico), Nydia Cappas, PsyD (Puerto Rico), Luis Franco, MD (Puerto Rico), Federico Montealegre, DVM, PhD, Msc (Puerto Rico), Nydia Ortiz, PsyD (Puerto Rico), José Pons, PhD, FPPR (Puerto Rico), Esdrás Vélez, JD, MPH (Puerto Rico), Diego Zavala, MSc, PhD, (Puerto Rico), Ana Torres-Martín, MD (Puerto Rico), Julio Cádiz, MD, MPH (Puerto Rico), Rafael Gómez-Cuevas (Colombia), José Javier Orengo, PhD(c) (España), Cesar A. Del Rey, MD (Panamá), Pedro Serrano, MD, PhD (España), Luis Serra-Majem, MD, PhD (España), José Ramón Calvo, MD, PhD (España).

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ALBERTO SANTIAGO CORNIER, EDITOR JEFE DIVISIÓN DE GENÉTICA DEL SAN JORGE CHILDREN’S HOSPITAL DIRECTOR CENTRO INVESTIGACIONES CLÍNICAS DEL SAN JORGE CHILDREN’S HOSPITAL CATEDRÁTICO ASOCIADO DE LA UNIVERSIDAD CENTRAL DEL CARIBE, DEPARTAMENTO DE PEDIATRÍA CATEDRÁTICO ASOCIADO DE LA PONCE HEALTH SCIENCES UNIVERSITY, DEPARTAMENTO DE SALUD PÚBLICA PRÁCTICA PRIVADA TORRE MÉDICA HOSPITAL SAN JORGE Y SER DE PUERTO RICO

esde la notificación del primer caso de COVID-19 se ha publicado una enorme cantidad de estudios. Estos han intentado aclarar las principales incógnitas acerca de la sintomatología, pruebas de detección, medidas de prevención o tratamiento de esta nueva enfermedad.

La rapidez de la transmisión del virus y la repercusión que este ha tenido en la sociedad provocó medidas inmediatas desde el punto de vista de salud pública en el mundo entero. Las medidas que se han tomado han dependido de la evidencia recopilada en cada coyuntura.

La pandemia del COVID-19 generó la mayor explosión de publicaciones científicas en la historia.. La proliferación ha sido tal que cada quince días se duplican referencias de los estudios.

Como respuesta a esta realidad, nuestra revista impresa y su versión digital han unificado recursos en una publicación que brinda un acceso abierto a todo lo que se va publicando sobre COVID-19.

Muchas de estas investigaciones han sido ágiles pero no necesariamente se han caracterizado por la calidad.

La intención de conocer de inmediato respuestas ante las interrogantes que plantea el virus ha generado cierta rectificación de artículos científicos, y cambios diarios en la exposición sobre la patogenia, prevención y el tratamiento de la COVID-19.

Como editores de una revista de medicina, ciencia y salud pública, nuestro rol es garantizar la calidad de las investigaciones que publicamos.

Esta cantidad nueva y prolífica de información científica supone en ocasiones que la calidad del resultado final del producto pueda estar limitada y sobre eso tomamos nota.

Ante esta pandemia que tantas situaciones novedosas y cambiantes ha traído, reforzar los comités editoriales de las revistas científicas con personas expertas en determinados temas ha sido imperativo. Hemos tenido que cambiar también la forma de atender a nuestros pacientes.

Ahora no solo usamos los métodos tradicionales y conocidos para el diagnóstico y el tratamiento Estamos usando nuevas herramientas, como la teleasistencia o telemedicina.

Estos son proyectos y estrategias que estaban contemplados para implementarse plenamente en las próximas décadas pero debido a las circunstancias históricas se han generalizado.

Hemos visto como el seguimiento de

los pacientes se ha alterado radicalmente. La consulta telefónica ha sustituido en muchos de los casos a la presencial, generando problemas de salud posteriores, especialmente en países de alta población con un bajo nivel formativo. Estas realidades han forzado una adaptación a esquemas de seguimiento y terapia que rompen el esquema tradicional de la entrevista clínica entre el profesional y sus pacientes.

Todavía quedan por identificar cuáles serán los resultados en salud de la teleasistencia en la población con enfermedades crónicas.

Nuestra Revista, como vocero de la comunidad científica del país, ha optado por organizar un gran esfuerzo que nos permita adaptarnos a la situación de pandemia generada por el virus. Hemos preparando una edición que cumpla con los criterios principales de la ciencia e inspire credibilidad.

En esta edición especial conmemorativa de los 15 años de La Revista Puertorriqueña de Medicina y Salud Pública seleccionamos una nueva revisión de los trabajos preparados por los prestigiosos científicos, Dr. Fernando Cabanillas y el Dr Javier Morales.

Esta edición presenta el principal trabajo realizado sobre los protocolos y el tratamiento en las salas de emergencia impactadas por la enfermedad del COVID-19. Es evidente que aún quedan preguntas y dudas médicas por discutir y aclarar, especialmente cuando haya pasado un tiempo prudente que permita obtener resultados de estudios longitudinales, o ensayos clínicos controlados.

La pandemia aún con lo dolorosa que es nos plantea una oportunidad única de crecer en asistencia sanitaria, investigación y divulgación. Ayudar en este avance es el empeño nuestro para con nuestros colegas profesionales de la salud, investigadores y pacientes.

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CO-INVESTIGADORES DEL ESTUDIO DE PROTOCOLO: - JAMES BRYAN, MD - RICARDO FERNÁNDEZ, MD - JUAN ARRAUT, MD - NOEL TOTTI, MD - JORGE BERTRÁN - JOSÉ ABREW ARBELO, MD PASARELL, MD - JOEL LÓPEZ FIGUEROA, MD

Protocolo de Estudio Clínico: CCAM20-01 Título del protocolo: Corticosteroides profilácticos para prevenir la tormenta de citocinas Covid-19 Nombre del Patrocinador: Hospital Español Auxilio Mutuo Dirección: Ave. Ponce de León # 715, San Juan, Puerto Rico 00918 Fase: 2 Fecha de aprobación: 13 de abril de 2020 (fecha de versión original del protocolo) 20 de abril de 2020 (revisión 01) 11 de mayo de 2020 (revisión 02) 27 de julio de 2020 (revisión 03) 29 de julio de 2020 (revisión 04) 18 de agosto de 2020 (revisión 05) 1 de octubre de 2020 (revisión 06) Acuerdo de Confidencialidad: La información contenida en este documento se considera confidencial y, excepto en la medida necesaria para obtener el consentimiento informado, no se puede divulgar a otra parte a menos que la ley o los reglamentos exijan dicha divulgación. Las personas a quienes se les divulge la información deben ser informadas de que la información es confidencial y no puede ser revelada por ellos.

-

LUIS COTO, MD MIRELIS ACOSTA RIVERA, MD MARGARITA BRUNO, MD IDALIA LIBOY, MD

Firma del Investigador Con mi firma, acepto supervisar personalmente la realización de este estudio y asegurar que se haga conforme con el protocolo, el consentimiento informado, los procedimientos de la Junta de Revisión Institucional (IRB) / Comité de Ética (CE), la Declaración de Helsinki, Conferencia Internacional sobre Pautas de armonización (ICH), Buenas prácticas clínicas (GCP) guías y las partes aplicables del Código de Regulaciones Federales de los Estados Unidos ó las regulaciones locales que rigen la realización de estudios clínicos.

Centro de Cáncer Auxilio Mutuo Institución Médica Fernando Cabanillas, MD Nombre del Investigador Principal

_____________________ Firma del Investigador Principal 13 de abril de 2020 Fecha

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ARTÍCULO / ORIGINAL 1.0. Sinopsis del estudio Este es un estudio piloto exploratorio de fase II diseñado para investigar si el tratamiento profiláctico con esteroides a corto plazo administrados a pacientes de alto riesgo de Covid-19, podría prevenir la tormenta de citoquinas y la progresión a la insuficiencia respiratoria. El alto riesgo se define en función de los marcadores serológicos de inflamación que incluyen anomalías de IL-6, ferritina, Ddimer, LDH, así como linfopenia y deterioro de la saturación de O2 ,en ó antes del 7mo al 10mo día del primer síntoma de Covid-19.

1.1 Este es un estudio no aleatorio que se llevará a cabo en el Hospital Auxilio Mutuo y posiblemente en otras instituciones por reclutar.

2.0. Calendario de estudios de evaluación 2.1 Al momento de ingresar ó antes de ingresar al estudio: 2.1.1 Historial y Examen físico 2.1.2 Laboratorios: CBC, CMP, LDH, gases arteriales en la sangre, suero IL-6, ferritina sérica, CRP, D-dimers, troponina 2.1.3 Estudios radiológicos: TC (Tomografía computarizada) sin contraste IV no más de 7 días antes de la fecha de ingreso al estudio.

2.1.4 Otros estudios: 2.1.4.1 Puede ser el PCR para detección molecular

Figura 1 14

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del virus SARS-Cov-2 o en la alternativa, la prueba rápida serológica (IgG, IgM) ó ambas (véase la figura 2). Los casos que son IgG positivos pero IgM negativos, no se considerarán elegibles, a menos que sean positivos por prueba molecular de PCR. 2.1.4.2 Saturación de O2 poroximetría de pulso 2.1.4.3 Prueba rápida de la influenza 2.2 Durante el estudio (aplica sólo a los pacientes elegibles para el tratamiento con metilprednisolona): 2.2.1 Saturación diaria de O2 por oximetría de pulso.

2.2.2 Signos vitales q 8 horas (no q 4 hrs) para reducir la posibilidad de contaminación del personal de enfermería 2.2.3 Desde el día 7 a partir de ingreso al estudio: repetir CBC, CMP, LDH, suero IL-6, ferritina sérica, CRP, d-dimers 2.2.4 Desde el día 14 a partir de ingreso al estudio: 2.2.4.1 repetir CBC, CMP, LDH, suero IL-6, ferritina sérica, CRP, d-dimers 2.2.4.2 repetir PCR para la detección molecular del virus SARS-Cov-2 2.2.5 4 Desde el día 28 a partir de ingreso al estudio: 2.2.5.1 repetir CBC, CMP, LDH, suero IL-6, ferritina sérica, CRP, d-dimers 2.2.5.2 repetir PCR para la detección molecular del virus SARS-Cov-2 2.2.5.3 Tomografía computarizada (TC) sin contraste IV 3.0. Trasfondo y fundamentos El manejo de Covid-19 con manifestaciones leves ha sido generalmente conservador.

Tradicionalmente, el tratamiento ha consistido en la observación en el hogar, siempre y cuando no haya dificultad para respirar o evidencia de pulmonía. La terapia de primera línea con hidroxicloroquina (Plaquenil) combinada con Azitromicina, se ha utilizado con resultados positivos preliminares1. La terapia plasmática se ha utilizado con éxito en un pequeño número de casos2. La vitamina C también se ha utilizado, aunque no hay resultados definitivos disponibles3.

El Covid-19 es un trastorno trifásico tipificado por una primera fase infecciosa que dura desde el primer inicio de los síntomas hasta 7-10 días después, cuando es seguido por una segunda fase considerada como la fase inflamatoria o pulmonar, con aparición de infiltrados pulmonares que más tarde es seguida por una fase de hiper inflamación caracterizada por El Síndrome de Dificultad Respiratoria Aguda (SDRA), shock e insuficiencia cardíaca.

Por razones poco claras, los pacientes no siempre proceden a desarrollar la segunda o tercera fase y se curan espontáneamente después de la primera fase.

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*La línea roja representa pacientes que han muerto. La línea azul representa los pacientes que han sobrevivido. La axis X, representa los números de días desde el inicio de enfermedad.

Esta segunda fase es precedida por una elevación de ciertos marcadores serológicos de inflamación como IL-6, CRP, LDH y ferritina, así como D-dimers4, 5. Ver ilustración 2.

No está claro por qué algunos pacientes entran en esta segunda fase de la enfermedad mientras que otros no, pero lo que sí queda claro es que la segunda fase ó fase inflamatoria, es causada por la activación de macrófagos pulmonares con posterior liberación de los mediadores inflamatorios. Estas moléculas eventualmente dañan la membrana alveolo-capilar, causando insuficiencia respiratoria. Estos son los pacientes que con frecuencia requerirán apoyo de ventiladores y eventualmente la mayoría muere. Esta segunda y tercera fase se deben en gran parte a la activación del sistema inmunológico del paciente, mientras que la primera fase está mediada principalmente por la propia infección viral.

Por lo general, la terapia antiinflamatoria con el anticuerpo anti-IL-6, Tocilizumab, se reserva para pacientes que están progresando mal, especialmente pacientes con pulmonía grave con niveles séricos elevados de IL-66. Sin embargo, una vez que estos pacientes tienen pulmonía, el tratamiento anti inflamatorio generalmente no es muy efectivo. Sin embargo, el uso de metilprednisolona se ha asociado con una reducción sustancial del riesgo de muerte, incluso si se administra tarde, cuando los pacientes ya tienen ARDS7. No obstante, si se administra tarde, la probabilidad de muerte es del 52%7.

El Dr. Angel Atienza, del Hospital Peset, en Valencia, España, ha desarrollado un enfoque diseñado para anticipar la segunda fase inflamatoria. Este Doctor ha propuesto que cuando aparecen los infiltrados pulmonares, el proceso ya no es uno infeccioso, sino un problema puramente inflamatorio o inmunológico que causa lesiones anatómicas a la membrana alveolo-capilar, resultando en dificultad respiratoria.

El Doctor Atienza utiliza una terapia con corticoesteroides a partir del sexto día de la presentación de los síntomas, administrada durante 5-7 días, con el objetivo de prevenir la fase inflamatoria. Los esteroides se utilizan específicamente para tratar aquellos casos, los cuales en el día 6 están febriles y muestran la elevación de marcadores inflamatorios serológicos sin manifestaciones pulmonares radiológicas avanzadas.

Según los informes, sus resultados iniciales son excelentes y las admisiones a la unidad de cuidados intensivos disminuyeron, con estadías hospitalarias acortadas y progresión clínica radiológica favorable, la cual él ha descrito como “espectacular” (comunicación personal).

En España e Italia este enfoque está ganando aceptación, pero en la actualidad no se considera como el estándar de atención. El uso de esteroides ha sido criticado, porque no hay evidencia de ensayos clínicos aleatorios para apoyar su uso para COVID-19.

Además, los medicamentos anti inflamatorios, podrían retrasar la eliminación del virus y aumentar el riesgo de infección secundaria. Sin embargo, no hay evidencia de que, según propuesto por el Dr. Atienza, un curso corto de esteroides administrado poco antes de la segunda fase de la enfermedad a los pacientes

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LOS PACIENTES ELEGIBLES PARA EL ESTUDIO SERÁN REGISTRADOS ANTES O EN EL DÍA 10 DEL INICIO DE SÍNTOMAS. LOS PACIENTES CUYOS SÍNTOMAS COMENZARON DESPUÉS DE 10 DÍAS PERO NO TIENEN FALLO RESPIRATORIO SERÁN ELEGIBLE SI AUN TIENEN SÍNTOMAS. con alto riesgo de entrar en la fase inflamatoria, haya tenido ningún impacto desfavorable en la enfermedad. Por lo tanto, la preocupación en cuanto a su aplicación se basa en motivos estrictamente teóricos. Los pocos datos disponibles desfavorables al uso de esteroides provienen de estudios en los cuales éstos se han utilizado demasiado tarde o demasiado temprano8.

La interleucina-6 elevada (IL-6) se ha asociado estrechamente con la necesidad de ventilación mecánica (p.00005). Además, el nivel máximo de IL-6 (corte 80 pg./ml) para cada paciente durante la enfermedad predijo la insuficiencia respiratoria con alta precisión (p.000005, AUC-0.98). El riesgo de insuficiencia respiratoria en pacientes con niveles de IL-6 de ≥80 pg./ml fue 22 veces mayor en comparación con los pacientes con niveles más bajos de IL-69.

En este protocolo, proponemos identificar a los pacientes con Covid-19 que corren un alto riesgo de desarrollar la tormenta de citoquinas y, consecuentemente, insuficiencia respiratoria. El objetivo es tratarlos a tiempo con corticosteroides para determinar si podemos evitar la tormenta de citoquinas.

4.0. Objetivos de estudio Objetivo principal: 1- Para disminuir el ritmo de progresión hacia la insuficiencia respiratoria hipoxémica en pacientes de alto riesgo con Covid-19, tratados con esteroides profilácticos durante la primera fase de la enfermedad. a. La insuficiencia respiratoria hipoxémica se define como: 1. Saturación de O2 < 90% o p02 <60 en el aire ambiente 16

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Objetivos secundarios 1. Determinar el porcentaje de supervivencia a los 28 días a partir de matricularse en este ensayo clínico.

2. Determinar si hay alguna mejoría en los marcadores inflamatorios después del tratamiento con corticosteroides.

3. Definir la duración de la hospitalización 4. Determinar la frecuencia de las admisiones a la UCI 5. Evaluaremos la proporción de pacientes con mejoría clínica, definida como el alta del hospital de pacientes con vida, una disminución de al menos 2 puntos desde el inicio en una escala ordinal modificada (de acuerdo a las recomendaciones del Grupo de Protocolos de I+D de la OMS), o ambos. [10] 5.1 La escala de seis puntos consta de las siguientes categorías: 1, no hospitalizado; 2, hospitalizado, que no requiere oxígeno suplementario; 3, hospitalizado, que requiere oxígeno suplementario; 4, hospitalizado, que requiere oxigenoterapia nasal de alto flujo, ventilación mecánica no invasiva, o ambas; 5, hospitalizado, que requiere ventilación mecánica invasiva, ECMO, o ambos; y 6, muerte.

5.0. Plan de investigación 5.1 Diseño general: Este es un estudio exploratorio piloto de fase II. Trata de un estudio no aleatorio que se llevará a cabo en el Hospital Auxilio Mutuo y posiblemente en otras instituciones a ser reclutadas.

5.2 Planificamos ingresar a un total de 100-500 pacientes con la expectativa de que al menos 20-100 de ellos serán elegibles para terapia con metilprednisolona para determinar si el riesgo de progresar a insuficiencia respiratoria puede reducirse mediante la administración de corticoesteroides.

5.3 Suponemos que <50% de los pacientes que cumplan con los criterios para tratamiento con metilprednisolona en este estudio desarrolla insuficiencia respiratoria si no recibiera tratamiento.

5.4 Si <50% de los pacientes con alto riesgo desarrollan insuficiencia respiratoria, consideraremos que el tratamiento fue exitoso.

6.0. Criterios de inclusión 6.1 Todos los pacientes diagnosticados con Covid-19 se registrarán en el estudio independientemente de su gravedad, pero sólo aquellos que cumplan con criterios de alto riesgo serán tratados con esteroides. Aquellos que no cumplan con los criterios sólo se registrarán sin necesidad

ARTÍCULO / ORIGINAL

de recopilar más datos, excepto laboratorios de referencia y una tomografía computarizada del tórax.

Deben firmar el formulario de consentimiento y el administrador de datos puede recopilar el resto de la información.

6.2 Los pacientes de 18 años o más diagnosticados con Covid-19 por PCR o mediante prueba serológica rápida, serán elegibles. El diagnóstico de Covid-19 se establecerá mediante la prueba molecular de PCR o con la prueba serológica rápida o ambas. Los casos que sean IgG positivos pero IgM negativo, no se considerarán elegibles a menos que sean positivos por prueba molecular de PCR y el primer síntoma de enfermedad es de 10 días o menos. Aquellos que sean IgM positivo pero PCR negativo, será considerado como “sospechoso para Covid-19”; sin embargo, si su presentación clínica es típica de Covid-19, se contarán como un diagnóstico positivo. Aquellos que sean IgM positivos pero PCR negativos, para propósitos de análisis serán divididos entre “polisintomáticos” (2 o más síntomas característicos de Covid-19) o “no polisintomáticos ””. Los síntomas considerados característicos son fiebre, tos, disnea, mialgia, diarrea, anosmia/ disgeusia, malestar general, dolor de cabeza, dolor

abdominal, síntomas neurológicos (parestesia, delirio, etc.)

6.3 Los pacientes elegibles se registrarán en el estudio en o antes de 10 días después del primer inicio de los síntomas.

6.4 Para tratarse con metilprednisolona, deben cumplir al menos con dos de los siguientes criterios en o poco antes del día 10 (pero no antes del día 7) desde el primer inicio de los síntomas, a fin de evitar el tratamiento durante la fase viral: 6.4. 1 Suero IL-6 > 10 pg/ml antes del día 10 6.4.2 Ferritina> 500 mg/ml antes del día 10 6.4.3 D-dimer >1mg/L (1.000 ng/ml) antes del día 10 6.4.4 CRP> 10 mg/dL (100 mg/L) antes del día 10 6.4.5 LDH por encima de lo normal antes del día 10 6.4.6 Linfopenia (conteo absoluto de linfocitos<900) antes del día 10 6.4.7 Saturación de O2 <94% por oximetría de pulso, pero más de 91%, antes del día 10 6.4.8 Tomografía computarizada del tórax con evidencia de infiltrado(]s).

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6.5 Interpretación de los resultados de la prueba rápida y la prueba molecular de PCR 6.5.1 Aquellos con prueba serológica positiva pero con prueba de PCR molecular negativa, serán analizados en función del contexto clínico. Vea a continuación.

6.5.2 Aquellos que presenten al menos 2 de los siguientes síntomas típicos de Covid-19 (tos, fiebre, disnea, diarrea, anosmia) se considerarán como casos probables de Covid-19, mientras que aquellos con uno o menos síntomas se considerarán casos poco probables, pero todavía se considerarán evaluables.

Se analizarán por separado.

6.5.3 Aquellos que sean positivos al PCR y serológicos positivos o negativos serán considerados como casos definitivos.

6.6 La puntuación “CALL” se utilizará en el análisis de todos los casos (11). Esta puntuación representa un índice compuesto basado en la presencia de comorbilidades, edad>60, linfopenia y LDH elevada. Aquellos casos con una puntuación >6 tienen un riesgo superior al 50% de complicaciones graves.

6.7 Se permitirá el tratamiento simultáneo con los siguientes medicamentos: hidroxicloroquina, azitromicina, vitamina C, doxiciclina, colchicina, zinc e ivermectina. Su uso no se considera una razón para la exclusión de este estudio.

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7.0. Criterios de exclusión 7.1 Cualquier paciente con esperanza de vida<1 mes.

7.2 Cualquier paciente que dependa de oxígeno.

7.3 Cualquier paciente con antecedentes de enfermedad pulmonar grave.

7.4 Cualquier paciente que dependa crónicamente de oxígeno debido a una enfermedad pulmonar previamente existente.

7.5 Cualquier persona con diabetes gravemente descontrolada a pesar de manejo adecuado.

7.6 Cualquier persona con infección bacteriana grave activa, como septicemia o pulmonía.

7.7 Cualquier persona que reciba Tocilizumab (terapia anti-IL-6) o terapia plasmática.

7.8 Cualquier paciente que ya esté recibiendo esteroides por otra enfermedad preexistente.

7.9 Los casos que son IgG positivos pero IgM negativos, no se considerarán elegibles a menos que sean positivos por prueba molecular de PCR y el primer síntoma de enfermedad fuera hace 10 días o menos.

8. Régimen de Manejo y Dosificación 8.1 Los pacientes serán admitidos a una habitación regular en el hospital (no en la UCI) 8.2 Se les vigilará estrechamente tomando los signos vitales cada 8 horas para garantizar que su estado respiratorio y cardiovascular no se deteriore.

8.3 Metilprednisolona 80mg IV inyección de dosis en bolo se administra diariamente x 5 días a partir del 1er día de matricularse en el estudio.

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9.0 Eventos Adversos 9.1 Se registrará la toxicidad de los esteroides.

9.2 Los efectos secundarios más comunes son: • jaqueca • náuseas y vómitos • aumento de peso • confusión, excitación e inquietud • hinchazón de tobillos, pies o manos • problemas de la piel, como acné, piel delgada y piel brillante • aumento en la sed • Infección • Hiperglucemia • Sangrado gastrointestinal • Hipertensión (aumento de la presión arterial) 10.0. Criterios de Respuesta Primaria para pacientes que reciben metilprednisolon 10.0.1 C10.0.1 Los criterios de respuesta clínica completa requieren lo siguiente: 10.0.1.1 No hay necesidad de apoyo de ventilador en ningún momento.

10.0.1.2. Saturación de O2 de > 93% en el día 14 de terapia 10.0.1.3 La persona está viva al día 28 desde la matrícula en estudio 10.0.1.4 TC del tórax con poca o ninguna evidencia de la enfermedad al día 28 desde la matrícula en el estudio 10.0.2 Los criterios de respuesta parcial clínica requieren que 2 de los siguientes están presentes en el día 14 del tratamiento: 10.0.2.1 No hay necesidad de apoyo de ventilador en ningún momento.

10.0.2.2 Saturación de O2 de > 93% en el día 14 de terapia 10.0.2.3 TC del tórax con poca o ninguna evidencia de la enfermedad al día 28 desde la matrícula en el estudio 10.1 Criterios de Respuesta Secundaria: 10.1.1 Disminución de al menos 25% en cualquiera de los siguientes marcadores: IL-6, ferritina, D-dimer, CRP o LDH para el día 14 10.1.2 Mejoría en el conteo absoluto de linfocitos en aquellos que presentan linfopenia. La mejoría se define como un aumento de 25 % o más para el día 14.

NO ESTÁ CLARO EL PORQUÉ ALGUNOS PACIENTES ENTRAN A LA SEGUNDA FASE DE ESTA ENFERMEDAD, MIENTRAS QUE OTROS NO, PERO LO QUE ESTÁ CLARO ES QUE LA SEGUNDA O FASE INFLAMATORIA ES CAUSADA POR LA ACTIVACIÓN DE MICROFAGOS PULMONARES 11.0. Manejo de Información 11.1 Los pacientes serán matriculados luego de entregar el formulario de consentimiento firmado.

11.2 La matrícula se realizará en el Auxilio Mutuo llamando al 787-758-2000 x 3569.

12. Análisis Estadístico 12.0 El análisis se centrará en comparar los valores previos y posteriores al tratamiento.

12.1 Los casos evaluables se consideran aquellos que tienen datos clínicos durante al menos 1 día posterior.

12.2 Debido al pequeño tamaño de la muestra, se utilizarán pruebas no paramétricas para los datos coincidentes.

12.2.1 Los cambios en los resultados de la PCR y la TC del tórax se analizarán con la prueba de chi-cuadrado de McNemar 12.2.2 Los cambios en los niveles de saturación de oxígeno, IL-6, ferritina, D-dimer, CRP, LDH se analizarán utilizando la prueba de los rangos con signos de Wilcoxon.

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In HR+, HER2– MBC

A SIGNIFICANT SURVIVAL IMPROVEMENT

With consistent results even in women likely to do worse1-6* Verzenio + fulvestrant helps to raise the bar of what is possible for pre/peri- and postmenopausal women with disease recurrence or progression following endocrine therapy (ET)

46.7-month mOS with Verzenio + fulvestrant (n=446) (95% CI: 39.2-52.2) vs 37.3-month mOS with fulvestrant alone (n=223) (95% CI: 34.4-43.2); HR=0.757 (95% CI: 0.606-0.945), P=.01372,7 *Visceral disease and primary ET resistance were studied in the clinical trial and could confer a less favorable prognosis. For more information on trial design, see below.

MONARCH 2 was a phase III, randomized, double-blind, placebo-controlled trial that enrolled 669 patients with HR+, HER2− MBC who progressed on or after ET. Pre/perimenopausal women (17%) were rendered postmenopausal prior to the study. Patients had received no chemotherapy and no more than 1 prior ET in the metastatic setting. Patients were randomized 2:1 to Verzenio + fulvestrant (n=446) or placebo + fulvestrant (n=223). Verzenio and placebo were dosed PO BID on a continuous dosing schedule until disease progression or unacceptable toxicity. 500 mg fulvestrant was administered by IM injection on days 1, 15, and 29 of the first month and once monthly thereafter. The primary endpoint was PFS. Key secondary endpoints were ORR, OS, and DoR.1,8 BID=twice a day; CI=confidence interval; DoR=duration of response; HR=hazard ratio; IM=intramuscular; mOS=median overall survival; ORR=objective response rate; OS=overall survival; PO=orally; PFS=progression-free survival.

Verzenio is indicated for the treatment of hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced or metastatic breast cancer (MBC)¹: • In combination with fulvestrant for women with disease progression following endocrine therapy SELECT IMPORTANT SAFETY INFORMATION Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Please see Select Important Safety Information throughout and Brief Summary of full Prescribing Information for Verzenio on the following pages.

For women with HR+, HER2− MBC with disease recurrence or progression on or after ET

9.4-month statistically significant mOS benefit2 Definitive OS results2,7

ENDPOINT: OS IN ITT POPULATION σSECONDARY SECONDARY ENDPOINT: OS IN ITT POPULATION2,7

• Results are based on a preplanned interim analysis and considered to be definitive, due to the observation of 77% (338/441) of the planned OS events needed for the final analysis

Verzenio + fulvestrant (n=446) Placebo + fulvestrant (n=223)

46.7

100

SURVIVAL PROBABILITY (%)

80

months

0.757

median OS with Verzenio + fulvestrant (95% CI: 39.2-52.2)

(95% CI: 0.606-0.945)

– The percentage of events at the time of analysis was 47.3% (n=211) and 57.0% (n=127) in the Verzenio + fulvestrant and fulvestrant alone arms, respectively

HR

P=.0137

60

Primary endpoint: PFS in the ITT population1,2 • 16.4-month mPFS with Verzenio + fulvestrant (n=446) (95% Cl: 14.4-19.3) vs 9.3-month mPFS with fulvestrant alone (n=223) (95% Cl: 7.4-12.7); HR=0.553 (95% CI: 0.449-0.681), P<.0001

37.3 months

40

median OS with placebo + fulvestrant (95% CI: 34.4-43.2)

20

0

0

6

12

18

24

30

36

42

48

54

60

• The percentage of PFS events at the time of analysis was 49.8% (n=222) and 70.4% (n=157) in the Verzenio + fulvestrant and fulvestrant alone arms, respectively

TIME (MONTHS)

446

410

384

339

302

265

234

202

101

23

0

223

201

191

170

148

122

99

82

42

3

0

The only CDK4 & 6 inhibitor to significantly improve OS regardless of menopausal status in combination with fulvestrant2,9

CDK4 & 6=cyclin-dependent kinases 4 and 6; ITT=intent-to-treat; mPFS=median progression-free survival.

SELECT IMPORTANT SAFETY INFORMATION Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Febrile neutropenia has been reported in <1% of patients exposed to Verzenio in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/ or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. Across clinical trials (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes.

Additional cases of ILD/pneumonitis have been observed in the

post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis.

Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.

Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue Verzenio in all patients with grade 3 or 4 ILD/pneumonitis.

Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2.

In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade <3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade <3 was 14 and 13 days, respectively.

For assessment of potential hepatotoxicity, monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Please see Select Important Safety Information throughout and Brief Summary of full Prescribing Information for Verzenio on the following pages.

In preplanned subgroup analyses

Consistent results in women with visceral disease and primary ET resistance1-6* *Visceral disease and primary ET resistance were studied in the clinical trial and could confer a less favorable prognosis. σ 8.1-MONTH mOS INCREASE IN WOMEN WITH VISCERAL DISEASE2

σ 7.2-MONTH mOS INCREASE IN WOMEN WITH PRIMARY ET RESISTANCE2

Verzenio + fulvestrant (n=245) Placebo + fulvestrant (n=128)

40.3

100

0.675

median OS with Verzenio + fulvestrant

(95% CI: 0.511-0.891)

0.686

median OS with Verzenio + fulvestrant

(95% CI: 0.451-1.043)

HR

32.2 months median OS with placebo + fulvestrant

20

0

months

HR

60

40

38.7

100

months

80 SURVIVAL PROBABILITY (%)

SURVIVAL PROBABILITY (%)

80

Verzenio + fulvestrant (n=112) Placebo + fulvestrant (n=60)

60

31.5 months

40

median OS with placebo + fulvestrant

20

0

6

12

18

24

30

36

42

48

54

0

60

0

6

12

18

24

30

36

42

48

54

60

TIME (MONTHS)

TIME (MONTHS)

245

228

217

184

162

141

124

102

57

13

0

112

101

92

85

73

63

52

42

20

7

0

128

111

105

89

75

58

47

37

21

3

0

60

51

44

38

31

25

17

14

5

1

0

• Visceral disease: ≥1 lesion on an internal organ or in the third space (eg, lung, liver, pleural, or peritoneal metastatic involvement)10

• Primary ET resistance: relapse within 2 years of starting adjuvant ET or progressive disease within the first 6 months of first-line ET for MBC1

Preplanned subgroup analyses of OS were performed for stratification factors of disease site (including visceral disease) and endocrine resistance (including primary ET resistance). Analyses were not adjusted for multiplicity, and the study was not powered to test the effect of Verzenio + fulvestrant among subgroups.11

Verzenio + fulvestrant delayed time to chemotherapy2 • Exploratory analysis: 50.2-month median time to chemotherapy with Verzenio + fulvestrant (n/N=200/446) vs 22.1-month median time to chemotherapy with fulvestrant alone (n/N=135/223); HR=0.625 (95% CI: 0.501-0.779) – 37.5% reduction in risk of progressing to chemotherapy • Time to chemotherapy is defined as time from randomization to initiation of first post-discontinuation chemotherapy. Patients who died prior to receiving chemotherapy (n=111) did not contribute an event to this analysis • This exploratory analysis was not controlled for type 1 error, and the study was not powered to test this endpoint

n=number of events; N=total number of patients.

SELECT IMPORTANT SAFETY INFORMATION Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary

vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Please see Select Important Safety Information throughout and Brief Summary of full Prescribing Information for Verzenio on the following pages.

Redefining Redefiningsurvival survivalexpectations expectationsfor for 22 women womenwith withHR+, HR+,HER2− HER2−MBC MBC

OSOS was was a key a key secondary secondary endpoint endpoint of of MONARCH MONARCH 2.22.2 2 2 Results Results areare based based onon a preplanned a preplanned interim interim analysis analysis and and considered considered to to bebe definitive. definitive.

See Seethe thedifference differenceVerzenio Verzeniocan canmake makefor forpatients patientsatatwww.verzenio.com/hcp www.verzenio.com/hcp SELECT SELECT IMPORTANT IMPORTANT SAFETY SAFETY INFORMATION INFORMATION

Verzenio Verzenio cancan cause cause fetal fetal harm harm when when administered administered to atopregnant a pregnant woman woman based based onon findings findings from from animal animal studies studies and and thethe mechanism mechanism of action. of action.

In In animal animal reproduction reproduction studies, studies, administration administration of abemaciclib of abemaciclib to pregnant to pregnant rats rats during during thethe period period of of organogenesis organogenesis caused caused teratogenicity teratogenicity and and decreased decreased fetal fetal weight weight at maternal at maternal exposures exposures that that were were similar similar to to thethe human human clinical clinical exposure exposure based based onon area area under under thethe curve curve (AUC) (AUC) at the at the maximum maximum recommended recommended human human dose. dose.

Advise Advise pregnant pregnant women women of of thethe potential potential riskrisk to to a fetus. a fetus.

Advise Advise females females of of reproductive reproductive potential potential to to use use effective effective contraception contraception during during treatment treatment with with Verzenio Verzenio and and forfor at at least least 3 weeks 3 weeks after after thethe lastlast dose. dose.

There There areare nono data data onon thethe presence presence of of Verzenio Verzenio in in human human milk milk or or its its effects effects onon thethe breastfed breastfed child child or or onon milk milk production. production.

Advise Advise lactating lactating women women notnot to breastfeed to breastfeed during during Verzenio Verzenio treatment treatment and and forfor at least at least 3 weeks 3 weeks after after thethe lastlast dose dose because because of of thethe potential potential forfor serious serious adverse adverse reactions reactions in in breastfed breastfed infants. infants.

Based Based onon findings findings in animals, in animals, Verzenio Verzenio may may impair impair fertility fertility in in males males of of reproductive reproductive potential. potential.

The The most most common common adverse adverse reactions reactions (all(all grades, grades, ≥10%) ≥10%) observed observed in MONARCH in MONARCH 2 for 2 for Verzenio Verzenio plus plus fulvestrant fulvestrant and and ≥2% ≥2% higher higher than than placebo placebo plus plus fulvestrant fulvestrant vs vs placebo placebo plus plus fulvestrant fulvestrant were were diarrhea diarrhea (86% (86% vs vs 25%), 25%), neutropenia neutropenia (46% (46% vs vs 4%), 4%), fatigue fatigue (46% (46% vs vs 32%), 32%), nausea nausea (45% (45% vs vs 23%), 23%), infections infections (43% (43% vs vs 25%), 25%), abdominal abdominal pain pain (35% (35% vs vs 16%), 16%), anemia anemia (29% (29% vs vs 4%), 4%), leukopenia leukopenia (28% (28% vs vs 2%), 2%), decreased decreased appetite appetite (27% (27% vs vs 12%), 12%), vomiting vomiting (26% (26% vs vs 10%), 10%), headache headache (20% (20% vs vs 15%), 15%), dysgeusia dysgeusia (18% (18% vs vs 3%), 3%), thrombocytopenia thrombocytopenia (16% (16% vs vs 3%), 3%), alopecia alopecia (16% (16% vs vs 2%), 2%), stomatitis stomatitis (15% (15% vs vs 10%), 10%), ALT ALT increased increased (13% (13% vs vs 5%), 5%), pruritus pruritus (13% (13% vs vs 6%), 6%), cough cough (13% (13% vs vs 11%), 11%), dizziness dizziness (12% (12% vs vs 6%), 6%), AST AST increased increased (12% (12% vs vs 7%), 7%), peripheral peripheral edema edema (12% (12% vs vs 7%), 7%), creatinine creatinine increased increased (12% (12% vs vs <1%), <1%), rash rash (11% (11% vs vs 4%), 4%), pyrexia pyrexia (11% (11% vs vs 6%), 6%), and and weight weight decreased decreased (10% (10% vs vs 2%).

2%).

The The most most frequently frequently reported reported ≥5% ≥5% Grade Grade 3 or 3 or 4 adverse 4 adverse reactions reactions that that occurred occurred in the in the Verzenio Verzenio arm arm vs vs thethe placebo placebo arm arm of MONARCH of MONARCH 22 were were neutropenia neutropenia (27% (27% vs vs 2%), 2%), diarrhea diarrhea (13% (13% vs vs <1%), <1%), leukopenia leukopenia (9% (9% vs vs 0%), 0%), anemia anemia (7%(7% vs vs 1%),1%), and and infections infections (6% (6% vs vs 3%).

3%).

Lab Lab abnormalities abnormalities (all(all grades; grades; Grade Grade 3 or 3 4) orfor 4) for MONARCH MONARCH 2 in2≥10% in ≥10% forfor Verzenio Verzenio plus plus fulvestrant fulvestrant and and ≥2% ≥2% higher higher than than placebo placebo plus plus fulvestrant fulvestrant vsvs placebo placebo plus plus fulvestrant fulvestrant were were increased increased serum serum creatinine creatinine (98% (98% vs vs 74%; 74%; 1%1% vs vs 0%), 0%), decreased decreased white white blood blood cells cells (90% (90% vs vs 33%; 33%; 23% 23% vs vs 1%),1%), decreased decreased neutrophil neutrophil count count (87% (87% vs vs 30%; 30%; 33% 33% vs vs 4%), 4%), anemia anemia (84% (84% vs vs 33%; 33%; 3%3% vs vs <1%), <1%), decreased decreased lymphocyte lymphocyte count count (63% (63% vs vs 32%; 32%; 12% 12% vs vs 2%), 2%), decreased decreased platelet platelet count count (53% (53% vs vs 15%; 15%; 2%2% vs vs 0%), 0%), increased increased ALT ALT (41% (41% vs vs 32%; 32%; 5%5% vs vs 1%),1%), and and increased increased AST AST (37% (37% vs vs 25%; 25%; 4%4% vs vs 4%).

4%).

Strong Strong and and moderate moderate CYP3A CYP3A inhibitors inhibitors increased increased thethe exposure exposure of of abemaciclib abemaciclib plus plus its its active active metabolites metabolites to atoclinically a clinically meaningful meaningful extent extent and and may may lead lead to increased to increased toxicity. toxicity.

Avoid Avoid concomitant concomitant use use of the of the strong strong CYP3A CYP3A inhibitor inhibitor ketoconazole. ketoconazole.

Ketoconazole Ketoconazole is predicted is predicted to increase to increase thethe AUC AUC of abemaciclib of abemaciclib byby upup to 16-fold. to 16-fold.

In patients In patients with with recommended recommended starting starting doses doses of 200 of 200 mgmg twice twice daily daily or or 150150 mgmg twice twice daily, daily, reduce reduce thethe PP-AL-US-2070 PP-AL-US-2070 01/2020 01/2020 ©Lilly ©Lilly USA, USA, LLCLLC 2020.

2020.

All rights All rights reserved. reserved.

Verzenio® Verzenio® is a is registered a registered trademark trademark owned owned or licensed or licensed

by Eli byLilly Eli Lilly andand Company, Company, its subsidiaries its subsidiaries or affiliates. or affiliates.

Verzenio Verzenio dose dose to to 100 100 mgmg twice twice daily daily with with concomitant concomitant use use of of strong strong CYP3A CYP3A inhibitors inhibitors other other than than ketoconazole. ketoconazole.

In patients In patients who who have have had had a a dose dose reduction reduction to 100 to 100 mgmg twice twice daily daily due due to adverse to adverse reactions, reactions, further further reduce reduce thethe Verzenio Verzenio dose dose to to 5050 mgmg twice twice daily daily with with concomitant concomitant use use of of strong strong CYP3A CYP3A inhibitors. inhibitors.

If aIfpatient a patient taking taking Verzenio Verzenio discontinues discontinues a strong a strong CYP3A CYP3A inhibitor, inhibitor, increase increase thethe Verzenio Verzenio dose dose (after (after 3 to 3 to 5 5 half-lives half-lives of the of the inhibitor) inhibitor) to the to the dose dose that that was was used used before before starting starting thethe inhibitor. inhibitor.

With With concomitant concomitant use use of moderate of moderate CYP3A CYP3A inhibitors, inhibitors, monitor monitor forfor adverse adverse reactions reactions and and consider consider reducing reducing thethe Verzenio Verzenio dose dose in in 5050 mgmg decrements. decrements.

Patients Patients should should avoid avoid grapefruit grapefruit products. products.

Avoid Avoid concomitant concomitant use use of of strong strong or or moderate moderate CYP3A CYP3A inducers inducers and and consider consider alternative alternative agents. agents.

Coadministration Coadministration of strong of strong or or moderate moderate CYP3A CYP3A inducers inducers decreased decreased thethe plasma plasma concentrations concentrations of abemaciclib of abemaciclib plus plus its its active active metabolites metabolites and and may may lead lead to to reduced reduced activity. activity.

With With severe severe hepatic hepatic impairment impairment (Child-Pugh (Child-Pugh Class Class C),C), reduce reduce thethe Verzenio Verzenio dosing dosing frequency frequency to to once once daily. daily.

The The pharmacokinetics pharmacokinetics of of Verzenio Verzenio in patients in patients with with severe severe renal renal impairment impairment (CLcr (CLcr <30 <30 mL/min), mL/min), end end stage stage renal renal disease, disease, or or in in patients patients onon dialysis dialysis is is unknown. unknown.

NoNo dosage dosage adjustments adjustments areare necessary necessary in in patients patients with with mild mild or or moderate moderate hepatic hepatic (Child-Pugh (Child-Pugh AA or or B) B) and/or and/or renal renal impairment impairment (CLcr (CLcr ≥30-89 ≥30-89 mL/min). mL/min).

Please Please see see Select Select Important Important Safety Safety Information Information throughout throughout and and Brief Brief Summary Summary of of fullfull Prescribing Prescribing Information Information forfor Verzenio Verzenio onon thethe following following pages. pages.

ALAL HCP HCP ISI_M2 ISI_M2 23OCT2019 23OCT2019 References: References: 1. Verzenio 1. Verzenio [package [package insert]. insert].

Indianapolis, Indianapolis, IN: IN: Eli Eli LillyLilly andand Company; Company; 2019.

2019.

2. Sledge 2. Sledge GWGW Jr, Toi Jr, Toi M, Neven M, Neven P, etP,al. etThe al. The effect effect of abemaciclib of abemaciclib plus plus fulvestrant fulvestrant on on overall overall survival survival in hormone in hormone receptor–positive, receptor–positive, ERBB2-negative ERBB2-negative breast breast cancer cancer thatthat progressed progressed on on endocrine endocrine therapy—MONARCH therapy—MONARCH 2: a2:randomized a randomized clinical clinical trialtrial [published [published online online September September 29,29, 2019].

2019].

JAMA JAMA Oncol.

Oncol. doi:10.1001/jamaoncol.2019.4782. doi:10.1001/jamaoncol.2019.4782.

3. Imkampe 3. Imkampe A, A, Bendall Bendall S, Bates S, Bates T. The T. The significance significance of the of the sitesite of recurrence of recurrence to to subsequent subsequent breast breast cancer cancer survival. survival.

EurEur J Surg J Surg Oncol.

Oncol.

2007;33:420-423.

2007;33:420-423.

4. Largillier 4. Largillier R, Ferrero R, Ferrero JM,JM, Doyen Doyen J, et J, al. et al.

Prognostic Prognostic factors factors in 1038 in 1038 women women with with metastatic metastatic breast breast cancer. cancer.

Ann Ann Oncol.

Oncol.

2008;19:2012-2019.

2008;19:2012-2019.

5. Solomayer 5. Solomayer EF,EF, DielDiel IJ, IJ, Meyberg Meyberg GC,GC, Gollan Gollan C, C, Bastert Bastert G. G. Metastatic Metastatic breast breast cancer: cancer: clinical clinical course, course, prognosis prognosis andand therapy therapy related related to the to the firstfirst sitesite of metastasis. of metastasis.

Breast Breast Cancer Cancer ResRes th th Treat.

Treat.

2000;59:271-278.

2000;59:271-278.

6. Cardoso 6. Cardoso F, Senkus F, Senkus E, Costa E, Costa A, et A, al. et al.

4 4ESO–ESMO ESO–ESMO international international consensus consensus guidelines guidelines for for advanced advanced breast breast cancer cancer (ABC (ABC 4). 4).

Annals Annals of of Oncology.

Oncology.

2018;29(8):1634-1657.

2018;29(8):1634-1657.

7. Data 7. Data on on file.file.

LillyLilly USA, USA, LLC. LLC. DOF-AL-US-0088.

DOF-AL-US-0088.

8. Sledge 8. Sledge GWGW Jr, Toi Jr, Toi M, Neven M, Neven P, etP,al. etMONARCH al. MONARCH 2: abemaciclib 2: abemaciclib in combination in combination with with fulvestrant fulvestrant in women in women with with HR+/HER2− HR+/HER2− advanced advanced breast breast cancer cancer who who hadhad progressed progressed while while receiving receiving endocrine endocrine therapy. therapy.

J Clin J Clin Oncol.

Oncol.

2017;35:2875-2884.

2017;35:2875-2884.

9. Turner 9. Turner NC,NC, Slamon Slamon DJ,DJ, Ro Ro J, et J, al. et Overall al. Overall survival survival with with palbociclib palbociclib andand fulvestrant fulvestrant in advanced in advanced breast breast cancer. cancer.

N Engl N Engl J Med. J Med. 2018;379:1926-1936.

2018;379:1926-1936.

10.10.

Data Data on on file.file.

LillyLilly USA, USA, LLC. LLC. ONC20171128a.

ONC20171128a.

11. Data 11. Data on on file.file.

LillyLilly USA, USA, LLC. LLC. ONC20180103a.

ONC20180103a.

VERZENIO® (abemaciclib) tablets, for oral use Initial U.S. Approval: 2017 BRIEF SUMMARY: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE VERZENIO® (abemaciclib) is indicated: • in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

• in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.

• as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Diarrhea Diarrhea occurred in 81% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and 90% of patients receiving VERZENIO alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and in 20% of patients receiving VERZENIO alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of VERZENIO dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis.

Hepatotoxicity In MONARCH 3, Grade ≥3 increases in ALT (6% versus 2%) and AST (3% versus 1%) were reported in the VERZENIO and placebo arms, respectively. In MONARCH 2, Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the VERZENIO and placebo arms, respectively.

In MONARCH 3, for patients receiving VERZENIO plus an aromatase inhibitor with Grade ≥3 ALT increased, median time to onset was 61 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 2, for patients receiving VERZENIO plus fulvestrant with Grade ≥3 ALT increased, median time to onset was 57 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 3, for patients receiving VERZENIO plus an aromatase inhibitor with Grade ≥3 AST increased, median time to onset was 71 days, and median time to resolution was 15 days. In MONARCH 2, for patients receiving VERZENIO plus fulvestrant with Grade ≥3 AST increased, median time to onset was 185 days, and median time to resolution was 13 days.

Monitor liver function tests (LFTs) prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Venous Thromboembolism In MONARCH 3, venous thromboembolic events were reported in 5% of patients treated with VERZENIO plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo. In MONARCH 2, venous thromboembolic events were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported.

Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Embryo-Fetal Toxicity

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue VERZENIO until toxicity resolves to ≤Grade 1, and then resume VERZENIO at the next lower dose.

Based on findings from animal studies and the mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.

Neutropenia Neutropenia occurred in 41% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and 37% of patients receiving VERZENIO alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and in 27% of patients receiving VERZENIO in MONARCH 1.

In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1 was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VERZENIO and for at least 3 weeks after the last dose.

Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Febrile neutropenia has been reported in <1% of patients exposed to VERZENIO in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2.

Inform patients to promptly report any episodes of fever to their healthcare provider.

Interstitial Lung Disease (ILD)/Pneumonitis Severe, life-threatening, or fatal lung disease (ILD) and/or pneumonitis can occur in patients treated with VERZENIO and other CDK 4/6 inhibitors. Across clinical trials (MONARCH 1, MONARCH 2, and MONARCH 3), 3.3% of VERZENIO-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported.

ADVERSE REACTIONS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease setting MONARCH 3 was a study of 488 women receiving VERZENIO plus an aromatase inhibitor or placebo plus an aromatase inhibitor. Patients were randomly assigned to receive 150 mg of VERZENIO or placebo orally twice daily, plus physician’s choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the VERZENIO arm and 13.9 months for the placebo arm. Median dose compliance was 98% for the VERZENIO arm and 99% for the placebo arm.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.

Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 13% of patients receiving VERZENIO plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. VERZENIO dose reductions due to neutropenia of any grade occurred in 11% of patients receiving VERZENIO plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor.

VERZENIO® (abemaciclib) tablets, for oral use

VERZENIO® (abemaciclib) tablets, for oral use

Verzenio, AL HCP BS 19SEP2019 - 7 x 10

AL HCP BS 19SEP2019

AL HCP BS 19SEP2019

PRINTER VERSION 1 OF 5

Table 1: Adverse Reactions ≥10% of Patients Receiving VERZENIO Plus Anastrozole or Letrozole and ≥2% Higher Than Placebo Plus Anastrozole or Letrozole in MONARCH 3 (Cont.)

Permanent treatment discontinuation due to an adverse event was reported in 13% of patients receiving VERZENIO plus an aromatase inhibitor and in 3% placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%).

Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of VERZENIO plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus an aromatase inhibitor included: 3 (1%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE event, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction.

The most common adverse reactions reported (≥20%) in the VERZENIO arm and ≥2% than the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia (Table 1). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia. Diarrhea incidence was greatest during the first month of VERZENIO dosing. The median time to onset of the first diarrhea event was 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions. Nineteen percent of patients with diarrhea required a dose omission and 13% required a dose reduction. The median time to the first dose reduction due to diarrhea was 38 days.

Table 1: Adverse Reactions ≥10% of Patients Receiving VERZENIO Plus Anastrozole or Letrozole and ≥2% Higher Than Placebo Plus Anastrozole or Letrozole in MONARCH 3 Placebo plus VERZENIO plus Anastrozole or Letrozole Anastrozole or Letrozole N=161 N=327 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Gastrointestinal Disorders Diarrhea 81 9 0 Nausea 39 <1 0 Abdominal pain 29 1 0 Vomiting 28 1 0 Constipation 16 <1 0 Infections and Infestations Infectionsa 39 4 <1 Blood and Lymphatic System Disorders Neutropenia 41 20 2 Anemia 28 6 0 Leukopenia 21 7 <1 Thrombocytopenia 10 2 <1 General Disorders and Administration Site Conditions Fatigue 40 2 0 Influenza like illness 10 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 27 0 0 Rash 14 <1 0 Pruritus 13 0 0 Metabolism and Nutrition Disorders Decreased appetite 24 1 0 Investigations Blood creatinine 19 2 0 increased 16 6 <1 Alanine aminotransferase increased 15 3 0 Aspartate aminotransferase increased Weight decreased 10 <1 0

30 20 12 12 12

1 1 1 2 0

0 0 0 0 0

29

2

<1

2 5 2 2

<1 1 0 <1

<1 0 <1 0

32 8

0 0

0 0

11 5 9

0 0 0

0 0 0

9

<1

0

4

0

0

7

2

0

7

1

0

3

<1

0

VERZENIO® (abemaciclib) tablets, for oral use

Verzenio, AL HCP BS 19SEP2019 - 7 x 10

AL HCP BS 19SEP2019

Placebo plus VERZENIO plus Anastrozole or Letrozole Anastrozole or Letrozole N=161 N=327 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 0 Dyspnea 12 <1 <1 Nervous System Disorders Dizziness 11 <1 0 a

9 6

0 <1

0 0

9

0

0

Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>1%) include upper respiratory tract infection, lung infection, and pharyngitis.

Additional adverse reactions in MONARCH 3 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with VERZENIO plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo.

Table 2: Laboratory Abnormalities ≥10% in Patients Receiving VERZENIO Plus Anastrozole or Letrozole and ≥2% Higher Than Placebo Plus Anastrozole or Letrozole in MONARCH 3

Laboratory Abnormality Creatinine increased White blood cell decreased Anemia Neutrophil count decreased Lymphocyte count decreased Platelet count decreased Alanine aminotransferase increased Aspartate aminotransferase increased

VERZENIO plus Placebo plus Anastrozole or Letrozole Anastrozole or Letrozole N=327 N=161 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % 98 2 0 84 0 0 82 13 0 27 <1 0 82 80

2 19

0 3

28 21

0 3

0 0

53

7

<1

26

2

0

36 48

1 6

<1 <1

12 25

<1 2

0 0

37

4

0

23

<1

0

Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.

MONARCH 2: VERZENIO in Combination with Fulvestrant Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy The safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2. The data described below reflect exposure to VERZENIO in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of VERZENIO plus fulvestrant in MONARCH 2.

Median duration of treatment was 12 months for patients receiving VERZENIO plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant.

Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 19% of patients receiving VERZENIO plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. VERZENIO dose reductions due to neutropenia of any grade occurred in 10% of patients receiving VERZENIO plus fulvestrant compared to no patients receiving placebo plus fulvestrant.

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Permanent study treatment discontinuation due to an adverse event was reported in 9% of patients receiving VERZENIO plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).

Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of VERZENIO plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving VERZENIO plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.

The most common adverse reactions reported (≥20%) in the VERZENIO arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache (Table 3). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.

b

c d

e f g

Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis.

Includes neutropenia, neutrophil count decreased.

Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.

Includes leukopenia, white blood cell count decreased.

Includes platelet count decreased, thrombocytopenia.

Includes asthenia, fatigue.

Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.

Table 4: Laboratory Abnormalities ≥10% in Patients Receiving VERZENIO Plus Fulvestrant and ≥2% Higher Than Placebo Plus Fulvestrant in MONARCH 2 VERZENIO plus Fulvestrant N=441

Table 3: Adverse Reactions ≥10% in Patients Receiving VERZENIO Plus Fulvestrant and ≥2% Higher Than Placebo Plus Fulvestrant in MONARCH 2 VERZENIO plus Fulvestrant Placebo plus Fulvestrant N=441 N=223 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Gastrointestinal Disorders Diarrhea 86 13 0 25 <1 0 Nausea 45 3 0 23 1 0 Abdominal Paina 35 2 0 16 1 0 Vomiting 26 <1 0 10 2 0 Stomatitis 15 <1 0 10 0 0 Infections and Infestations 43 5 <1 25 3 <1 Infectionsb Blood and Lymphatic System Disorders 46 24 3 4 1 <1 Neutropeniac 29 7 <1 4 1 0 Anemiad 28 9 <1 2 0 0 Leukopeniae 16 2 1 3 0 <1 Thrombocytopeniaf General Disorders and Administration Site Conditions 46 3 0 32 <1 0 Fatigueg Edema peripheral 12 0 0 7 0 0 Pyrexia 11 <1 <1 6 <1 0 Metabolism and Nutrition Disorders Decreased appetite 27 1 0 12 <1 0 Respiratory, Thoracic and Mediastinal Disorders Cough 13 0 0 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 16 0 0 2 0 0 Pruritus 13 0 0 6 0 0 Rash 11 1 0 4 0 0 Nervous System Disorders Headache 20 1 0 15 <1 0 Dysgeusia 18 0 0 3 0 0 Dizziness 12 1 0 6 0 0 Investigations 13 4 <1 5 2 0 Alanine aminotransferase increased 12 2 0 7 3 0 Aspartate aminotransferase increased Creatinine increased 12 <1 0 <1 0 0 Weight decreased 10 <1 0 2 <1 0 a

Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.

VERZENIO® (abemaciclib) tablets, for oral use

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Placebo plus Fulvestrant N=223

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Creatinine increased

98

1

0

74

0

0

White blood cell decreased

90

23

<1

33

<1

0

Neutrophil count decreased

87

29

4

30

4

<1

Anemia

84

3

0

33

<1

0

Lymphocyte count decreased

63

12

<1

32

2

0

Platelet count decreased

53

<1

1

15

0

0

Alanine aminotransferase increased

41

4

<1

32

1

0

Aspartate aminotransferase increased

37

4

0

25

4

<1

Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired.

VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1) Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting Safety data below are based on MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR+, HER2- metastatic breast cancer. Patients received 200 mg VERZENIO orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months.

Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each) abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia. Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%).

Deaths due to adverse events during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection (2 patients) or pneumonitis (1 patient).

The most common reported adverse reactions (≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia (Table 5). Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib.

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Table 5: Adverse Reactions (≥10% of Patients) in MONARCH 1

All Grades %

VERZENIO N=132 Grade 3 %

Gastrointestinal Disorders Diarrhea 90 Nausea 64 Abdominal pain 39 Vomiting 35 Constipation 17 Dry mouth 14 Stomatitis 14 Infections and Infestations Infections 31 General Disorders and Administration Site Conditions Fatiguea 65 Pyrexia 11 Blood and Lymphatic System Disorders Neutropeniab 37 Anemiac 25 Thrombocytopeniad 20 Leukopeniae 17 Metabolism and Nutrition Disorders Decreased appetite 45 Dehydration 10 Respiratory, Thoracic and Mediastinal Disorders Cough 19 Musculoskeletal and Connective Tissue Disorders Arthralgia 15 Nervous System Disorders Headache 20 Dysgeusia 12 Dizziness 11 Skin and Subcutaneous Tissue Disorders Alopecia 12 Investigations Creatinine increased 13 Weight decreased 14 a b c

d e

Grade 4 % 0 0 0 0 0 0 0

Effect of Other Drugs on VERZENIO

5

2

13 0

0 0

19 5 4 5

5 0 0 <1

Other Strong CYP3A Inhibitors In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking VERZENIO discontinues a strong CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. Patients should avoid grapefruit products.

3 2

0 0

0

0

0

0

0 0 0

0 0 0

0

0

<1 0

0 0

Table 6: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1

Creatinine increased White blood cell decreased Neutrophil count decreased Anemia Lymphocyte count decreased Platelet count decreased ALT increased AST increased

DRUG INTERACTIONS

20 5 2 2 <1 0 0

Includes asthenia, fatigue.

Includes neutropenia, neutrophil count decreased.

Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.

Includes platelet count decreased, thrombocytopenia.

Includes leukopenia, white blood cell count decreased.

All Grades % 98 91 88 68 42 41 31 30

VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.

VERZENIO N=132 Grade 3 % <1 28 22 0 13 2 3 4

Grade 4 % 0 0 5 0 <1 0 0 0

CYP3A Inhibitors Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity.

Ketoconazole Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold.

Moderate CYP3A Inhibitors With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements, if necessary.

Strong and Moderate CYP3A Inducers Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose (see Data).

Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data Animal Data In an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses ≥4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or nodulated ribs. At 4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose.

Lactation Risk Summary There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose.

Females and Males of Reproductive Potential

Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.3 mg/dL) occurred within the first 28-day cycle of

Pregnancy Testing Based on animal studies, VERZENIO can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with VERZENIO.

VERZENIO® (abemaciclib) tablets, for oral use

VERZENIO® (abemaciclib) tablets, for oral use

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Contraception Females VERZENIO can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for at least 3 weeks after the last dose.

Infertility Males Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential.

Pediatric Use The safety and effectiveness of VERZENIO have not been established in pediatric patients.

Geriatric Use Of the 900 patients who received VERZENIO in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) Grade 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased. No overall differences in safety or effectiveness of VERZENIO were observed between these patients and younger patients.

Renal Impairment No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr ≥30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown.

Hepatic Impairment No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C).

OVERDOSAGE There is no known antidote for VERZENIO. The treatment of overdose of VERZENIO should consist of general supportive measures.

Rx only.

Additional information can be found at www.verzenio.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright ©2019, Eli Lilly and Company. All rights reserved.

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Revista Puertorriqueña de Medicina y Salud Pública

29

ARTÍCULO / ORIGINAL

PREVALENCIA DE HIPOGLICEMIA Y CALIDAD DE VIDA EN PACIENTES HISPANOS CON DIABETES MELLITUS TIPO 2 AUTORES: Vivian S. Green, PhD, MS, LND Public Health Program, Ponce Health Sciences University vgreen@psm.edu (Vivian S. Green es el autor para correspondencia)

PALABRAS CLAVE: Hipoglucemia, diabetes, hispano, Puerto Rico, calidad de vida

Soreli Santana Public Health Program, Ponce Health Sciences University Ssantana13@stu.psm.edu

KEYWORDS: hypoglycemic, diabetes, Hispanic, Puerto Rico, quality of life

Mayra Roubert Public Health Program, Ponce Health Sciences University mroubert@psm.edu Yemile Ron-Suarez, MD Merck & Co., Inc., Carolina, PR, USA yemile_ron@merck.com Luis Carlos Mejia-Rivera, PhD, MD Merck & Co., Inc., Carolina, PR, USA luis.mejia-rivera@merck.com Felipe Arbelaez, MD, MBA Merck & Co., Inc., Kenilworth, NJ, USA felipe_arbelaez@merck.com Homero Monsanto, PhD Merck & Co., Inc., Carolina, PR, USA homero_monsanto@merck.com Edgar I. Miranda, PhD Merck & Co., Inc., Carolina, PR, USA edgar.i.miranda.avalo@merck.com Cecile Marqués-Goyco, MD Merck & Co., Inc., Carolina, PR, USA cecile_marques-goyco@merck.com Juan C. Orengo, MD, MPH, PhD Public Health Program, Ponce Health Sciences University jorengo@psm.edu

30

Revista Puertorriqueña de Medicina y Salud Pública

EL PUERTO RICO REAL-LIFE EFFECTIVENESS AND CARE PATTERNS OF DIABETES MANAGEMENT (RECAP-DM)

CONFLICTO DE INTERÉS: YR, HM, LCM-R, EIM y CM-G son empleados de Merck & Co., Inc., Carolina, PR, EEUU.; FA es Merck & Co., Inc., Kenilworth, NJ, Estados Unidos; JCO era un empleado de Merck & Co., Inc., Carolina, PR, EEUU cuando se diseñó el estudio.

FINANCIACIÓN: MSD (IA) LLC, Carolina, Puerto Rico CONTRIBUCIONES DE LOS AUTORES: VSG, SS, MR y JCO trabajaron en la implementación del estudio, análisis de datos, interpretación de resultados y redacción del manuscrito; YR, HM, FA, LCM-R, EIM, CM-G y JCO colaboraron en el diseño de la investigación. El manuscrito fue revisado y aprobado por todos los autores.

AGRADECIMIENTOS: Queremos agradecer a los pacientes que participaron voluntariamente en el estudio y a los médicos que colaboraron en la implementación del proyecto.

ARTÍCULO / ORIGINAL RESUMEN

ABSTRACT

En Puerto Rico la prevalencia de la diabetes mellitus tipo 2 (DMT2) es del 15,5% (2016). Los objetivos de nuestro estudio fueron: 1) evaluar la prevalencia de hipoglucemia en pacientes con DMT2 que toman sulfonilureas; 2) evaluar la prevalencia de pacientes con DMT2 que no están en la meta de HbA1c de <7%; 3) evaluar la evaluación del autocuidado, la calidad de vida y la adherencia general al tratamiento. Se realizó un estudio exploratorio transversal en consultorios médicos privados en todo Puerto Rico (2016-2017). Los pacientes con diagnóstico de DMT2 tratados con sulfonilureas fueron invitados a participar en el estudio. Los datos sobre el cumplimiento, la calidad de vida, el estilo de vida y los factores conductuales fueron informados por el participante y se recopilaron los datos clínicos de la historia clínica. Se utilizaron estadísticas descriptivas e inferenciales para resumir los datos generales de los pacientes. (260 participantes fueron inscritos en el estudio). Durante los últimos seis meses la hipoglucemia autoinformada fue del 41,2%, siendo el 58,9% la prevalencia de pacientes con la última HbA1c <7%. El 85,3% de los participantes siempre utilizaron sus medicamentos según lo prescrito por su médico. El 60,3% de los participantes no sigue una dieta especial para diabéticos y el 67,2% no sigue un programa de ejercicios de rutina. La puntuación del Índice EQ-5D para los pacientes hipoglucémicos fue de 0,77 (DE=0,21) y para los pacientes no hipoglucémicos fue de 0,85 (DE=0,14) (p <0,05). La prevalencia de hipoglucemia autoinformada se encuentra en el rango de otros estudios realizados en Asia y Europa; el objetivo de HbA1c<7 no se alcanzó en el 41,1% de la muestra. Estos hallazgos resaltan la necesidad médica insatisfecha de tratamiento que puede ayudar a los pacientes a alcanzar los objetivos del tratamiento con DMT2.

In Puerto Rico the prevalence of Type 2 Diabetes Mellitus (T2DM) is 15,5% (2016). The objectives of our study were: 1) to assess the prevalence of hypoglycemia in T2DM patients taking sulfonylureas; 2) to assess the prevalence of T2DM patients who are not at the HbA1c goal of <7%; 3) to assess self-care evaluation, quality of life and the general adherence to treatment. An exploratory cross-sectional study was conducted in private medical offices across Puerto Rico (2016-2017). Patients with a diagnosis of T2DM treated with sulfonylureas were invited to participate in the study. Data on adherence, quality of life, lifestyle/behavioral factors were reported by the participant and clinical data from the medical record were collected. Descriptive and inferential statistics were used to summarize general data of the patients. (260 participants were enrolled in the study). During the last six months the self-reported hypoglycemia was 41,2%, being 58,9% the prevalence of patients with the last HbA1c <7%. 85,3% of the participants always used their medicines as prescribed by their doctor. The 60,3% of the participants do not follow a special diabetic diet and 67,2% do not follow a routine exercise program. The EQ-5D Index score for hypoglycemic patients was 0.77 (SD=0.21) and for non-hypoglycemic patients was 0.85 (SD=0.14) (p <0.05).

The prevalence of self-reported hypoglycemia is in the range of other studies conducted in Asia and Europa; the target of HbA1c < 7 was not achieved by the 41,1% of the sample. These findings highlight the unmet medical need for treatment that can help patients achieve T2DM treatment goals.

INTRODUCCIÓN La prevalencia de diabetes mellitus (DM) en Puerto Rico se encuentra entre las más altas de América Latina y el Caribe1. Se estima que casi 400 000 personas entre 20 a 79 años tienen diabetes en Puerto Rico. Según el Sistema de Vigilancia de los Factores de Riesgo del Comportamiento (BRFSS, por sus siglas en inglés) de los Centros para el Control y la Prevención de Enfermedades (CDC) en 2010, al 8,7% de la población de los Estados Unidos se le había informado que tenía DM y en 2018 la prevalencia era del 11%, siendo para Puerto Rico de un 15,5% 2.

La DM fue la tercera causa de muerte en Puerto Rico en el 2016 y así desde el 2004 3,4. La tasa de mortalidad por DM más alta en Puerto Rico fue durante el 2011 (75,5 por cada 100 000 habitantes), pero datos de 2016 mostraron que la tasa de mortalidad fue de 66,3 por cada 100 000 habitantes3,4.

En Puerto Rico, en el 2013, el presupuesto invertido a DM ascendió a $138 416 722 y el grupo de edad entre 65 a 69 años invirtió aun más con aproximadamente $25,4 millones.

La diabetes mellitus tipo 2 es la forma más común de diabetes mellitus (DM2) y representa el 90% de todos los casos diagnosticados en todo el mundo A su vez es la causa principal de morbilidad y mortalidad5, particularmente con enfermedad cardiovascular, neuropatía y enfermedad renal crónica6,7. Además, dado que las enfermedades cardiovasculares y la DM son la primera y la tercera causa de muerte en Puerto Rico (2016) respectivamente, la prevención y el tratamiento de la diabetes mellitus son de máxima prioridad4.

Se estima que el 80-90% de los pacientes con DM2 requieren tratamientos farmacológicos de un tipo u otro. El objetivo del tratamiento es controlar los parámetros glucémicos (HbA1c Objetivo <7%, American Diabetes Association, 2014) para minimizar

el riesgo de complicaciones a largo plazo y aliviar cualquier síntoma8.

Sin embargo, se ha documentado que el control glucémico intensivo puede conducir a eventos hipoglucémicos en pacientes diabéticos, por lo que actúa como un obstáculo significativo en los esfuerzos de control glucémico en el tratamiento del paciente9. La hipoglucemia ocurre cuando los niveles de glucosa en sangre se encuentran por debajo de la línea de base, generalmente a 70 mg /dL8 o menos.

En algunos pacientes diabéticos la respuesta al glucagón se ve afectada y su respuesta a otras hormonas (epinefrina y adrenalina) puede elevar los niveles de glucosa en sangre. El problema de estos pacientes surge debido a su tratamiento: la insulina y los agentes hipoglucemiantes orales (OHA), como las sulfonilureas (SU), aumentan la producción de insulina, por lo que los niveles de glucosa no pueden volver a su rango normal10.

Según los hallazgos de tres grandes ensayos aleatorios controlados (ACCORD, ADVANCE, VADT)11,13, la Revista Puertorriqueña de Medicina y Salud Pública

31

Todos

relevancia clínica de los eventos hipoglucémicos se ha vuelto cada vez más importante en las guías internacionales para el tratamiento de DM2. La Declaración de Consenso 2013 del Algoritmo de Manejo Integral de la Diabetes de AACE destacó que “minimizar el riesgo de hipoglucemia es una prioridad. Es una cuestión de seguridad, adherencia y costo”.14En los estudios de Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) Asia Pacífico y RECAP DM de la Unión Europea, el 36% de los pacientes tratados en la región de Asia Pacífico y el 38% de los pacientes tratados en la región de la Unión Europea informaron síntomas de hipoglucemia.15,16. En Puerto Rico, donde la diabetes es altamente predominante, la prevalencia de hipoglucemia en pacientes tratados con SU en un entorno real aún no se ha evaluado. Por lo tanto, los objetivos generales de este estudio fueron: 1) evaluar la prevalencia de hipoglucemia (autoinformada o documentada en la historia clínica del participante) en pacientes diabéticos tipo 2 tratados con SU (como monoterapia o en combinación con metformina) en Puerto Rico y 2) estimar la prevalencia de pacientes que alcanzan la meta de HbA1c de <7%.

32

Revista Puertorriqueña de Medicina y Salud Pública

VIUDO/A

MATERIAL Y MÉTODOS Se realizó un estudio exploratorio de corte transversal en consultorios médicos privados en las regiones norte y sur de Puerto Rico durante los años 2016-2017.

Los pacientes con un diagnóstico de diabetes mellitus tipo 2 tratados con sulfonilureas como monoterapia o en combinación con metformina y otros criterios de inclusión fueron invitados a participar en el estudio. Los objetivos del estudio fueron, primero, evaluar la prevalencia de hipoglucemia en pacientes con diabetes mellitus tipo 2 que toman sulfonilureas en Puerto Rico; segundo, evaluar la prevalencia de pacientes con diabetes mellitus tipo 2 en Puerto Rico que no están en el objetivo de HbA1c de <7 %; y tercero, evaluar el autocuidado, la calidad de vida y la adherencia general al tratamiento. La población de estudio eran pacientes adultos diagnosticados con diabetes mellitus tipo 2 de acuerdo con los criterios de la ADA a) Síntomas de DM más concentración de glucosa en plasma casual ≥200 mg/dl (11.1 mmol/l); b) FPG ≥ 126 mg/dl (7,0 mmol/l); y c) PG≥200 mg /dl de 2 h (11.1 mmol/l) durante un OGTT) de 30 años de edad o más que han estado tomando SU (terapia mono o en combinación con metformina) durante al menos 6 meses.

18.6%

Escuela primaria

19.6%

2.7%

31.4%

28.5%

34.6%

126

47

33

39

72

2

0.8%

14%

31.8% 3.7%

19.6%

21

Ama de casa Discapacitado

31 48

38

59

79

1.3%

17.9%

2%

27

Hipoglucémico media (SD)

14%

7 4

27.8%

13.1%

Retirado

14 36 DIVORSIADO/A

3

36.4%

14.6%

21

14

21.7%

22

-4.3 , 0.7

11.5 (11.4)

42.2%

9.2%

42.1%

34 48

Medio tiempo Desempleado (Buscando trabajo)

13.7%

45 109 CASADO/A

15

82

48.6%

9.7 (8.7)

95% IC de la diferencia

42.4%

4.8 , 12.0*

48.3 (14.6)

No Hipoglucémico media (SD)

64

19

29 53

43.9%

Duración de la DM

56.7 (13.3)

25.2%

74

52%

Edad del diagnóstico

65 2.6 , 9.6* SOLTERO/A

22.8%

59.7(14.6)

25.2%

Trabajando tiempo completo

Edad

27

25%

65.8 (13.2)

25.2%

19.6%

38

* Diferencia estadísticamente significativa (p<0.05)

40

17.8%

21

15.4%

CARACTERÍSTICAS SOCIODEMOGRÁFICAS DE LA MUESTRA

11.2%

31.5%

ARTÍCULO / ORIGINAL

0

2

Escuela Universitario Postgrado secundaria

Durante la visita de rutina al consultorio, el participante completó una serie de cuestionarios de pacientes para recopilar datos notificados por el paciente sobre la experiencia de haber padecido hipoglucemia (incluida la frecuencia/gravedad), la adherencia al tratamiento, la calidad de vida (QoL) y los factores de estilo de vida/comportamiento. Además, se recopilaron datos médicos prespecificados de los expedientes médicos para el período de 6 meses anterior a la fecha de inscripción del paciente al estudio, los cuales incluyeron datos demográficos del paciente, factores de riesgo, historial de enfermedad/medicación, uso de recursos y HbA1c, entre otros valores de laboratorio. Se utilizaron estadísticas descriptivas para resumir los datos generales de los pacientes y las pruebas de Chi cuadrado, OR y T para comparar grupos. El muestreo no fue probabilístico. Se usó una fórmula de muestra aleatoria simple para calcular el tamaño de la muestra, siendo esta de 260 pacientes. Todos los participantes dieron su consentimiento informado para la inclusión en el estudio antes de participar en el mismo. El estudio se realizó de conformidad con la Declaración de Helsinki y el protocolo fue aprobado por la Junta de Revisión Institucional de la Ponce Health Sciences University.

RESULTADOS El 36,7% de la muestra eran hombres y el 63,3% mujeres. La edad media fue de 63,4 años (DE=14) y la mediana fue de 65 años.

La edad promedio de las mujeres fue de 63,7 años (DE=14) y la de los hombres de 63,1 años (DE=14); las diferencias no fueron estadísticamente significativas.

La edad media al diagnóstico de diabetes mellitus (DM) fue de 53,2 años (DE=14) y la mediana de 55 años; en las mujeres, la edad promedio al diagnóstico fue de 53,7 años (DE=14) y en los hombres fue de 52,5 años (DE=15); la duración promedio de la enfermedad desde el diagnóstico fue de 10,4 años (DE=10) y la mediana de 8 años, en mujeres fue de 10,1 (DE=9,7) y en hombres de 10,9 (DE=10,4) la mediana fue de 8,5 años y 7 años para mujeres y hombres respectivamente, sin diferencias estadísticamente significativas.

En los últimos seis meses, el 41,2% de los participantes en el estudio informaron un episodio de hipoglucemia como se define en el estudio. En cuanto a la relación entre hombres y mujeres, 40% (38) y 43,1% (69) respectivamente informaron algún episodio de hipoglucemia.

En la tabla 1 podemos ver la edad media en el momento del diagnóstico y la duración promedio de la DM según el paciente que informó haber sufrido un episodio de hipoglucemia o no. Encontramos diferencias estadísticamente significativas en la edad del paciente y en la edad de diagnóstico. Los pacientes con hipoglucemia tenían una edad menor y eran más jóvenes cuando fueron diagnosticados. También podemos observar los resultados relacionados con las características sociodemográficas de la muestra, tanto para los pacientes que notificaron hipoglucemia como los que no la notificaron.

El 66,4% (168) de la muestra informó que

sus padres también habían sido diagnosticados con DM, para los participantes no hipoglucémicos fue del 58,5% (89) y para los hipoglucémicos del 75,2% (79), por lo que se encontro una diferencia estadísticamente significativa (p <0.05) para estos dos grupos, lo que representa para los pacientes con hipoglucemia 2,01 veces más posibilidades (OR) de tener padres diabéticos (IC 95%: 1,16; 3,49).

El 65% (169) de la muestra nunca había fumado; aquellos que habían dejado de fumar o fumaban actualmente representaban el 25,8% (67) y 8,8% (23) respectivamente.

En relación con los participantes no hipoglucémicos, el 63,4% (97) nunca había fumado, el 28,1% (43) había dejado de fumar y el 8,5% (13) continuó fumando; para los pacientes con hipoglucemia, el 67% (72) nunca había fumado, el 22,4% (24) había dejado de fumar y el 9,3% (10) fumaba actualmente.

El 49,8% (129) de los participantes informaron que realizaban algún tipo de actividad física, siendo el 53,9% (82) de los no hipoglucémicos y el 43,9% (47) de los hipoglucémicos. El 69,8% (180) de la muestra notificó que ingiere una dieta baja en azúcar, lo que corresponde al 73,5% (111) de los pacientes no hipoglucémicos y al 64,5% (69) de los hipoglucémicos. Una dieta baja en calorías es seguida por el 46,5% (111) de los participantes, esta misma dieta es seguida por el 48,7% (73) de los no hipoglucémicos y el 43,4% (46) de los hipoglucémicos.

El índice de masa corporal (IMC) medio de la muestra fue de 30 (DE=6,8) y la mediana de 28,6 en hipoglucémicos; el promedio fue de 31,3 (DE=6,7) y la mediana fue de 30,2, en no hipoglucémicos, la media fue de 29 (DE=6,8) y la mediana de 27,3; al comparar las medias encontramos una diferencia estadísticamente significativa (p <0.05)

ARTÍCULO / ORIGINAL con una diferencia entre las medias de -2,3 (95% Ci -4,0, -0,6). Los pacientes no hipoglucémicos tienen 1,9 (IC 95% 1.1.3.2) más posibilidades de tener un peso saludable que los pacientes que presentaron hipoglucemia en los últimos seis meses.

En la tabla 2 podemos observar la clasificación de los participantes según el índice de masa corporal.

En el 67,5% (172) de la muestra no se informaron cambios en el peso en los últimos seis meses ni en el 62,6% (67) de los pacientes con hipoglucemia y el 70,9% (105) de los participantes no hipoglucémicos. Por otro lado, el 9,4% (24) de los participantes informaron pérdida de peso, así como el 13,1% (14) de los pacientes con hipoglucemia y el 6,8% (10) de los pacientes sin hipoglucemia (Figura 1). No encontramos diferencias estadísticamente significativas en la ganancia o pérdida de peso entre pacientes con hipoglucemia y pacientes no hipoglucémicos. Sin embargo, se observa una mayor pérdida de peso en pacientes con hipoglucemia.

Los pacientes que informaron haber tenido un episodio de hipoglucemia en los últimos seis meses informaron haber sufrido “leve” (síntomas de bajo nivel de azúcar en la sangre definidos como poca o ninguna interrupción de las actividades, y no sienten la ayuda necesaria para controlar los síntomas), “moderado” (síntomas de bajo nivel de azúcar en la sangre definidos como cierta interrupción de actividades, pero no siente la asistencia necesaria para controlar los síntomas), “grave” (síntomas de bajo nivel de azúcar en la sangre definidos como que sentían que necesitaba la ayuda de otros para controlar los síntomas (por ejemplo, para llevar comida o bebida) o “muy grave”

Tabla 2. Clasificación del índice de masa corporal (IMC)

* Diferencia estadísticamente significativa (p<0.05)

Revista Puertorriqueña de Medicina y Salud Pública

33

MSP ARTÍCULO / ORIGINAL ARTÍCULO / ORIGINAL (síntomas de bajo nivel de azúcar en la sangre definidos como atención médica necesaria (por ejemplo, llamar a una ambulancia, visitar una sala de emergencias u hospital, o ser visto por un médico o enfermera) síntomas en el 68,9% (73) , 29,9% (32), 6,5% (7) y 2,8% (3) respectivamente. 16,9% (25) informaron que no sentían “ninguna preocupación” por sus síntomas, 18,7% (20) “sin molestias”, 34,6 % (37) una “pequeña molestia”, 15% (16) “algo de incomodidad” y 8,4% (9) “mucha incomodidad “.

En relación con la información que el médico discutió en el momento del diagnóstico de DM encontramos que la dieta, los niveles de glucosa en la sangre, el control de la presión arterial, la salud emocional, el manejo del nivel alto de azúcar en la sangre y la

No hypoglycemic

6.80%

patients

Hypoglycemic

13.10%

patients

0.00%

2.00%

4.00%

34

Revista Puertorriqueña de Medicina y Salud Pública

6.00%

8.00%

10.00% 12.00%

14.00% Prevalence

cobertura del seguro de salud se discutieron menos con los hipoglucémicos, siendo esta diferencia estadísticamente significativo (p <0.05). En la información discutida por el médico con el paciente en una revisión de seguimiento de la patología encontramos que a los pacientes hipoglucémicos se

Tabla 3. Información discutida por el médico con el paciente al momento del diagnóstico

* Diferencia estadísticamente significativa (p<0.05)

Figura 1. Prevalencia de pérdida de peso notificada por el participante

les habla menos sobre la dieta, la salud emocional y el manejo del nivel alto de azúcar en la sangre, siendo para estas características la diferencia estadísticamente significativa (p <0.05).

Las tablas 3 y tabla 4 presentan la información que fue discutida por el médico con el

Tabla 4. Información discutida por el médico con el paciente en una visita de seguimiento

ARTÍCULO / ORIGINAL

* Diferencia estadísticamente significativa (p<0.05)

paciente en el momento del diagnóstico de DM y se dialoga en una revisión de la enfermedad, respectivamente.

El 26,3% (40) de los no hipoglucémicos y el 21% (22) de los hipoglucémicos notificaron que nunca omiten alimentos cuando trabajan, mientras que el 0,7% (1) de los no hipoglucémicos y el 3,8% (4) de ellos lo hacen. El 46,7% (121) de los participantes han sido referidos a un educador en diabetes o a un dietista o nutricionista, el 43% (46) de los pacientes con hipoglucemia informaron que fueron referidos a uno de los especialistas anteriores mientras que los no hipoglucémicos el 49,3% (75) informó haber recibido referidos. De los que recibieron un referido, el 50% (60) fue en los primeros meses, el 5% (6) en los primeros tres meses, el 10% (12) en los primeros seis meses, el 11,7% (14) en el primer año, el 12,5 % (15) después del primer año y 10,8% (13) nunca asistieron a la cita. En relación con los pacientes con hipoglucemia, el 32,6% (15) fue en los

primeros meses, el 6,5% (3) en los primeros tres meses, el 4,3% (2) en los primeros seis meses, el 21,7% (10) en el primer año, el 17,4% (8) después del primer año y el 17,4% (4) nunca asistieron a la cita en comparación con el 61.6% (45), 2,7% (2), 13,7% (10), 5,5% (4), 9,6% (7) y 6,8% (5) de pacientes no hipoglucémicos. Los pacientes que presentaron hipoglucemia visitaron al educador o al dietista en menor frecuencia durante los primeros tres meses y lo visitaron más en el primer año, siendo estas diferencias estadísticamente significativas (p <0.05).

El 58,6% (150) de la muestra informó que no desembolsó dinero para pagar los medicamentos recetados para la diabetes, el 28,5% (73) pagó un copago, el 3,9% (10) pagó por algunos de ellos y el 9% (23) pagó por todos. Para el 59,8% (153) es muy importante en el diálogo con el médico, el costo de los medicamentos en la elección de su tratamiento médico, para el 8,2% (21) no es importante.

La tabla 5 presenta los valores clínicos de la muestra total para pacientes con episodios de hipoglucemia en los últimos seis meses y, para aquellos participantes que no los notificaron, encontramos diferencias estadísticamente significativas (p <0.05) en los valores de HDL, triglicéridos y cintura. La prevalencia de participantes con el último valor de HbA1c <7% fue del 58,9%.

En relación con la calidad de vida, se modificaron las respuestas al cuestionario EQ-5D-3L. Las tres posibles respuestas a cada dimensión se redujeron a dos, si el participante no presentaba ningún problema se consideraba “sin problemas” y si el participante respondía “algún problema” (el paciente presenta limitaciones para realizar alguna actividad) o se sentía incapacitado en la dimensión estudiada se consideró “con problemas”. En la tabla 6 podemos ver los resultados para cada Revista Puertorriqueña de Medicina y Salud Pública

35

MSP ARTÍCULO / ORIGINAL ARTÍCULO / ORIGINAL Tabla 5. Valores clínicos

dimensión en el caso de que el participante respondió “sin problemas”, según el participante informó si había sufrido hipoglucemia o no. Para la dimensión de movilidad, dolor y ansiedad/ depresión encontramos una diferencia estadísticamente significativa (p<0.05), presentando los pacientes con hipoglucemia 1.8 (IC 95%: 1.1, 3.0) más posibilidad de presentar problemas de movilidad, 1.9 (IC 95%): 1.2.3.2) más posibilidades de presentar problemas de dolor y 2,3 (IC 95%: 1.4.3.9) más posibilidades de presentar ansiedad/ depresión.

El puntaje del índice EQ-5D (las cinco preguntas del EQ-5D-3L se usaron para calcular este puntaje, el 0 se refiere al peor estado de salud (muerte) y el 1 al mejor estado de salud) fue de 0.82 (DE=0.17) para toda la muestra del estudio, siendo para los pacientes hipoglucémicos de 0,77 (DE=0,21) y para los pacientes no hipoglucémicos de 0,85 (DE=0.14), encontrando esta diferencia estadísticamente significativa (p <0.05), para una diferencia de las medias de 0,08 (IC del 95% de diferencia: - 1,26; - 0,35 ) DISCUSIÓN En nuestro estudio la prevalencia de hipoglucemia informada por los pacientes con diabetes tipo 2 tratados con sulfonilureas fue del 41,2%, lo que corresponde a la prevalencia encontrada en otros estudios. En el estudio RECAP-DM de Asia-Pacífico realizado por Chan et al (2010) en una muestra de 2257 pacientes con diabetes tipo 2, la prevalencia de hipoglucemia fue del 35,8%, siendo el 41,7% la prevalencia en China (muestra de 484 pacientes), similar a la encontrada en Puerto Rico. Por otro lado, la prevalencia en Taiwán fue del 29,4% en una muestra de 609 pacientes. En general, en el estudio de Chan et al., el 11,6% informó síntomas “graves” de hipoglucemia y el 8,2% síntomas “muy graves”. En nuestro estudio encontramos 6,1% y 2,6% respectivamente, que es similar al encontrado en China que fue de 6,9% y 4,0% respectivamente16. En el estudio realizado por Alvarez-Guisasola et al (2008) en varios países europeos (España, Francia, Alemania, 36

Revista Puertorriqueña de Medicina y Salud Pública

* Diferencia estadísticamente significativa (p<0.05)

Reino Unido, Polonia, Noruega y Finlandia), en una muestra de 1709 pacientes diagnosticados con diabetes tipo 2 con una edad promedio de 62.9 ± 10,6 años, la prevalencia general de hipoglucemia encontrada fue de un 38,4%, la prevalencia más baja se encontró en Alemania con un 24,2% y la más alta en el Reino Unido con un 53,8%, mientras que la más similar a Puerto Rico se encontró en Francia, que fue de un 38,7 %. Como en nuestro estudio no se encontraron diferencias estadísticamente significativas relacionadas con el valor objetivo de una HbA1c en los límites recomendados entre los pacientes que

informaron hipoglucemia y los que no15.

Majanovic et al (2017) en el estudio RECAP-DM en la región de los Balcanes con una muestra de 573 pacientes con diabetes tipo 2 y una edad media de 67,2 años encontraron una prevalencia de hipoglucemia del 36,6%; de estos, 62,8% tenían síntomas leves, 31,2% moderados, 4% severos y 2 % muy severos, resultados similares a los nuestros17.

González y Cols. en el estudio RECAP-DM realizado en Argentina en el 2015 con una muestra de 397 participantes y una edad promedio de 62,5 años encontraron una prevalencia de hipoglucemia autoinformada de 45,5%

ARTÍCULO / ORIGINAL y diabetes controlada del 36,4%; para Puerto Rico la prevalencia fue de 41,2% y 58,9% respectivamente. Similar a nuestro estudio, el tiempo promedio con el diagnóstico de diabetes en Argentina fue de 10 años con una edad promedio de 52,7 años al tiempo del diagnóstico, siendo Puerto Rico de 10,4 años y 53,2 años18.

En el estudio Exhype realizado en Suecia en 2010 por Petterson et al. con una muestra de 430 pacientes, la prevalencia informada de hipoglucemia fue del 34%19. También en Suecia, Lundkvist et al (2005) encontraron una prevalencia de hipoglucemia del 37% en una muestra de 399 pacientes diabéticos tipo 2 con una edad media de 65 ± 11 años20.

Rombopoulos et al. (2013) en el estudio HYPO implementado en Grecia, en una muestra de 6631 pacientes con diabetes tipo 2, evidenciaron que la prevalencia estimada de hipoglucemia informada por los pacientes fue del 41,9%, presentando el 41% del total de la muestra los valores de la HbA1c en los límites recomendados21. En España en 2013, Orozco-Beltrán et al. encontraron una prevalencia de hipoglucemia (eventos de salud no graves) informada por pacientes con diabetes tipo 2 del 39% 22. Edidge et al. (2015) en un metanálisis encontraron una prevalencia del 33% (IC 95% 24% - 42%) de hipoglucemia en los paciente tratados con terapia con sulfonilureas23.

En relación con el IMC, en nuestro estudio encontramos una mayor prevalencia de obesidad (51,4%) en los pacientes que informaron al menos un episodio de hipoglucemia frente a los que no notificaron hipoglucemia. Sin embargo, no encontramos diferencias estadísticamente significativas al agrupar las categorías en “sobrepeso + obesidad” y “peso saludable”. En el estudio de Álvarez-Guisasola (2008) no encontraron diferencias en el peso entre los pacientes que informaron un episodio de hipoglucemia y los que no lo informaron15. Petterson et al.

(2011) encontraron que los pacientes que no presentaban hipoglucemia o hipoglucemia leve tenían un IMC de 28.8 ± 4.4 frente a 28.5 ± 4.1 en pacientes con hipoglucemia moderada o peor19. Nunes et al. (2017) en un estudio realizado en 143 635 pacientes con diabetes tipo 2 que usaron sulfonilureas, el IMC promedio de la muestra total fue de 32.3 kg/m2. En pacientes con algún evento de hipoglucemia, el IMC fue de 31,7 kg/m2 y en aquellos que no presentaron hipoglu-

LOS OBJETIVOS DEL ESTUDIO FUERON, PRIMERO, EVALUAR LA PREVALENCIA DE HIPOGLUCEMIA EN PACIENTES CON DIABETES MELLITUS TIPO 2 QUE TOMAN SULFONILUREAS EN PUERTO RICO; SEGUNDO, EVALUAR LA PREVALENCIA DE PACIENTES CON DIABETES MELLITUS TIPO 2 EN PUERTO RICO QUE NO ESTÁN EN EL OBJETIVO DE HBA1C DE <7 %; Y TERCERO, EVALUAR EL AUTOCUIDADO, LA CALIDAD DE VIDA Y LA ADHERENCIA GENERAL AL TRATAMIENTO.

cemia, de 32,4 kg/m2. En nuestra muestra fue de 30kg/m2, 31.3 kg/m2 y 29 kg/m2 para el total de participantes, pacientes que informaron hipoglucemia y los que no respectivamente24.

Majanovic et al. (2017) encontraron que un 28,2% informó un aumento de peso en el último año, en nuestro estudio el 23,1% notificó lo mismo 17.

Petterson et al. (2011) encontraron una puntuación del índice EQ-5D no ponderada para toda la muestra de 0.81 ± 0.22 similar a la encontrada por nosotros que fue de 0.82 ± 0.17. En ese estudio agruparon a los pacientes que no habían notificado hipoglucemia con los que informaron hipoglucemia leve. Ambos grupos de pacientes fueron comparados con aquellos que habían notificado una hipoglucemia moderada o peor. La puntuación del índice EQ-5D fue de 0.83 ± 0.21 y 0.75 ± 0.26 respectivamente19. Rombopoulos et al. encontraron que los pacientes que informaron un episodio de hipoglucemia tenían una peor calidad de vida que aquellos que no presentaron ningún evento de hipoglucemia21. Zhang et al. (2010) en su revisión sistemática de la carga de hipoglucemia en pacientes con diabetes tipo 2 encontraron que los pacientes que presentaron algún evento de hipoglucemia tenían valores de

calidad de vida (EQ-5D) más bajos que aquellos que no presentaron ningún evento. También encontraron valores más bajos al evaluar el puntaje de la Escala Visual Analógica25. Marrett et al. (2009) en un estudio basado en Internet y con una muestra de 1984 pacientes con DM2 en tratamiento con agentes antihiperglucemiantes orales encontraron que los pacientes con hipoglucemia informaron una peor puntuación del índice EQ-5D que aquellos que no la presentaron (0,78 frente a 0,86) 26. En nuestro estudio, los valores del índice EQ-5D fueron de 0.85 ± 0.14 y 0.77 ± 0.21 para los pacientes que no informaron hipoglucemia y para aquellos que la notificaron. Respectivamente, otros autores encontraron valores similares a estos; a su vez, las puntuaciones de la Escala Visual Analógica fueron más bajas para los pacientes con hipoglucemia que para los que no la informaron20.

Aproximadamente el 25% de las hospitalizaciones en pacientes de edad avanzada se deben a hipoglucemia 27. Zhang et al. (2010) encontraron un mayor costo médico y una mayor pérdida de días de trabajo.

López et al. (2015) encontraron que en 367 602 pacientes con diabetes tipo 2, beneficiarios de Medicare, el 2,9% de los blancos solicitaron servicios de salud relacionados con eventos de hipoglucemia en comparación con el 3,6% de los hispanos y el 4,7% de los negros, lo que podría generar inequidad en la salud 25,28.

Estos datos refuerzan la importancia de realizar estudios como el que hemos presentado.

Las generalizaciones del presente estudio pueden estar limitadas por las características del tipo de diseño, incluso cuando se trata de un estudio del mundo real. El estudio fue exploratorio con un diseño transversal. La falta de información en Puerto Rico relacionada con los eventos de hipoglucemia en pacientes con diabetes tipo 2 justifica este tipo de estudio con el fin de encontrar respuestas y desarrollar nuevas preguntas que puedan guiar nuevos estudios. Al ser un estudio transversal, no nos permite temporalizar la información obtenida.

No podemos establecer la relación causa-efecto, por ejemplo, en nuestro

Revista Puertorriqueña de Medicina y Salud Pública

37

ARTÍCULO / ORIGINAL estudio, los pacientes que presentaron hipoglucemia tenían un IMC más alto que aquellos que no, mientras que en la literatura encontramos resultados opuestos. Por otro lado, una mayor proporción de pacientes con hipoglucemia informaron haber perdido peso, podríamos plantearnos la siguiente pregunta: ¿los pacientes con hipoglucemia tienen un IMC similar a los que no tienen hipoglucemia y antes de un episodio de hipoglucemia presentan una disminución de peso? Otro tipo de sesgo que podemos encontrar es el de recuerdo. Incluso teniendo en cuenta estas limitaciones, el estudio es de gran importancia porque es el primero de este tipo que se lleva a cabo en Puerto Rico en un entorno del mundo real y proporciona información muy útil para pacientes y médicos. Por ejemplo, encontramos valores altos de triglicéridos y niveles bajos de HDL en pacientes con hipoglucemia que fueron estadísticamente significativos y valores más altos en colesterol, LDL, presión sistólica y diastólica, creatinina y HbA1c también en estos pacientes, con diferencias no estadísticamente significativas.

CONCLUSIONES Como resumen final, podemos decir que la prevalencia de hipoglucemia en pacientes con diabetes mellitus tipo 2 tratados con sulfonilureas en Puerto Rico es similar a la encontrada en la literatura. Los pacientes que informaron un episodio de hipoglucemia tuvieron más limitaciones en la movilidad, más dolor y ansiedad/depresión, lo que evidencia una puntuación más baja de índice calidad de vida. Por último, un gran número de pacientes no tenía la HbA1c controlada.

Tabla 6. Dimensiones EQ

REFERENCIAS

1. IDF Diabetes Atlas 6th Edition. (n.d.). Country Estimates Table 2013. Retrieved from htpp://www.idf. org/atlasmap/atlasmap 2.

Centers for Disease Control and Prevention, CDC. (2019). BRFSS Prevalence & Trends Data [online].

Retrieved Sept. 23, 2019, from https://www.cdc.gov/ brfss/brfssprevalence/ 3. Sánchez-Hernández, E., Morales-González, J. J., Machín-Rivera, S., & Torres-Concepción, K. (2015, Septiembre). Informe de Salud de Puerto Rico 2015. Resumen General de la Salud en Puerto Rico. San Juan, Puerto Rico: Departamento de Salud de Puerto Rico 4. Departamento de Salud (2019). Informe Annual de Estadísticas Vitales: Defunciones, años 2015 y 2016.

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Relationship between blood glucose level and mortality in type 2 diabetes mellitus: a systematic review. Diabetes Med, 16, 2-13.

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G ilet, H., Gruenberg, J., Bader, G., & Viala-Danten, M. (2012). Demonstrating the burden of hypoglycemia on Patients’ Quality of life in Diabetes Clinical Trials: Measurement Considerations for Hypoglycemia. Value in Health , 15, 1036-1041. doi:http:// dx.doi.org/10.1016/j.jval.2012.06.002 7. Real, J., & Carmena, R. (2004). La diabetes tipo 2 o la enfermedad incomprendida. Revista Clínica Española(1), 1-2.

8. American Diabetes Association. (2015). Hypoglycemia (Low Blood Sugar). Retrieved from http://www. diabetes.org/living-with-diabetes/treatment-and-care/ blood-glucose-control/hypoglycemia-low-blood.html 9. Morales, J., & Schneider, D. (2014). Hypoglycemia. The American Journal of Medicine, 127(S17-S24). doi:http://dx.doi.org/10.1016/j.amjmed.2014.07.004 10. US Department of Health and Human Services, N. N. (2008, October). Hypoglycemia. Retrieved from www.diabetes.niddk.nih.gov 11. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of Intensive Glucose Lowering in Type 2 Diabetes. Vol 358; 2008:2545-2559.

12. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. Jan 8 2009;360(2):129-139.

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Patel A, MacMahon S, Chalmers J, et al.

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. Jun 12 2008;358(24):2560-2572.

14. Garber AJ, Abrahamson MJ, Barzilay JI, et al.

AACE Comprehensive Diabetes Management, Endocr Pract. 2013;19(Suppl 2):1-38 15. Alvarez Guisasola F, Tofe Povedano S, Krishnarajah G, Lyu R, Mavros P, Yin D. Hypoglycaemic symptoms, treatment satisfaction, adherence and their associations with glycaemic goal in patients with type 2 diabetes mellitus: findings from the Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) Study. Diabetes Obes Metab. Jun 2008;10 Suppl 1:25-32.

* Diferencia estadísticamente significativa (p<0.05)

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16. Chan, S. P., Ji, L. N., Nitiyanant, W., Baik, S. H., & Sheu, W. H. H. (2010). Hypoglycemic symptoms in patients with type 2 diabetes in Asia-Pacific-Real-life effectiveness and care patterns of diabetes management: The RECAP-DM study.

Diabetes Research and Clinical Practice,89(2).

DOI:10.1016/j.diabres.2010.05.008 17. Majanovic SK . Janez A . Lefterov I . Tasic S .

Cikac T. The Real-Life Effectiveness and Care Patterns of Diabetes Management Study for Balkan Region (Slovenia, Croatia, Serbia, Bulgaria): A Multicenter, Observational, Cross-Sectional Study. Diabetes Ther (2017) 8:929–940. DOI 10.1007/s13300-0170288-x 18. Gonzalez C, et al. Prevalence of hypoglycemia among a sample of sulfonylurea-treated patients with Type 2 diabetes mellitus in Argentina: The real-life effectiveness and care patterns of diabetes management (RECAP-DM) study. Endocrinol Diabetes Nutr. 2018. https://doi.org/10.1016/j. endinu.2018.05.014 19.

Pettersson B, Rosenqvist U, Deleskog A, Journath G, Wändell P.Self-reported experience of hypoglycemia among adults with type 2 diabetes mellitus (Exhype). Diabetes research and clinical practice, 92 (2011): 19-25.

20. Lundkvist J, Berne C, ·Bolinder B, ·Jönsson L. The economic and quality of life impact of hypoglycemia. Eur J Health Econom 2005 · 50:197– 202 DOI 10.1007/s10198-005-0276-3 21.

Rombopoulos G, Hatzikou M, Latsou D, Yfantopoulos J.The prevalence of hypoglycemia and its impact on the quality of life (QoL) of type 2 diabetes mellitus patients (The HYPO Study).

HORMONES 2013, 12(4):550-558 22. Orozco-Beltrán D,Mezquita-Raya P, Ramírez de Arellano A, Galán M. Self-Reported Frequency and Impact of Hypoglycemic Events in Spain. Diabetes Ther (2014) 5:155–168.

DOI 10.1007/s13300-014-0057-z 23. Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC, Gray LJ, Davies MJ, et al. (2015) Prevalence and Incidence of Hypoglycaemia in 532,542 People with Type 2 Diabetes on Oral Therapies and Insulin: A Systematic Review and Meta-Analysis of Population Based Studies. PLoS ONE 10(6): e0126427. doi:10.1371/journal. pone.0126427 24.

Nunes AP, Iglay K, Radican L, Engel SS, Yang J, Doherty MC, Dore DD. Hypoglycaemia seriousness and weight gain as determinants of cardiovascular disease outcomes among sulfonylurea users. Diabetes Obes Metab. 2017;1–11 25.

Zhang Y, Wieffer H, Modha R, Balar B, Pollack M, Krishnarajah G.The Burden of Hypoglycemia in Type 2 Diabetes: A Systematic Review of Patient and Economic Perspectives. JCOM (2010); 17 (12):547-557 26.

M arrett E1, Stargardt T, Mavros P, Alexander CM. Patient-reported outcomes in a survey of patients treated with oral antihyperglycaemic medications: associations with hypoglycaemia and weight gain. Diabetes Obes Metab. 2009 Dec;11(12):1138-44. doi: 10.1111/j.1463-1326.2009.01123.x. Epub 2009 Sep 16.

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A hrén B. Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes. Vascular Health and Risk Management 2013:9 155–163 28.

L opez JM1, Bailey RA1, Rupnow MF. Demographic Disparities Among Medicare Beneficiaries with Type 2 Diabetes Mellitus in 2011: Diabetes Prevalence, Comorbidities, and Hypoglycemia Events. Popul Health Manag. 2015 Aug;18(4):283-9. doi: 10.1089/pop.2014.0115. Epub 2015 Feb 3.

In adults In adults whowho havehave T2D T2D and and diabetic diabetic nephropathy nephropathy (ie, DKD) (ie, DKD) withwith albuminuria albuminuria >300>300 mg/day, mg/day,

INVOKANA® INVOKANA® is the is the onlyonly SGLT2i SGLT2i indicated indicated to slow to slow thethe progression progression of DKD of DKD 1-4 1-4 andand reduce reduce the the risk risk of hospitalization of hospitalization for heart for heart failure failure

INVOKANA® INVOKANA® is theisonly the only T2D therapy T2D therapy approved approved by the byFDA the to FDA reduce to reduce the risk theof risk end-stage of end-stage kidney kidney disease disease (ESKD), (ESKD), doubling doubling of serum of serum creatinine, creatinine, cardiovascular cardiovascular (CV)(CV) death, death, and hospitalization and hospitalization for heart for heart failure failure in adults in adults 1 1 who who havehave T2D and T2Ddiabetic and diabetic nephropathy nephropathy with with albuminuria albuminuria >300>300 mg/day mg/day

In patients In patients withwith DKD*DKD* and T2D and T2D 5 5 The landmark The landmark CREDENCE CREDENCE trial primary trial primary composite composite outcome outcome : : • End-stage • End-stage kidneykidney disease† disease†

(dialysis,(dialysis, transplant, transplant, or eGFR <15) or eGFR <15)

• Doubling • Doubling of serum of serum creatinine creatinine • Renal• death‡ Renal death‡ • CV death • CV death HR=0.70 (95% HR=0.70 CI: 0.59, (95%0.82); CI: 0.59, P=0.00001 0.82); P=0.00001

‡There were ‡There notwere enough not events enoughtoevents evaluate to evaluate the risk of the renal riskdeath of renal (placebo, death (placebo, n=5; n=5; INVOKANA®, INVOKANA®, n=2). INVOKANA® n=2). INVOKANA® is not indicated is not indicated to reduce tothe reduce risk the of renal risk of death. renal death. § § Prespecified Prespecified secondary secondary endpoint. endpoint.

6§ 6§ • Reduced • Reduced risk ofrisk hospitalization of hospitalization for heart for failure heart failure

39% RRR||39% in hospitalization RRR|| in hospitalization for heartfor failure heart failure 1,5 • Proven • Proven safetysafety profileprofile in patients in patients with anwith eGFR anof eGFR 30 toof<90 30 to <901,5

Similar overall SimilarAEs overall withAEs INVOKANA® with INVOKANA® vs placebo vs placebo (35.1 vs 37.9 (35.1per vs 100 37.9 patient-years). per 100 patient-years).

Male Male GMI incidence GMI incidence was 0.84% wasvs0.84% 0.09%vsper 0.09% 100 patient-years, per 100 patient-years, respectively. respectively.

DKA incidence DKA incidence was 0.22% wasvs0.22% 0.02%vsper 0.02% 100 patient-years, per 100 patient-years, respectively. respectively.

No imbalance No imbalance in fracture in fracture or or amputation. amputation.

Hypotension Hypotension incidence incidence was 2.8%was vs 1.5%, 2.8% respectively. vs 1.5%, respectively.

Hypoglycemia Hypoglycemia incidence incidence was 4.43was vs 4.89 4.43per vs 4.89 100 patient-years, per 100 patient-years, respectively. respectively.

LearnLearn moremore at INVOKANAhcp.com. at INVOKANAhcp.com.

INDICATIONS INDICATIONS

Limitations Limitations of Use of Use INVOKANA® INVOKANA® is not recommended is not recommended in patients in patients with type with1 diabetes type 1 diabetes mellitus. mellitus.

INVOKANA® INVOKANA® (canagliflozin) (canagliflozin) is indicated: is indicated: It may increase It may increase the riskthe of diabetic risk of diabetic ketoacidosis ketoacidosis in theseinpatients. these patients.

• as an •adjunct as an adjunct to diet to and diet exercise and exercise to improve to improve glycemic glycemic controlcontrol in adults in adults INVOKANA® INVOKANA® is not recommended is not recommended for usefor to improve use to improve glycemic glycemic controlcontrol with type with2 diabetes type 2 diabetes mellitusmellitus in adults in with adults type with2 diabetes type 2 diabetes mellitusmellitus with anwith eGFR anless eGFR than less30than mL/30 mL/ • to reduce • to reduce the riskthe of major risk of adverse major adverse cardiovascular cardiovascular eventsevents (cardiovascular (cardiovascular is likelyistolikely be ineffective to be ineffective in this setting in this setting based based min/1.73 min/1.73 m2. INVOKANA® m2. INVOKANA® death, death, nonfatal nonfatal myocardial myocardial infarction, infarction, and nonfatal and nonfatal stroke)stroke) in adults in with adults with upon its upon mechanism its mechanism of action. of action. type 2 diabetes type 2 diabetes mellitusmellitus and established and established cardiovascular cardiovascular diseasedisease (CVD) (CVD) • to reduce • to reduce the riskthe of end-stage risk of end-stage kidneykidney diseasedisease (ESKD),(ESKD), doubling doubling of serum of serum creatinine, creatinine, cardiovascular cardiovascular (CV) death, (CV) death, and hospitalization and hospitalization for heart forfailure heart failure in adults in with adults type with2 diabetes type 2 diabetes mellitusmellitus and diabetic and diabetic nephropathy nephropathy with with albuminuria albuminuria greatergreater than 300 than mg/day 300 mg/day

IMPORTANT IMPORTANT SAFETY SAFETY INFORMATION INFORMATION trials evaluating trials evaluating patients patients with type with2 type diabetes 2 diabetes who had who either had either established established CONTRAINDICATIONS CONTRAINDICATIONS cardiovascular diseasedisease or wereoratwere risk at forrisk cardiovascular for cardiovascular disease.disease.

The risk The risk • Serious • Serious hypersensitivity hypersensitivity reaction reaction to INVOKANA®, to INVOKANA®, such assuch anaphylaxis as anaphylaxis or or cardiovascular of lower-limb of lower-limb amputations amputations was observed was observed at bothatthe both 100-mg the 100-mg and 300-mg and 300-mg angioedema angioedema once-daily once-daily dosagedosage regimens. regimens.

• Patients • Patients on dialysis on dialysis WARNINGS WARNINGS AND PRECAUTIONS AND PRECAUTIONS • Lower-Limb • Lower-Limb Amputation: Amputation: An increased An increased risk of risk lower-limb of lower-limb amputations amputations associated associated with INVOKANA® with INVOKANA® use versus use versus placebo placebo was observed was observed in CANVAS in CANVAS (5.9 vs(5.9 2.8 vsevents 2.8 events per 1000 per patient-years) 1000 patient-years) and CANVAS-R and CANVAS-R (7.5 vs(7.5 4.2 vs 4.2 eventsevents per 1000 per patient-years), 1000 patient-years), two randomized, two randomized, placebo-controlled placebo-controlled

PleasePlease read additional read additional Important Important SafetySafety Information Information and Brief andSummary Brief Summary of full of full Prescribing Prescribing Information Information for INVOKANA®, for INVOKANA®, on theon following the following pages.pages.

AE=adverse AE=adverse event; CREDENCE=Canagliflozin event; CREDENCE=Canagliflozin and Renaland Events Renal in Events in Diabetes with Diabetes Established with Established Nephropathy Nephropathy Clinical Evaluation; Clinical Evaluation; DKA=diabetic DKA=diabetic References: References: 1. INVOKANA® 1. INVOKANA® [prescribing [prescribing information]. information].

Titusville,Titusville, NJ: Janssen NJ: Pharmaceuticals, Janssen Pharmaceuticals, Inc. 2. Jardiance® Inc. 2. Jardiance® ketoacidosis; ketoacidosis; DKD=diabetic DKD=diabetic kidney disease; kidneyGMI=genital disease; GMI=genital mycotic infection; mycotic infection; [prescribing [prescribing information]. information].

Ridgefield, Ridgefield, CT: Boehringer CT: Boehringer Ingelheim Ingelheim Pharmaceuticals, Pharmaceuticals, Inc. 3. Farxiga® Inc. 3. Farxiga® [prescribing [prescribing information]. information].

HR=hazard HR=hazard ratio; RRR=relative ratio; RRR=relative risk reduction; risk reduction; SGLT2i=sodium-glucose SGLT2i=sodium-glucose TM TM Wilmington, Wilmington, DE: AstraZeneca DE: AstraZeneca Pharmaceuticals Pharmaceuticals LP. 4.

Steglatro LP. 4.

Steglatro [prescribing [prescribing information]. information].

Whitehouse Whitehouse Station, NJ: Station, Merck NJ: Merck co-transporter co-transporter 2 inhibitor;2 inhibitor; T2D=typeT2D=type 2 diabetes.2 diabetes.

Sharp & Dohme Sharp &Corp., Dohmea subsidiary Corp., a subsidiary of Merckof&Merck Co., Inc. & Co., 5. Perkovic Inc. 5. Perkovic V, Jardine V,MJ, Jardine NealMJ, B, etNeal al. Canagliflozin B, et al. Canagliflozin and renaland renal eGFR is measured eGFR is measured in mL/min/1.73 in mL/min/1.73 m2. m2. outcomes outcomes in type 2in diabetes type 2 diabetes and nephropathy. and nephropathy.

N Engl J N Med. Engl2019;380(24):2295-2306.

J Med. 2019;380(24):2295-2306.

Supplementary Supplementary appendixappendix availableavailable *With albuminuria *With albuminuria >300 mg/day. >300 mg/day. at: doi:10.1056/NEJMoa1811744.

6. Mahaffey 6. Mahaffey KW, Jardine KW,MJ, Jardine Bompoint MJ, Bompoint S, et al. Canagliflozin S, et al. Canagliflozin and cardiovascular and cardiovascular and renaland renal †End-stage†End-stage kidney disease kidney was disease defined wasasdefined dialysis as fordialysis ≥30 days, for ≥30 kidney days, kidney at: doi:10.1056/NEJMoa1811744. outcomes in type 2in diabetes type 2 diabetes mellitus and mellitus chronic and kidney chronicdisease kidneyindisease primary in and primary secondary and secondary cardiovascular cardiovascular prevention prevention transplantation, transplantation, or an eGFRor<15 an mL/min/1.73 eGFR <15 mL/min/1.73 m2 sustained m2 sustained for ≥30 days. for ≥30 days.outcomes || || groups. Circulation. groups. Circulation.

2019;140(9):739-750.

2019;140(9):739-750.

RRR was calculated RRR was calculated using the following using the formula: following100 formula: x (1–HR).

100 x (1–HR).

IMPORTANT SAFETY INFORMATION (cont'd)

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2020

October 2020

cp-122493v3

• Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with INVOKANA®; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKANA®, treat, and monitor until signs and symptoms resolve.

• Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA®. Prior to initiation, consider factors that contribute to fracture risk.

DRUG INTERACTIONS • UGT Enzyme Inducers: Co-administration with rifampin lowered INVOKANA® exposure, which may reduce the efficacy of INVOKANA®.

For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA®, increase the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA® 100 mg. The dose may be increased to 300 mg once daily in patients currently tolerating INVOKANA® 200 mg and who require additional glycemic control.

For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is coadministered with INVOKANA®, increase the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA® 100 mg. Consider adding another antihyperglycemic agent in patients who require additional glycemic control.

• Digoxin: There was an increase in the AUC and mean peak drug concentration of digoxin when co-administered with INVOKANA® 300 mg. Monitor appropriately.

• Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

• Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

USE IN SPECIFIC POPULATIONS • Pregnancy: INVOKANA® is not recommended in pregnant women, especially during the second and third trimesters.

• Lactation: INVOKANA® is not recommended while breastfeeding.

• Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established.

• Geriatric Use: Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300-mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years.

• Renal Impairment: The efficacy and safety of INVOKANA® for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using INVOKANA® for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury. INVOKANA® is contraindicated in patients with ESKD on dialysis.

• Hepatic Impairment: INVOKANA® has not been studied in patients with severe hepatic impairment and is not recommended in this population.

OVERDOSAGE • In the event of an overdose, contact the Poison Control Center and employ the usual supportive measures.

ADVERSE REACTIONS • The most common adverse reactions associated with INVOKANA® (5% or greater incidence) were female genital mycotic infections, urinary tract infections, and increased urination.

cp-68813v5

WARNINGS AND PRECAUTIONS (cont'd) • Lower-Limb Amputation: (cont'd) Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA® in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA® in the two trials). Some patients had multiple amputations, some involving both lower limbs.

Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

Before initiating INVOKANA®, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.

• Volume Depletion: INVOKANA® can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®.

Patients with impaired renal function (eGFR less than 60 mL/min/ 1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA® in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.

• Ketoacidosis: Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been identified in patients with type 1 and 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®.

In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. The risk of ketoacidosis may be greater with higher doses. Fatal cases of ketoacidosis have been reported in patients taking INVOKANA®. Before initiating INVOKANA®, consider factors in patient history that may predispose to ketoacidosis.

For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKANA® for at least 3 days prior to surgery. Monitor for ketoacidosis and temporarily discontinue in other clinical situations known to predispose to ketoacidosis. Ensure risk factors for ketoacidosis are resolved prior to restarting therapy. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKANA® and seek medical attention immediately if signs and symptoms occur.

• Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including INVOKANA®.

Treatment with SGLT2 inhibitors increases this risk. Evaluate for signs and symptoms and treat promptly.

• Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA® may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA®.

• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and lifethreatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement.

Discontinue INVOKANA®.

• Genital Mycotic Infections: INVOKANA® increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.

Please read Brief Summary of full Prescribing Information for INVOKANA®, on the following pages.

INVOKANA®

(canagliflozin) tablets, for oral use Brief Summary of Prescribing Information.

INDICATIONS AND USAGE INVOKANA (canagliflozin) is indicated: • as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).

• to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

Limitations of Use INVOKANA is not recommended in patients with type 1 diabetes mellitus.

It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions].

INVOKANA is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2.

INVOKANA is likely to be ineffective in this setting based upon its mechanism of action.

CONTRAINDICATIONS • Serious hypersensitivity reaction to INVOKANA, such as anaphylaxis or angioedema [see Warnings and Precautions and Adverse Reactions].

• Patients on dialysis [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Lower Limb Amputation: An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Adverse Reactions].

Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA in the two trials). Some patients had multiple amputations, some involving both lower limbs.

Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation.

The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

Before initiating INVOKANA, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur.

Volume Depletion: INVOKANA can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions]. There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.

Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including INVOKANA. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. The risk of ketoacidosis may be greater with higher doses. Fatal cases of ketoacidosis have been reported in patients taking INVOKANA. INVOKANA is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage].

INVOKANA® (canagliflozin) tablets Patients treated with INVOKANA who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with INVOKANA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, INVOKANA should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating INVOKANA, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.

For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKANA for at least 3 days prior to surgery [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information].

Consider monitoring for ketoacidosis and temporarily discontinuing INVOKANA in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting INVOKANA. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKANA and seek medical attention immediately if signs and symptoms occur.

Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including INVOKANA. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions].

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia.

INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with INVOKANA presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately.

Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with INVOKANA. These reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions].

Bone Fracture: An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA in the CANVAS trial [see Clinical Studies (14.2) in Full Prescribing Information]. Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions].

INVOKANA® (canagliflozin) tablets

INVOKANA® (canagliflozin) tablets

ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: • Lower Limb Amputation [see Warnings and Precautions] • Volume Depletion [see Warnings and Precautions] • Ketoacidosis [see Warnings and Precautions] • Urosepsis and Pyelonephritis [see Warnings and Precautions] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] • Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) [see Warnings and Precautions] • Genital Mycotic Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Bone Fracture [see Warnings and Precautions] Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Pool of Placebo-Controlled Trials for Glycemic Control: The data in Table 1 is derived from four 26-week placebo-controlled trials where INVOKANA was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age.

Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2).

Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg.

Table 1: Adverse Reactions from Pool of Four 26−Week Placebo-Controlled Studies Reported in ≥ 2% of INVOKANA-Treated Patients*

• The rate of lower limb amputations associated with the use of INVOKANA 100 mg relative to placebo was 12.3 vs 11.2 events per 1000 patient-years, respectively, with 2.6 years mean duration of follow-up.

• Incidence rates of adjudicated events of diabetic ketoacidosis (DKA) were 0.21 (0.5%, 12/2,200) and 0.03 (0.1%, 2/2,197) per 100 patient-years of follow-up with INVOKANA 100 mg and placebo, respectively.

• The incidence of hypotension was 2.8% and 1.5% on INVOKANA 100 mg and placebo, respectively.

Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes: The occurrence of adverse reactions for INVOKANA was evaluated in patients participating in placebo- and activecontrolled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R. The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 patients to INVOKANA) were consistent with those listed in Table 1. Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively).

In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.

In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated.

Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.

Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Lower Limb Amputation: An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.2) in Full Prescribing Information]. The amputation data for CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively.

Table 2: CANVAS Amputations

Placebo N=646

INVOKANA 100 mg N=833

INVOKANA 300 mg N=834

Urinary tract infections‡

3.8%

5.9%

4.4%

Increased urination§

0.7%

5.1%

4.6%

Thirst#

0.1%

2.8%

2.4%

Constipation

0.9%

1.8%

2.4%

Nausea

1.6%

2.1%

2.3%

N=312

N=425

N=430

Female genital mycotic infections†

2.8%

10.6%

11.6%

Vulvovaginal pruritus

0.0%

1.6%

3.2%

N=334

N=408

N=404

0.7%

4.2%

3.8%

Adverse Reaction

Male genital mycotic infections¶

* The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. ‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.

Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes.

Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).

Placebo-Controlled Trial in Diabetic Nephropathy: The occurrence of adverse reactions for INVOKANA was evaluated in patients participating in CREDENCE, a study in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria > 300 mg/day [see Clinical Studies (14.3) in Full Prescribing Information]. These data reflect exposure of 2,201 patients to INVOKANA and a mean duration of exposure to INVOKANA of 137 weeks.

Patients with an amputation, n (%) Total amputations Amputation incidence rate (per 1000 patient-years) Hazard Ratio (95% CI)

Placebo N=1441

INVOKANA 100 mg N=1445

INVOKANA 300 mg N=1441

INVOKANA (Pooled) N=2886

22 (1.5)

50 (3.5)

45 (3.1)

95 (3.3)

33

83

79

162

2.8

6.2

5.5

5.9

--

2.24 (1.36, 3.69)

2.01 (1.20, 3.34)

2.12 (1.34, 3.38)

Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

Table 3: CANVAS-R Amputations

25 (0.9) 36

INVOKANA 100 mg (with up-titration to 300 mg) N=2904 45 (1.5) 59

4.2

7.5

--

1.80 (1.10, 2.93)

Placebo N=2903 Patients with an amputation, n (%) Total amputations Amputation incidence rate (per 1000 patient-years) Hazard Ratio (95% CI)

Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

INVOKANA® (canagliflozin) tablets

INVOKANA® (canagliflozin) tablets

Renal Cell Carcinoma: In the CANVAS trial (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.2) in Full Prescribing Information], the incidence of renal cell carcinoma was 0.15% (2/1331) and 0.29% (8/2716) for placebo and INVOKANA, respectively, excluding patients with less than 6 months of follow-up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to INVOKANA could not be established due to the limited number of cases.

Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume.

In clinical trials for glycemic control, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 4) [see Use in Specific Populations].

Table 4: Proportion of Patients With at Least One Volume DepletionRelated Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control)

Table 5: Incidence of Hypoglycemia* in Randomized Clinical Studies of Glycemic Control

Baseline Characteristic Overall population 75 years of age and older† eGFR less than 60 mL/min/1.73 m2† Use of loop diuretic†

Comparator Group* % 1.5% 2.6% 2.5% 4.7%

INVOKANA 100 mg % 2.3% 4.9% 4.7% 3.2%

INVOKANA 300 mg % 3.4% 8.7% 8.1% 8.8%

* Includes placebo and active-comparator groups † Patients could have more than 1 of the listed risk factors Falls: In a pool of nine clinical trials with mean duration of exposure to INVOKANA of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The higher risk of falls for patients treated with INVOKANA was observed within the first few weeks of treatment.

Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and INVOKANA, respectively.

In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and INVOKANA, respectively.

In the pooled analysis of 8 randomized trials evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis.

Hypoglycemia: In all glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control [see Clinical Studies (14.1) in Full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 5).

Monotherapy (26 weeks) Overall [N (%)] In Combination with Metformin (26 weeks) Overall [N (%)] Severe [N (%)]† In Combination with Metformin (52 weeks) Overall [N (%)] Severe [N (%)]† In Combination with Sulfonylurea (18 weeks) Overall [N (%)] In Combination with Metformin + Sulfonylurea (26 weeks) Overall [N (%)] Severe [N (%)]† In Combination with Metformin + Sulfonylurea (52 weeks) Overall [N (%)] Severe [N (%)]† In Combination with Metformin + Pioglitazone (26 weeks) Overall [N (%)] In Combination with Insulin (18 weeks) Overall [N (%)] Severe [N (%)]†

Placebo (N=192) 5 (2.6) Placebo + Metformin (N=183)

INVOKANA 100 mg (N=195) 7 (3.6) INVOKANA 100 mg + Metformin (N=368)

INVOKANA 300 mg (N=197) 6 (3.0) INVOKANA 300 mg + Metformin (N=367)

3 (1.6) 0 (0) Glimepiride + Metformin (N=482) 165 (34.2) 15 (3.1) Placebo + Sulfonylurea (N=69) 4 (5.8) Placebo + Metformin + Sulfonylurea (N=156) 24 (15.4) 1 (0.6) Sitagliptin + Metformin + Sulfonylurea (N=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (N=115) 3 (2.6)

16 (4.3) 1 (0.3) INVOKANA 100 mg + Metformin (N=483) 27 (5.6) 2 (0.4) INVOKANA 100 mg + Sulfonylurea (N=74) 3 (4.1) INVOKANA 100 mg + Metformin + Sulfonylurea (N=157) 43 (27.4) 1 (0.6)

INVOKANA 100 mg + Metformin + Pioglitazone (N=113) 3 (2.7)

17 (4.6) 1 (0.3) INVOKANA 300 mg + Metformin (N=485) 24 (4.9) 3 (0.6) INVOKANA 300 mg + Sulfonylurea (N=72) 9 (12.5) INVOKANA 300 mg + Metformin + Sulfonylurea (N=156) 47 (30.1) 0 INVOKANA 300 mg + Metformin + Sulfonylurea (N=377) 163 (43.2) 15 (4.0) INVOKANA 300 mg + Metformin + Pioglitazone (N=114) 6 (5.3)

Placebo (N=565) 208 (36.8) 14 (2.5)

INVOKANA 100 mg (N=566) 279 (49.3) 10 (1.8)

INVOKANA 300 mg (N=587) 285 (48.6) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Bone Fracture: In the CANVAS trial [see Clinical Studies (14.2) in Full Prescribing Information], the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities.

Laboratory and Imaging Tests: Increases in Serum Creatinine and Decreases in eGFR: Initiation of INVOKANA causes an increase in serum creatinine and decrease in estimated GFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes.

Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Clinical Pharmacology (12.1) in Full Prescribing Information]. The acute effect on eGFR reverses after treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with INVOKANA. Increases in Serum Potassium: In a pooled population of patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with INVOKANA 100 mg, and 1.3% of patients treated with INVOKANA 300 mg.

INVOKANA® (canagliflozin) tablets

INVOKANA® (canagliflozin) tablets

In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensinconverting-enzyme inhibitors, and angiotensin-receptor blockers [see Use in Specific Populations].

In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed with INVOKANA 100 mg relative to placebo.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-HighDensity Lipoprotein Cholesterol (non-HDL-C): In the pool of four glycemic control placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups.

Dose-related increases in non-HDL-C with INVOKANA were observed.

Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.

Increases in Hemoglobin: In the pool of four placebo-controlled trials of glycemic control, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal.

Decreases in Bone Mineral Density: Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.1) in Full Prescribing Information]. At 2 years, patients randomized to INVOKANA 100 mg and INVOKANA 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both INVOKANA doses and 0.4% at the distal forearm for patients randomized to INVOKANA 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to INVOKANA 100 mg was 0%.

Postmarketing Experience: Additional adverse reactions have been identified during post-approval use of INVOKANA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ketoacidosis Acute Kidney Injury Anaphylaxis, Angioedema Urosepsis and Pyelonephritis Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) DRUG INTERACTIONS UGT Enzyme Inducers: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy.

For patients with eGFR 60 mL/min/1.73 m2 or greater, if an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA, increase the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA 100 mg. The dose may be increased to 300 mg once daily in patients currently tolerating INVOKANA 200 mg and who require additional glycemic control.

For patients with eGFR less than 60 mL/min/1.73 m2, if an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA, increase the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA 100 mg. Consider adding another antihyperglycemic agent in patients who require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in Full Prescribing Information].

Digoxin: There was an increase in the AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.

Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary: Based on animal data showing adverse renal effects, INVOKANA is not recommended during the second and third trimesters of pregnancy.

Limited data with INVOKANA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage.

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5-times the 300 mg clinical dose, based on AUC. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1C >7 and has been reported to be as high as 20-25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations: Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Animal Data: Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.

In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC. Lactation: Risk Summary: There is no information regarding the presence of INVOKANA in human milk, the effects on the breastfed infant, or the effects on milk production. Canagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKANA is not recommended while breastfeeding.

Data: Animal Data: Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established.

Geriatric Use: In 13 clinical trials of INVOKANA, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to INVOKANA [see Clinical Studies (14.1) in Full Prescribing Information].

Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger

INVOKANA® (canagliflozin) tablets

INVOKANA® (canagliflozin) tablets

patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in Full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo).

Renal Impairment: The efficacy and safety of INVOKANA for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.1) in Full Prescribing Information]. These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of study.

Patients with renal impairment using INVOKANA for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions].

Efficacy and safety studies with INVOKANA did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. INVOKANA is contraindicated in patients with ESKD on dialysis [see Contraindications and Clinical Pharmacology (12.1) in Full Prescribing Information].

Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in Full Prescribing Information].

OVERDOSAGE In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

Lower Limb Amputation: Inform patients that INVOKANA is associated with an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions].

Volume Depletion: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Ketoacidosis: Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of INVOKANA, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue INVOKANA and seek medical attention immediately [see Warnings and Precautions].

Serious Urinary Tract Infections: Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions].

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with INVOKANA. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions].

Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].

Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions, such as urticaria, rash, anaphylaxis, and angioedema, have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions].

Bone Fracture: Inform patients that bone fractures have been reported in patients taking INVOKANA. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions].

Pregnancy: Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with INVOKANA [see Use in Specific Populations]. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.

Lactation: Advise women that breastfeeding is not recommended during treatment with INVOKANA [see Use in Specific Populations].

Laboratory Tests: Inform patients that due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine [see Drug Interactions].

Missed Dose: If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time.

Active ingredient made in Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from Mitsubishi Tanabe Pharma Corporation © 2013 - 2019 Janssen Pharmaceutical Companies cp-109200v3

PROTAGONISTAS

CAMBIO

DEL

Ileana Quiñones vicepresidenta y gerente general de iPR Pharmaceuticals (AstraZeneca) y presidenta entrante de PIA

Wendy Perry, presidenta saliente de PIA y gerente general de la operación comercial de Merck

De izquierda a derecha: Iván Román, asesor de la junta de directores de PIA David Thompson, director de operaciones de AbbVie Biotechnology Gail Towers Nolan, principal oficial de estrategia de Invest Puerto Rico Dra. Amarilys Silva, directora ejecutiva del PRCCI Iván Lugo, director ejecutivo de INDUNIV Víctor Cruz, vicepresidente y gerente general de Eli Lilly) Rafael Castro, vicepresidente de operaciones de PIA Alejandro Drevón, vicepresidente y gerente general de operaciones comerciales de AbbVie

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PUERTO RICO, PUEDE DIRIGIRSE A LA META DE RETOMAR SU ROL TRASCENDENTAL COMO REFERENTE MUNDIAL FARMACÉUTICO Y DE DISPOSITIVOS MÉDICOS, OBJETIVO APOYADO POR LAS AUTORIDADES DE LOS EE.UU. PARA REDUCIR LA DEPENDENCIA DE CHINA, EN UNA PANDEMIA QUE HA HECHO QUE ALGUNAS FARMACÉUTICAS PIENSEN EN APOSTAR POR LA ISLA PARA MANUFACTURAR PRODUCTOS CONTRA EL COVID-19.

• Pilares de la industria farmacéutica • Ciencia e innovación detrás del PRCCI • ¿Qué son los tratamientos biológicos en el cuerpo?

• La industria farmacéutica en Puerto Rico • Unidos por la exportación mundial de productos manufacturados en Puerto Rico • Red biotecnológica con impacto en la formación de profesionales en Puerto Rico Revista Puertorriqueña de Medicina y Salud Pública

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SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

Pilares de la industria farmaceútica Por Luis Penchi Agencia Latina de Noticias de Medicina y Salud Pública

n estudio comparativo sobre la industria farmacéutica a nivel internacional que se publicó en febrero, posicionó a Puerto Rico como uno de los mejores destinos para inversión. La Isla es ya el centro de un programa piloto de interconexión digital que permitirá un rastreo de producción manufacturera y de la creación de pruebas de detección para Covid19 y otros productos relacionados con la pandemia.

Los hallazgos del estudio y otras gestiones podrían producir “un regreso a casa” del talento que se ha ido del país, pero podría retornar en medio de un proceso en que Estados Unidos busca el regreso de producción farmacéutica crítica que escapó al extranjero.

Gail Towers, principal oficial de estrategia de Invest Puerto Rico que se dedica a promover inversiones para la Isla, dijo a la Revista de Medicina y Salud Pública (MSP) que las perspectivas en ese sentido sobre esta jurisdicción son positivas dado a que ya se iniciaron conversaciones con el nuevo gobierno entrante para canalizar y seguir ese camino.

Towers apuntó que varias empresas establecidas localmente están trabajando con productos antivirales que permitirán combatir el Covid19 y otras

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enfermedades. Además, se anticipa un desarrollo de productos regenerativos desde el punto de vista genético y la biotecnología, que son según dijo, el futuro de la medicina.

Se anticipa que la Isla será un centro de terapias genéticas que promoverán además el turismo médico.

Towers apuntó que continuará conversaciones ya iniciadas con la Universidad de Puerto Rico (UPR) para que esa institución se enfoque en la industria, estimule más la investigación científica y evite la fuga de talentos que la Isla ha experimentado.

“Le llamamos a este proceso uno de polinización en la industria. Como las abejas distribuyen su producto, así está pasando con gente de aquí que está distribuyendo su conocimiento pero después va a regresar”, puntualizó.

Towers sostuvo que su organización está optimista sobre los resultados del estudio que se realiza junto con la Asociación de Industrias Farmacéuticas de Puerto Rico (PIA).

La ejecutiva aseguró que la percepción sobre la condición de la industria y la impresión de que hay plantas dejando la Isla no se corresponde con la realidad.

Agregó que a pesar de que esa percepción ha sido dominante en los pasados 10 o 12 años, lo que ha ocurrido realmente es que han habido resultados positivos en los cambios que se han experimentado, por ejemplo, en la automatización en la producción.

“Los productos se están logrando de manera más eficiente y la línea de producción aquí es muy buena, lo que es una diferencia comparativa que es ventajosa”, explicó Towers. Sobre el estudio, Towers explicó que el mismo comparará a Puerto Rico globalmente con empresas nacionales en Estados Unidos. El análisis incluirá el respaldo académico que tiene la industria y el desarrollo de una adecuada cultura. El estudio incluirá experiencias de los pasados diez años.

SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

En la actualidad, Puerto Rico es un área ideal para el restablecimiento de industrias farmacéuticas que se han movido al exterior. “Con los niveles actuales de costo que mantiene la Isla, que son muy razonables, y el perfil de destrezas tan alto que tiene la Isla, esta es una opción lógica de inversión”.

Estas posibilidades se amplían con la aprobación de una legislación federal que permitirá a la Isla convertirse en un punto de distribución no solo para América del Norte, sino incluso para América del Sur. Explicó que el estatuto permitirá la distribución de productos de manufactura europea respaldados desde Bruselas.

Añadió que un ejemplo sobre las posibilidades específicas de la Isla incluyen la producción y el mercadeo de mascarillas que se producen a un costo muy bajo en Asia, pero este se encarece cuando hay que emplear el producto de manera sellada e higienizada.

Un producto de este tipo cuya manufactura sea finalizada de manera higiénica en la Isla tendrá el sello de hecho en Estados Unidos, lo que mejorará sus posibilidades de venta, según expuso.

En términos de empleos, industria farmacéutica genera más de 68,000 puestos de trabajo indirectos e inducidos en el resto de la economía. https://piapr.org/

Hay productos que pueden ser clasificados en la categoría de críticos a nivel clínico, que requieren que todas sus partes sean ensambladas de manera correcta.

“Si una parte de este tipo de producto no es conectado correctamente puede ocasionar la muerte de un paciente”. Esa es la parte del proceso que beneficiará a Puerto Rico porque el trabajo final del producto se hará aquí y esto dará más confianza a la Administración de Alimentos y Medicamentos de los Estados Unidos (FDA) para su aprobación, estipuló.

La Isla además participará de manera prioritaria en una cadena de conexión digital tipo 5G que comunicará laboratorios en Texas, Indianápolis, Purdue y Hawaii.

La cadena rastreará la producción y conectará información fundamental.

De esta manera, Puerto Rico se convertirá en el plan piloto

nacional para el uso de tecnología de comunicación en el proceso productivo, lo que le proporcionará una ventaja global.

Al presente, la Isla tiene varias empresas elaborando pruebas anti-Covid y otros productos relacionados con la lucha contra la pandemia, al tiempo que Towers admitió que la industria farmacéutica está en plena evolución con la producción y distribución de vacunas.

Explicó que anteriormente este tipo de industria se basaba en productos químicos, pero ahora las 200 versiones de vacuna anti Covid se han concentrado en biotecnología.

“La necesidad de una mayor sofisticación de estos productos no va a terminar cuando termine la actual emergencia de la pandemia”, concluyó.

Gail Towers Nolan Principal Oficial de Estrategia de Invest Puerto Rico

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SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

Ciencia e innovación detrás del PRCCI Por Luis Penchi Agencia Latina de Noticias de Medicina y Salud Pública

El Consorcio de Investigación Clínica de Puerto Rico (PRCCI, por sus siglas en inglés), adscrito al Fideicomiso de Ciencias, Tecnología e Investigación de Puerto Rico, continúa con la tarea de la promoción y expansión de Puerto Rico como centro de ensayos clínicos para obtener resultados positivos para la economía, la clase médica y los pacientes.

El PRCCI está actualmente a cargo de la Dra. Amarilys Silva como directora ejecutiva y responsable de promover la investigación clínica en la Isla.

En entrevista con Medicina y Salud Pública (MSP), la doctora Amarilys Silva habló sobre la labor de este consorcio de investigación en beneficio de los avances de distintos tratamientos tanto para la Isla como el mundo.

Dra. Amarilys Silva Directora Ejecutiva del PRCCI

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La industria farmacéutica representa el 25% del Producto Interno Bruto de la Isla. En el 2019, las exportaciones de Puerto Rico en la industria farmacéutica representaron alrededor del 60% de todos los productos exportados. https://piapr.org

¿Cuál es la función del Consorcio de Investigación Clínica de Puerto Rico?

Es una fundación sin fines de lucro adscrita al Fideicomiso de Ciencias, Tecnología e Investigación de Puerto Rico. Somos una subsidiaria.

Nosotros operamos bajo nuestra compañía matriz que es el Fideicomiso. El Consorcio fue fundado con el propósito de investigar cuáles eran las necesidades en Puerto Rico a nivel de investigación clínica y sus capacidades. Se crea con la misión de expandir la investigación clínica de la Isla y con la visión de que Puerto Rico se convierta un lugar ideal para conducir estudios clínicos en hispanos a nivel global.

Por su parte, el Fideicomiso de Ciencias, Tecnología e Investigación de Puerto Rico, según la Ley Pública 214, es una organización sin fines de lucro creada en el 2004 para impulsar la participación y creación de empleos de la Isla en la economía global del conocimiento al promover la inversión y el financiamiento de la investigación y el desarrollo de la ciencia y la tecnología.

El Fideicomiso invierte, facilita y aumenta la capacidad de avanzar continuamente la economía de Puerto Rico y el bienestar de los ciudadanos mediante empresas

basadas en la innovación, la ciencia, la tecnología y su base industrial.

Ha creado 18 programas con 200 empleados en las áreas estratégicas de investigación y desarrollo, salud pública y emprendimiento. ¿Quiénes son parte del Consorcio de Investigación Clínica de Puerto Rico?

Es una red de centros de investigación que incluye centros hospitalarios, entidades académicas y también otros centros privados especializados. Nosotros enlazamos todos estos centros, que en este momento son 28, y los promovemos y le damos visibilidad de esta capacidad que tiene nuestro país a las farmacéuticas fuera de Puerto Rico. ¿Cuántos protocolos tienen activos?

Son más de 300 oportunidades en este momento las que se han logrado promover. Por el virus del COVID-19, son muchas las investigaciones que se centran en la pandemia.

Muchas de estas se apoyan para los pacientes que se encuentran hospitalizados por condiciones severas por el coronavirus, pero también hay varias investigaciones clínicas para pacientes ambulatorios.

SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

Estas investigaciones también apoyan avances en todas las afecciones que tengan alta prevalencia en Puerto Rico, como en el área oncológica.

Lo que buscamos es alinear todos estos estudios para las enfermedades para crear avances en las condiciones con más alta incidencia en Puerto Rico, como lo son también las enfermedades cardiovasculares, diabetes y enfermedades inflamatorias, entre otras. ¿Cómo es el proceso para solicitar el apoyo del PRCCI?

El Fideicomiso entrelaza las compañías farmacéuticas con los centros de investigación.

Se manejan los procesos administrativos relacionados y se promueven los centros de investigación fuera de la Isla para que estos centros y las capacidades sean conocidos a nivel global. De esta manera pueden ser utilizados para conducir las investigaciones, que vienen en su mayoría de las industrias farmacéuticas, que tienen muchos de sus grupos de investigación fuera de Puerto Rico. ¿Cuál ha sido el área de investigación que usted considere de más avance?

Con los programas de las investigaciones, una de las áreas más significativas que ha tenido grandes avances con estos estudios ha sido en pacientes con psoriasis, ya que en estos pacientes decae su calidad de vida tanto física como psicológica y con

estos estudios clínicos se ha logrado poder mejorar sus condiciones de vida.

Por una parte están las industrias farmacéuticas, después los centros de investigación, pero en el centro están los pacientes. Nosotros lo que hacemos es enlazarlos desde el punto de vista de calidad y regulatorio, y asegurarnos de que todos los procesos se completen, de manera tal que ese estudio comience, que se dé muy bien desde el punto de vista regulatorio y que nuestros investigadores pue dan participar en publicaciones y tengan la oportunidad de seguir participando en otros estudios clínicos que puedan llegar. ¿Ofrecen servicios directamente a pacientes?

Parte de los servicios que el Fideicomiso provee es la asistencia de reclutamiento de pacientes o estrategias de reclutamiento en las que se trabaja con un grupo de pacientes en Puerto Rico. Por esto se educa al paciente acerca de lo que es la investigación clínica, el por qué estar en una investigación clínica y los beneficios que puede llegar a tener al participar en ella.

Es importante resaltar que estos estudios clínicos pueden ayudar a muchos pacientes que no tienen otra oportunidad para su vida y llega a ser su única esperanza para poder sobrevivir a la afección que padecen.

El PRCCI es una red de centros de investigación que incluye centros hospitalarios, entidades académicas y también otros centros privados especializados.

Hasta el momento son 28 los centros que se promueven a las farmacéuticas fuera de Puerto Rico.

Promueve protocolos clínicos en condiciones de mayor incidencia en Puerto Rico, como las enfermedades cardiovasculares, diabetes, enfermedades inflamatorias y COVID19, entre otras.

Es una fundación sin fines de lucro adscrita al Fideicomiso de Ciencias, Tecnología e Investigación de Puerto Rico.

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SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

La Industria farmacéutica en Puerto Rico Y SU APORTE A LA VANGUARDIA MUNDIAL DE LOS MEDICAMENTOS POR MÁS DE SEIS DÉCADAS

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Iván Lugo Director Ejecutivo de INDUNIV

SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

La industria farmacéutica de Puerto Rico lleva más de 60 años desde que se establecieron las primeras facilidades de manufactura en la isla, y esta ha llegado a ocupar uno de los cinco primeros lugares tanto en la manufactura de medicamentos y productos, como en el desarrollo de la biotecnología.

Una tercera parte de nuestra economía depende de la industria farmacéutica en la Isla, de esta manera el director ejecutivo del “Industr y Universit y Research Center”, entidad sin fines de lucro que reúne al sector privado, la academia y al gobierno para impulsar esta industria (INDUNIV), Iván Lugo, explicó en entrevista para la Revista Medicina y Salud Pública (MSP) cómo Puerto Rico ha sido uno de los más grandes exportadores de medicamentos a nivel mundial.

El director ejecutivo aseguró que el éxito obtenido por la industria farmacéutica en Puerto Rico a través de regulaciones e incentivos económicos ha permitido la exportación a más de 100 países alrededor del mundo. ¿Cuál ha sido el papel de ustedes con la integración de nuevas farmacéuticas al país?

Puerto Rico es el exportador farmacológico más grande ante cualquier estado de la nación americana. Un 68% de las exportaciones de Puerto Rico provienen de esta industria, que además ocupa la posición de los primeros siete empleadores en las industrias farmacéuticas en los Estados Unidos. En adición, tenemos una gran presencia de la industria de dispositivos médicos en la Isla.

La integración de distintas farmacéuticas se da gracias a diversos estudios que determinan si estas se encuentran preparadas tanto con la mano de obra, como con el conocimiento para poder manejar este tipo de facilidades. Otros elementos que se miden son la competitividad, la seguridad y el que sean gobiernos estables, de altas tecnologías y calidad.

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¿Cómo se integra la labor de la academia en este andamiaje?

El elemento académico y crítico es vital para tener una fuerza laboral y para emplear la manufactura. Más del 80% del personal que trabaja en la industria farmacéutica en Puerto Rico tiene un grado de bachillerato, por lo que es importante que las instituciones académicas estén al tanto del desarrollo del talento requerido para esta industria.

El avance que se ha conseguido con los estudiantes y personas que quieren estar en la industria ha sido grande, y estamos seguros de que Puerto Rico seguirá siendo uno de los pioneros en preparar a estudiantes para entrar en la industria, ya que hace enriquecer el ámbito de la innovación en el estudiantado y para la isla. ¿Cómo está la industria de los dispositivos médicos en Puerto Rico?

La Organización Mundial de la Salud (OMS) define el término de dispositivo médico como aquel que hace referencia a un instrumento, aparato o máquina utilizado en la prevención, el diagnóstico o el tratamiento de una enfermedad o condición, o para detectar, medir, restaurar, corregir o modificar la estructura o función del cuerpo con fines de salud. Los dispositivos médicos son esenciales para que la prevención, el diagnóstico, el tratamiento y la rehabilitación de enfermedades y dolencias sean seguras y eficaces.

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SUPLEMENTO / PROTAGONISTAS DEL CAMBIO En Puerto Rico operan un sinnúmero de compañías que manufacturan diferentes dispositivos médicos para enfermedades como la diabetes, lo que resulta en que se puedan hacer muchas otras pruebas en la Isla.

Aún se espera que los dispositivos médicos sigan siendo un avance en la Isla ya que son pocos los hospitales que llegan a utilizarlos de manera frecuente. Estos dispositivos pueden llegar a prevenir algunas enfermedades cardiovasculares de la mejor manera.

Tenemos muchos factores que aportan al éxito de la industria en la Isla, entre estos la competitividad, la gran cantidad de investigaciones en fármacos y en dispositivos, y muchos más estudios en vacunas. Por ejemplo, estudios recientes que se han realizado demostraron que factores genéticos también podrían afectar a las personas infectadas con COVID-19.

Puerto Rico es el exportador farmacológico más grande ante cualquier estado de la nación americana.

Un 68% de las exportaciones de Puerto Rico salen de su industria y son los primeros 7 empleadores en las industrias farmacéuticas en Estados Unidos.

Aún se espera que los dispositivos médicos sigan siendo un avance que marque un precedente en la industria farmacéutica puertorriqueña.

La Isla ha logrado posicionarse desde el campo de desarrollo de la biotecnología.

— Iván Lugo, director ejecutivo de INDUNIV

¿Cómo el sector farmacéutico ha trabajado con el sector privado en beneficio de la sociedad?

Cuando comenzó la pandemia, el talento, la academia, la empresa privada y el gobierno se unieron. Esto nos dejó saber el potencial que continúa teniendo nuestra unión multisectorial y estamos orgullosos de la estrecha colaboración que siempre nos ha caracterizado. ¿Cómo han logrado ser resilientes en Puerto Rico en medio de tantas situaciones de salud pública?

A pesar de tantos eventos que han ocurrido en Puerto Rico, nunca han faltado productos farmacológicos, que son productos esenciales para la salud.

La Isla siempre ha demostrado resiliencia ya que la industria tiene buenos planes de continuidad de negocios.

Es por esto que en Puerto Rico, cuando ocurre algún evento significativo como lo han sido los huracanes, terremotos y ahora la pandemia, las empresas han podido seguir adelante en sus operaciones y además han apoyando a las diferentes comunidades afectadas.

Yo creo que la parte de resiliencia de Puerto Rico queda muy demostrada. Tenemos la infraestructura necesaria para responder a una emergencia de manera efectiva.

Estamos realmente preparados para todo lo que venga.

Mejores Ensayos Clínicos • Proveer retroalimentación y recomendaciones acertadas para ayudar a mejorar el rendimiento de los centros de investigación.

• Proceso íntegro de incorporación de personal y gestión de

calidad continua • Acceso a un sistema de gestión de ensayos clínicos (CTMS) para mejorar eficiencias.

• Presupuestos consistentemente mayores para ensayos.

Más Ensayos Clínicos • Mercadear los

recursos de sus ensayos clínicos a posibles patrocinadores y CROs.

• Dirigirse estratégicamente a patrocinadores con proyectos alineados a las capacidades

del consorcio.

Ensayos Clínicos Más Rápidos • Apoyar los procesos iniciales de los estudios para ensayos clínicos.

• Apalancar mejores prácticas de colegas

para optimizar los esfuerzos iniciales.

• Centralizar las negociaciones de contratos y presupuestos.

- PRCCI

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SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

Unidos por la exportación mundial de productos manufacturados en Puerto Rico LAS INDUSTRIAS FARMACÉUTICAS PUDIERAN VERSE COMO ENTES SEPARADOS, PERO DETRÁS DE LA LABOR DE CADA UNA EXISTE UN BIEN COMÚN: LOS PACIENTES. POR TAL RAZÓN, REUNIDAS BAJO LA ASOCIACIÓN DE LA INDUSTRIA FARMACÉUTICA DE PUERTO RICO (PIA, POR SUS SIGLAS EN INGLÉS), TODAS CONFORMAN ESTRATEGIAS QUE PRECISAMENTE REDUNDAN EN CONTINUAR POSICIONANDO A PUERTO RICO COMO UN LUGAR IDÓNEO TANTO PARA EL DESARROLLO DE LA INDUSTRIA COMO PARA LA EXPORTACIÓN DE SUS PRODUCTOS A NIVEL MUNDIAL.

En medio de una pandemia global que ha causado el cierre de empresas y la c o n t ra c c i ó n e c o n ó mi c a debido a la pérdida de empleos que han ocasionado la fuga de talentos, precisamente las empresas farmacéuticas se han convertido en las protagonistas, no solo como empleadoras

de los profesionales de este campo preparados en la Isla, sino como los centros que tienen en sus manos la salud de muchos puertorriqueños con el desarrollo de tratamientos y medicamentos esenciales, como la nueva era que dio comienzo con la llegada del COVID19.

Víctor Cruz Vicepresidente y General de Eli Lilly

Alejandro Drevón Vicepresidente y Gerente General de Operaciones Comerciales de AbbVie

David Thompson Director de Operaciones de AbbVie Biotechnology

Iván Román Asesor de la Junta de Directores de PIA

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SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

“Hoy suplimos a más de 100 países”

afirmó por su parte el ingeniero Iván Román, asesor de la Junta de Directores de PIA.

“Hemos visto la transformación de la industria hacia una de alta tecnología y biotecnología. Precisamente mucho de esto se debe a la colaboración que hemos tenido todas las industrias en la Isla y sobretodo, su infraestructura”, sostuvo David Thompson, director de operaciones de AbbVie Biotechnology en Barceloneta.

De otra parte, Alejandro Drevón, vicepresidente y gerente general de operaciones comerciales de Abbvie, indicó que entre el 20 y el 25 por ciento de los recaudos que llegan al fondo de Puerto Rico, llegan a través de la industria farmacéutica.

“También está la parte del capital humano. El que la industria esté sólida en Puerto Rico ha provocado que la educación en ciencias y tecnología sea una más fuerte. Desde el punto de vista de innovación, esto ha convertido a Puerto Rico en un punto estratégico”, aseguró Drevón.

Precisamente la evolución de la ciencia ha provocado que desde que se identifica una molécula como posible diana de tratamiento, la manufactura en la Isla demuestre el rol importante entre el tiempo del estudio de la molécula, hasta la primera dosis otorgada a un paciente.

“El trabajar juntos como industrias nos ha permitido que esa innovación precisamente sea una más rápida y que el lanzamiento de esos productos sea uno más rápido”, afirmó Víctor

Cruz, vicepresidente y gerente general de la farmacéutica Eli Lilly.

Como ejemplo, Thompson sostuvo el éxito del medicamento Humira, “que tiene entre 12 indicaciones de uso, como por ejemplo en la enfermedad de artritis y el medicamento Synthroid, para la enfermedad de tiroides, con más de 1 millón de recetas anualmente y se manufactura desde Puerto Rico para el mundo”.

Igualmente Cruz sostuvo que la Isla posee una de las industrias más grandes en la producción de medicamentos de insulina para pacientes con diabetes tipo 1.

“Lo mismo ocurre con la parte oncológica, donde antes muchas enfermedades eran sentencias de muerte. Las nuevas terapias oncológicas que salvan vidas, salen de Puerto Rico. Innovaciones terapéuticas en artritis reumatoide, en psoriasis, también en enfermedades cardiovasculares”, celebró por su parte Drevón.

“Hoy suplimos a más de 100 países”, afirmó por su parte el ingeniero Iván Román, asesor de la Junta de Directores de PIA. Asimismo, como punto evolutivo, anunció que el primer producto biológico para hacerle frente al coronavirus “lo descubre la empresa Eli Lilly, que en este momento está en etapa de transferencia de tecnología y hace una colaboración a nivel global para que la empresa farmacéu-

tica Amgen la manufacture, y se decide hacer en Puerto Rico”.

“Se trata de anticuerpos monoclonales. Y las industrias farmacéuticas, si alguna no tiene la capacidad de manufacturar, por ejemplo, se une en colaboración con otra que sí lo haga”, añadió.

Precisamente para lograr esta contínua evolución que va de la mano con la innovación científica, se debe continuar fomentando que más jóvenes se interesen por las ciencias, la tecnología y materias relacionadas a la industria, enfatizó por su parte Drevón.

“Nosotros también abogamos porque nuestros empleados tengan todas las protecciones necesarias tanto para la producción como para la respuesta de eventos como los que hemos atravesado”, sostuvo Thompson, refiriéndose a los eventos por los que la Isla ha atravesado como el huracán María, los terremotos y ahora la pandemia global del coronavirus.

“Han sido oportunidades que nos han permitido como país demostrar que estos retos los hemos podido convertir en ventajas competitivas para nosotros”, concluyó por su parte Cruz, vicepresidente y gerente general de la farmacéutica Lilly.

Rafael Castro Vicepresidente de Operaciones de PIA

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SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

Red biotecnológica con impacto en la formación de profesionales en Puerto Rico LA ASOCIACIÓN DE LA INDUSTRIA FARMACÉUTICA DE PUERTO RICO (PIA, POR SUS SIGLAS EN INGLÉS) NO ES TAN SOLO UNA RED DE INDUSTRIAS QUE HAN LOGRADO POSICIONAR A LA ISLA A NIVEL MUNDIAL, GENERANDO ALREDEDOR DE 18 MIL EMPLEOS Y CON 13 EMPRESAS PUERTORRIQUEÑAS AFILIADAS, SINO QUE UNO DE SUS PRINCIPALES CAPITALES ESTÁ EN LA FORMACIÓN DE LOS PROFESIONALES DE ESTE CAMPO EN LA ISLA, DESDE LA ACADEMIA.

Para Wendy Perry, gerente general de Merck en la operación comercial y presidenta saliente de PIA, e Ileana Quiñones, ingeniera, vicepresidenta y gerente general de iPR Pharmaceuticals, subsidiaria de AstraZeneca y presidenta entrante de PIA, precisamente el desarrollo del campo de la manufactura y

biotecnología en Puerto Rico han provocado un efecto dominó en la formación del capital humano, pues todas las carreras han sido adaptadas a la demanda tecnológica y científica que precisamente ha destacado a la Isla como punto estratégico de la producción de medicamentos y dispositivos médicos a nivel global.

Wendy Perry Gerente General de la operación comercial de Merck y presidenta saliente de PIA

Ileana Quiñones Vicepresidenta y Gerente General de iPR Pharmaceuticals (AstraZeneca) y presidenta entrante de PIA

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“SE DEBEN VIABILIZAR LAS ESTRATEGIAS DE INVERSIÓN EN PUERTO RICO. ES IMPORTANTE RECONOCER QUE HASTA LA FECHA, LA INDUSTRIA HA INVERTIDO ALREDEDOR DE $10 MIL MILLONES EN CAPITAL. DE ESOS HAY $450 MILLONES INVERTIDOS EN EL ÁREA BIOFARMACÉUTICA”, ENFATIZÓ QUIÑONES

PIA tiene 13 compañías miembros que pertenecen a las primeras 20 compañías farmacéuticas a nivel mundial. Precisamente, este crecimiento ha justificado el que sea el talento puertorriqueño la columna vertebral en estas compañías.

“Yo me gradué del Colegio de Ingeniería de la Universidad de Puerto Rico en Mayagüez. Y no solamente uno se hace parte de la industria, sino que tenemos un rol importante en lo que es la educación. Trabajamos bien de cerca con todas las universidades en Puerto Rico, no tan solo como talentos de la industria farmacéutica, sino como talentos que aporten a la economía de Puerto Rico”, explicó Perry.

Hay que seguir fortaleciendo el clima de negocios en la Isla para continuar el trabajo realizado”, enfatizó por su parte Quiñones, vicepresidenta y gerente general de iPR Pharmaceuticals.

Precisamente para continuar la inversión de capital, se establecieron colaboraciones junto a la Universidad de Puerto Rico, Recinto de Mayagüez y su Departamento de Biología, para la creación de un bachillerato en Ciencias de Biotecnología Industrial.

“Estamos orgullosos de que no solo desarrollamos talentos, sino que nuestros talentos contribuyan a las comunidades”, añadió.

“Y de igual manera, con la Escuela de Ingeniería del Colegio de Mayagüez, en la creación de un minor en in g e nie ría f ar m a c é utic a. O t ro gran logro fue con la Universidad Politécnica de Puerto Rico, debido a la necesidad de automatización de primera, y hace unos dos años nació la Automatización en Manufactura”, abundó.

Clave la capital de inversión

Los Pacientes Primero

De otra parte, el futuro de la Isla y el éxito del ecosistema de la industria farmacéutica debe regirse por la continuidad de las inversiones realizadas en el país.

“Se deben viabilizar las estrategias de inversión en Puerto Rico. Es importante reconocer que hasta la fecha, la industria ha invertido alrededor de $10 mil millones en capital. De esos hay $450 millones invertidos en el área biofarmacéutica.

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Otra de las labores que ambas profesionales destacaron fue la del apoyo del campo farmacéutico al nacimiento de la organización mediante alianzas, Los Pacientes Primero. Esta iniciativa nació durante el inicio de la pandemia en la Isla a causa del coronavirus para suplir de sus tratamientos a los pacientes con condiciones crónicas del país.

“No tan solo f ue de capital económico, sino de horas voluntarias de nuestros empleados para ayudar a las comunidades”, apuntó Quiñones.

Por su parte, Perry destacó que precisamente toda esta labor permite seguir despertando el interés en los jóvenes para continuar fomentando su formación profesional y educativa.

“YO ME GRADUÉ DEL COLEGIO DE INGENIERÍA DE LA UNIVERSIDAD DE PUERTO RICO EN MAYAGÜEZ. Y NO SOLAMENTE UNO SE HACE PARTE DE LA INDUSTRIA, SINO QUE TENEMOS UN ROL IMPORTANTE EN LO QUE ES LA EDUCACIÓN. TRABAJAMOS BIEN DE CERCA CON TODAS LAS UNIVERSIDADES EN PUERTO RICO, NO TAN SOLO COMO TALENTOS DE LA INDUSTRIA FARMACÉUTICA, SINO COMO TALENTOS QUE APORTEN A LA ECONOMÍA DE PUERTO RICO”, EXPLICÓ PERRY.

SUPLEMENTO / PROTAGONISTAS DEL CAMBIO

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INDICATIONS INDICATIONS Retevmo Retevmo is aiskinase a kinase inhibitor inhibitor indicated indicated for for thethe treatment treatment of: of: • adult • adult patients patients with with metastatic metastatic RETRET fusion-positive fusion-positive non-small non-small cellcell lung lung cancer cancer (NSCLC) (NSCLC) • adult • adult andand pediatric pediatric patients patients 12 years 12 years of age of age andand older older with with advanced advanced or metastatic or metastatic RET-mutant RET-mutant medullary medullary thyroid thyroid cancer cancer (MTC) (MTC) who who require require systemic systemic therapy therapy • adult • adult andand pediatric pediatric patients patients 12 years 12 years of age of age andand older older with with advanced advanced or metastatic or metastatic RETRET fusion-positive fusion-positive thyroid thyroid cancer cancer who who require require systemic systemic therapy therapy andand who who areare radioactive radioactive iodine-refractory iodine-refractory (if radioactive (if radioactive iodine iodine is appropriate) is appropriate) These These indications indications are are approved approved under under accelerated accelerated approval approval based based on on overall overall response response raterate (ORR) (ORR) andand duration duration of response of response (DoR).

(DoR).

Continued Continued approval approval for for these these indications indications maymay be contingent be contingent upon upon verification verification andand description description of clinical of clinical benefit benefit in confirmatory in confirmatory trials. trials.

RET=rearranged RET=rearranged during during transfection. transfection.

IMPORTANT IMPORTANT SAFETY SAFETY INFORMATION INFORMATION Hepatotoxicity: Hepatotoxicity: Serious Serious hepatic hepatic adverse adverse reactions reactions occurred occurred in 2.6% in 2.6% of patients of patients treated treated with with Retevmo.

Retevmo.

Increased Increased aspartate aspartate aminotransferase aminotransferase (AST) (AST) occurred occurred in 51% in 51% of patients, of patients, including including Grade Grade 3 or3 4orevents 4 events in 8% in 8% andand increased increased alanine alanine aminotransferase aminotransferase (ALT) (ALT) occurred occurred in 45% in 45% of patients, of patients, including including Grade Grade 3 or3 4orevents 4 events in 9%. in 9%.

TheThe median median time time to first to first onset onset for for increased increased ASTAST waswas 4.1 4.1 weeks weeks (range: (range: 5 days 5 days to 2toyears) 2 years) andand increased increased ALTALT waswas 4.1 4.1 weeks weeks (range: (range: 6 days 6 days to 1.5 to 1.5 years). years).

Monitor Monitor ALTALT andand ASTAST prior prior to initiating to initiating Retevmo, Retevmo, every every 2 weeks 2 weeks during during thethe firstfirst 3 months, 3 months, then then monthly monthly thereafter thereafter andand as clinically as clinically indicated. indicated.

Withhold, Withhold, reduce reduce dose dose or permanently or permanently discontinue discontinue Retevmo Retevmo based based on on thethe severity. severity.

Hypertension Hypertension occurred occurred in 35% in 35% of patients, of patients, including including Grade Grade 3 hypertension 3 hypertension in 17% in 17% andand Grade Grade 4 in4one in one (0.1%) (0.1%) patient. patient.

Overall, Overall, 4.6% 4.6% hadhad their their dose dose interrupted interrupted andand 1.3% 1.3% hadhad their their dose dose reduced reduced for for hypertension. hypertension.

Treatment-emergent Treatment-emergent hypertension hypertension waswas most most commonly commonly managed managed with with anti-hypertension anti-hypertension medications. medications.

Do Do notnot initiate initiate Retevmo Retevmo in patients in patients with with uncontrolled uncontrolled hypertension. hypertension.

Optimize Optimize blood blood pressure pressure prior prior to to initiating initiating Retevmo.

Retevmo.

Monitor Monitor blood blood pressure pressure after after 1 week, 1 week, at least at least monthly monthly thereafter, thereafter, andand as clinically as clinically indicated. indicated.

Initiate Initiate or adjust or adjust anti-hypertensive anti-hypertensive therapy therapy as appropriate. as appropriate.

Withhold, Withhold, reduce reduce dose, dose, or or permanently permanently discontinue discontinue Retevmo Retevmo based based on on thethe severity. severity.

Please Please seesee Important Important Safety Safety Information Information andand Brief Brief Summary Summary of of Prescribing Prescribing Information Information forfor Retevmo Retevmo onon subsequent subsequent pages. pages.

Response in patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic RET fusion-positive thyroid cancer (non-medullary thyroid cancer (non-MTC)),* and advanced or metastatic RET-mutant MTC1 Metastatic RET Fusion-Positive NSCLC Treatment naive (n=39)

Previously treated with platinum chemotherapy (n=105)

85% ORR1

64% ORR1

Responses in intracranial lesions were observed in

(95% CI: 70, 94) 0% CR + 85% PR

(95% CI: 54, 73) 1.9% CR + 62% PR

10 of 11

Median DoR not yet reached

Median DoR was 17.5 months

(95% CI: 12, NE); median follow-up: 7.4 months1,3

(95% CI: 12, NE); median follow-up: 12.1 months1,3

Advanced or Metastatic RET Fusion-Positive Thyroid Cancer (Non-MTC) Systemic therapy naive‡ (n=8)

100% ORR1 (95% CI: 63, 100) 12.5% CR + 88% PR

Median DoR not yet reached

previously treated patients with measurable brain metastases1† CNS DoR was ≥6 months in all responders with measurable brain metastases1† No patients received radiation therapy to the brain within 2 months prior to study entry1

Advanced or Metastatic RET-Mutant MTC

Previously treated§ (n=19)

Cabozantinib/vandetanib treatment naive (n=88)

Previously treated with cabozantinib and/or vandetanib|| (n=55)

79% ORR1

73% ORR1

69% ORR1

(95% CI: 54, 94) 5.3% CR + 74% PR

Median DoR was 18.4 months

(95% CI: NE, NE); (95% CI: 7.6, NE); median follow-up: 8.8 months1,3 median follow-up: 17.5 months1,3

(95% CI: 62, 82) 11% CR + 61% PR

(95% CI: 55, 81) 9% CR + 60% PR

Median DoR was 22.0 months

Median DoR not yet reached

(95% CI: NE, NE); median follow-up: 7.8 months1,3

(95% CI: 19.1, NE); median follow-up: 14.1 months1,3

Find RET. Find results on Retevmo.com.

Trial Design The phase I/II, multicohort, open-label, single-arm, multicenter LIBRETTO-001 trial evaluated the efficacy of Retevmo in a population of 702 patients with metastatic RET fusion-positive NSCLC (n=332),¶ advanced or metastatic RET fusion-positive thyroid cancer (non-MTC)# (n=38), advanced or metastatic RET-mutant MTC (n=306), and certain other advanced solid tumors with RET alterations (n=26).** The study enrolled the following cohorts: systemic therapy-naive patients (n=39††) and previously treated (n=105††‡‡) patients who had progressed on platinum-based chemotherapy with metastatic RET fusion-positive NSCLC; systemic therapy-naive (n=8‡††) and previously treated (n=19§††) patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC); and treatment-naive (n=88††) and previously treated (n=55||††) patients with advanced or metastatic RET-mutant MTC. Major efficacy outcomes were ORR and DoR. In phase II, the dose for Retevmo was 160 mg PO BID.1,4,5§§ ORR was defined as CR + PR and was assessed by independent review committee (IRC) according to RECIST v1.1.1 All results reviewed by an IRC.1,3

*Primary tumor histologies included papillary thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid cancer, and Hurthle cell thyroid cancer.1 † Patients previously treated with platinum-based chemotherapy and with measurable CNS lesions at baseline according to IRC assessment.1 ‡ Patients in this cohort received no prior systemic therapy other than radioactive iodine (RAI).1 § Patients in this cohort received a prior systemic therapy (including sorafenib, lenvatinib, or both) other than RAI.1 || The efficacy of Retevmo was evaluated in 55 patients with RET-mutant advanced MTC who were previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001.1 ¶ Patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and those without prior systemic therapy were enrolled in separate cohorts.1 # Non-medullary thyroid cancers (non-MTC) by histology included papillary (n=31), poorly differentiated (n=4), anaplastic (n=2), and Hurthle cell (n=1).1,4 **Other tumors included pancreatic cancer (n=7), colon cancer (n=5), and adrenal gland carcinoma (n=3).4 †† Number of patients included in the initial efficacy analysis. Efficacy was based on patients who had at least 6 months of follow-up.1 ‡‡ Efficacy was evaluated in 105 adult patients with metastatic RET fusion-positive NSCLC who were previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. All 105 patients received systemic therapy. 58 of the 105 patients received prior anti-PD-1/PD-L1 therapy, and 50 of the 105 patients received a prior multikinase inhibitor (MKI).1,4 §§ Patients with RET-mutant NSCLC and RET-mutant thyroid cancer (non-MTC) were not enrolled in the trial since RET is not the driver of tumor growth in these cancers.1,6 BID=twice daily; CI=confidence interval; CNS=central nervous system; CR=complete response; DoR=duration of response; NE=not estimable; ORR=objective response rate; PO=orally; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors.

Adverse Reactions and Laboratory Abnormalities • The most common adverse reactions, including laboratory abnormalities, (≥25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation • Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequent serious adverse reaction (in ≥2% of patients) was pneumonia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3). Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received Retevmo Adverse reactions resulting in permanent discontinuation in patients who received Retevmo included increased ALT (0.4%), sepsis (0.4%), increased AST (0.3%), drug hypersensitivity (0.3%), fatigue (0.3%), and thrombocytopenia (0.3%) • Dose interruptions due to an adverse reaction occurred in 42% of patients who received Retevmo. Adverse reactions requiring dosage interruption in ≥2% of patients included ALT increased, AST increased, hypertension, diarrhea, pyrexia, and QT prolongation • Dose reductions due to an adverse reaction occurred in 31% of patients who received Retevmo. Adverse reactions requiring dosage reductions in ≥2% of patients included ALT increased, AST increased, QT prolongation, and fatigue Retevmo® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

PP-SE-US-0397 11/2020 © Lilly USA, LLC 2020. All rights reserved.

IMPORTANT SAFETY INFORMATION FOR RETEVMO® (selpercatinib 40 mg, 80 mg capsules) (CONT’D) Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients.

Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction.

Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment.

Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo.

Grade ≥3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivity occurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years).

Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg. Upon resolution of the event, resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity.

Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing. Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose.

There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequently reported serious adverse reaction (in ≥ 2% of patients) was pneumonia.

Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (33%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) ≥20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Concomitant use of strong and moderate CYP3A inhibitors increases selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation.

Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently.

Concomitant use of strong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older.

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] ≥30 mL/Min, estimated by Cockcroft-Gault). A recommended dosage has not been established for patients with severe renal impairment or endstage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

SE HCP ISI All_25AUG2020

Please see Brief Summary of Prescribing Information for Retevmo on subsequent pages.

References: 1. Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 2. Drilon A, Hu ZI, Lai GGY, et al. Targeting RETdriven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. 3. Data on File, Lilly USA, LLC, DOF-SEUS-0032. 4. Data on File, Lilly USA, LLC, DOF-SE-US-0033. 5. Phase 1/2 study of LOXO-292 in patients with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). https://clinicaltrials.gov/ct2/show/NCT03157128. Updated July 2, 2020. Accessed July 16, 2020. 6. Mulligan LM. GDNF and the RET receptor in cancer: new insights and therapeutic potential. Front Physiol. 2019;9:1873.

RETEVMO™ (selpercatinib) capsules, for oral use Initial U.S. Approval: 2020

Risk of Impaired Wound Healing

BRIEF SUMMARY: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE RETEVMO (selpercatinib) is a kinase inhibitor indicated for the treatment of: • • •

Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy are radioactive iodine-refractory (if radioactive iodine is appropriate)

These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

CONTRAINDICATIONS: None

Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity Based on data from animal reproduction studies, and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for at least 1 week after the final dose.

ADVERSE REACTIONS

WARNINGS AND PRECAUTIONS

Clinical Trial Experience

Hepatotoxicity Serious hepatic adverse reactions occurred in 2.6% of patients treated with RETEVMO. Increased AST occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased ALT occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years).

Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue RETEVMO based on the severity.

Hypertension Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue RETEVMO based on the severity.

QT Interval Prolongation RETEVMO can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction.

Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating RETEVMO and during treatment.

Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue RETEVMO based on the severity.

Hemorrhagic Events Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥ 3 hemorrhagic events occurred in 2.3% of patients treated with RETEVMO including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis.

Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage.

Hypersensitivity Hypersensitivity occurred in 4.3% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range: 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.

If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg. Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity.

Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.

RETEVMO™ (selpercatinib) capsules, for oral use

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing.

SE HCP BS 08MAY2020

RETEVMO, SE HCP BS 08MAY2020 - 7.5 x 10.25

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

RET Gene Fusion or Gene Mutation Positive Solid Tumors The pooled safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent at 160 mg orally twice daily evaluated in 702 patients in LIBRETTO-001. Among 702 patients who received RETEVMO, 65% were exposed for 6 months or longer and 34% were exposed for greater than one year. Among these patients, 95% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily.

The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 52% were male; and 69% were White, 22% were Asian, 5% were Hispanic/Latino, and 3% were Black. The most common tumors were NSCLC (47%), MTC (44%), and non-medullary thyroid carcinoma (5%).

Serious adverse reactions occurred in 33% of patients who received RETEVMO. The most frequent serious adverse reaction (in ≥ 2% of patients) was pneumonia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in > 1 patient included sepsis (n = 3), cardiac arrest (n = 3) and respiratory failure (n = 3).

Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation included increased ALT (0.4%), sepsis (0.4%), increased AST (0.3%), drug hypersensitivity (0.3%), fatigue (0.3%), and thrombocytopenia (0.3%).

Dosage interruptions due to an adverse reaction occurred in 42% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in > 2% of patients included ALT increased, AST increased, hypertension, diarrhea, pyrexia, and QT prolongation.

Dose reductions due to an adverse reaction occurred in 31% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in > 2% of patients included ALT increased, AST increased, QT prolongation and fatigue.

The most common adverse reactions, including laboratory abnormalities, (≥ 25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

Table 1 summarizes the adverse reactions in LIBRETTO-001.

Table 1: Adverse Reactions (>15%) in Patients Who Received RETEVMO in LIBRETTO-001

Adverse Reaction

RETEVMO (n=702) Grades 1-4 (%)

Grade 3-4 (%)

39 37 25 23 23 15

0 3.4* 0.6* 0.6* 1.9* 0.3*

35

18

Gastrointestinal Dry Mouth Diarrhea1 Constipation Nausea Abdominal pain2 Vomiting Vascular Hypertension RETEVMO™ (selpercatinib) capsules, for oral use

SE HCP BS 08MAY2020

PRINTER VERSION 1 OF 3

Table 1: Adverse Reactions (>15%) in Patients Who Received RETEVMO in LIBRETTO-001 (Cont.)

Adverse Reaction

RETEVMO (n=702) Grades 1-4 (%)

Grade 3-4 (%)

General Fatigue3 35 2* 4 Edema 33 0.3* Skin Rash5 27 0.7* Nervous System 23 1.4* Headache6 Respiratory 18 0 Cough7 Dyspnea8 16 2.3 Investigations Prolonged QT interval 17 4* Blood and Lymphatic System Hemorrhage9 15 1.9 1 Diarrhea includes diarrhea, defecation urgency, frequent bowel movements, and anal incontinence 2 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain 3 Fatigue includes fatigue, asthenia, malaise.

4 Edema includes edema, edema peripheral, face edema, eye edema, eyelid edema, generalized edema, localized edema, lymph edema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, peripheral swelling 5 Includes rash, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash pruritic 6 Headache includes headache, sinus headache, tension headache, 7 Includes cough, productive cough 8 Includes dyspnea, dyspnea exertional, dyspnea at rest 9 Hemorrhage includes epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, gastric hemorrhage, hemorrhage intracranial, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic anemia, intraabdominal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, pelvic hematoma, periorbital hematoma, pharyngeal hemorrhage, pulmonary contusion, purpura, retroperitoneal hematoma, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, vessel puncture site hematoma * Only includes a grade 3 adverse reaction.

Clinically relevant adverse reactions in <15% of patients who received RETEVMO include hypothyroidism (9%).

Increased Creatinine In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

DRUG INTERACTIONS Effects of Other Drugs on RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally acting antacid).

Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations, which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently.

Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity. Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO. Effects of RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

USE IN SPECIFIC POPULATIONS Pregnancy

Table 2 summarizes the laboratory abnormalities in LIBRETTO-001.

Risk Summary

Table 2: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-001

Based on findings from animal studies, and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus.

RETEVMO1

Laboratory Abnormality Grades 1-4 (%)

Grades 3-4 (%) Chemistry Increased AST 51 8 Increased ALT 45 9 Increased glucose 44 2.2 Decreased albumin 42 0.7 Decreased calcium 41 3.8 Increased creatinine 37 1.0 Increased alkaline phosphatase 36 2.3 Increased total cholesterol 31 0.1 Decreased sodium 27 7 Decreased magnesium 24 0.6 Increased potassium 24 1.2 Increased bilirubin 23 2.0 Decreased glucose 22 0.7 Hematology Decreased leukocytes 43 1.6 Decreased platelets 33 2.7 1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 675 to 692 patients.

RETEVMO™ (selpercatinib) capsules, for oral use

SE HCP BS 08MAY2020

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal Data Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥ 100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss. At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax).

Lactation Risk Summary There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the final dose.

RETEVMO™ (selpercatinib) capsules, for oral use

SE HCP BS 08MAY2020

Females and Males of Reproductive Potential Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily.

Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the final dose.

Males Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the final dose.

Infertility RETEVMO may impair fertility in females and males of reproductive potential.

Pediatric Use The safety and effectiveness of RETEVMO have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 12 years of age.

The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications.

Animal Toxicity Data In 4-week general toxicology studies in rats, animals showed signs of physeal hypertrophy and tooth dysplasia at doses resulting in exposures ≥ approximately 3 times the human exposure at the 160 mg twice daily clinical dose. Minipigs also showed signs of minimal to marked increases in physeal thickness at the 15 mg/kg high dose level (approximately 0.3 times the human exposure at the 160 mg twice daily clinical dose). Rats in both the 4- and 13-week toxicology studies had malocclusion and tooth discoloration at the high dose levels (≥1.5 times the human exposure at the 160 mg twice daily clinical dose) that persisted during the recovery period.

Geriatric Use Of 702 patients who received RETEVMO, 34% (239 patients) were ≥ 65 years of age and 10% (67 patients) were ≥ 75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were ≥65 years of age and younger patients.

Renal Impairment No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] >30 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr <30 mL/min) or end-stage renal disease.

Hepatic Impairment Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment. No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment.

Rx only.

Additional information can be found at www.retevmo.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright ©2020, Eli Lilly and Company. All rights reserved.

SE HCP BS 08MAY2020 RETEVMO™ (selpercatinib) capsules, for oral use

SE HCP BS 08MAY2020

DIFERENCIAS INMUNOGÉNICAS DE LAS VACUNAS NEUMOCÓCICAS

SUPLEMENTO ESPECIAL

KAREN MARTÍNEZ ROBLES, MD MÉDICA DE LA PONTIFICIA UNIVERSIDAD JAVERIANA DE COLOMBIA COLABORADORA REVISTA MEDICINA Y SALUD PÚBLICA

treptococcus pneumoniae, comúnmente llamado neumococo, es la primera causa de n e u m o ní a adquirida en la comunidad (NAC) en todo el mundo y es responsable también de casos de otitis media, sinusitis, meningitis y bacteriemia, aunque en menor medida.

Dado su alta carga de morbimortalidad en la población general, la inmunización contra neumococo ha sido una estrategia de salud pública necesaria para disminuir la incidencia de enfermedad neumocócica, a través de dos tipos de vacunas: la polisacárida (PPSV23) y la conjugada (PCV13) que por sus diferencias a nivel inmunogénico, deben ser usadas según las recomendaciones de los Centros para el Control y Prevención de Enfermedades (CDC por sus siglas en inglés).

La vacuna PCV13 se recomienda para:

2 AÑOS

Todos los niños menores de 2 años en series de 4 dosis (2 meses, 4 meses, 6 meses y 12 a 15 meses).

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Personas con afecciones que debilitan su sistema inmune.

DADO SU ALTA CARGA DE MORBIMORTALIDAD EN LA POBLACIÓN GENERAL, LA INMUNIZACIÓN CONTRA NEUMOCOCO HA SIDO UNA ESTRATEGIA DE SALUD PÚBLICA NECESARIA PARA DISMINUIR LA INCIDENCIA DE ENFERMEDAD NEUMOCÓCICA.

INTRODUCCIÓN Streptococcus pneumoniae, comúnmente llamado neumococo, es una bacteria gram positiva que cuenta con una cápsula de polisacáridos externa a su pared celular como principal mecanismo de virulencia y que, además permite su clasificación en al menos 98 serotipos con diferencias a nivel inmunogénico y de sintomatología.

Este microorganismo es la primera causa de neumonía adquirida en la comunidad (NAC) en todo el mundo, y es responsable también de producir otitis media, sinusitis, meningitis y bacteriemia, aunque en menor medida. Las tasas de morbilidad y mortalidad asociadas a la enfermedad neumocócica son notablemente altas y aunque la susceptibilidad frente al neumococo es universal, existen poblaciones que se encuentran en un mayor riesgo que otras como son los niños, los adultos mayores y los pacientes inmunocomprometidos.

Es por esto que, la vacunación contra el neumococo nace como una estrategia de prevención y como la opción más rentable para los sistemas de salud a la hora de abordar las infecciones neumocócicas en toda la población.

Actualmente, existen dos tipos de vacunas antineumocócicas disponibles en el mercado: la polisacárida (PPSV23) y la conjugada (PCV13).

La primera recibe su nombre por los 23 polisacáridos capsulares parcialmente purificados que la componen, es decir que, cubre 23 serotipos

(1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F y 33F) de neumococo causantes del 50 al 60% de casos de enfermedad neumocócica en adultos. Por otro lado, se encuentra la PCV13 que se clasifica como una vacuna conjugada debido a que los 13 polisacáridos (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F y 23F) presentes en ella están unidos covalentemente (conjugados) a una proteína no tóxica similar a la toxina diftérica que logra desencadenar una respuesta dependiente de células T que conduce a la producción de anticuerpos y a la creación de memoria inmunológica en caso de reexposición. ¿Qué tipo de respuesta inmunológica producen las vacunas conjugadas en comparación con las polisacáridas?

Como se mencionó anteriormente, la vacuna PPSV23 por su composición de sólo polisacáridos, induce una respuesta inmune T independiente, lo que quiere decir que no involucra la activación de los linfocitos T, sino que los polisacáridos activan directamente a los linfocitos B que son los encargados de producir anticuerpos específicos, con la única diferencia de que, en este caso, la respuesta inmunológica es un poco más débil que la producida por una vacuna conjugada. La inmunidad se desarrolla 2 a 3 semanas después de recibir la vacuna y los niveles de anticuerpos persisten por al menos 5 años, pero no se generan células de memoria.

Por el contrario, la respuesta inmunológica que desencadena la vacuna PCV13 tiene como intermediario principal a los linfocitos T que favorecen la proliferación y diferenciación de los linfocitos B para que éstos produzcan anticuerpos, así como también, células de memoria en caso de reexposición al agente patógeno. Esto lo logra a través de la proteína que se encuentra en su estructura, lo que la hace más efectiva en menores de 2 años de edad porque su sistema inmunológico no responde adecuadamente a los antígenos polisacáridos por sí solos, por lo que se requiere de un antígeno proteíco para desencadenar una respuesta inmunológica efectiva.

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Cabe resaltar que la vacuna PCV13 tiene un efecto adicional al generar inmunidad a nivel de la mucosa. Dado que la bacteria suele estar presente en la nariz o garganta de pacientes sanos, especialmente de lactantes y niños pequeños, éstos se consideran el principal reservorio de la población. El uso de la vacuna conjugada cumple un papel fundamental a la hora de disminuir la incidencia de enfermedad neumocócica y erradicar el neumococo en la nasofaringe de este grupo etario y de forma añadida, crea un “efecto rebaño” en el que se reduce también la incidencia de enfermedad neumocócica en adultos gracias a la vacunación pediátrica. En conclusión, ésta clara diferencia frente a la respuesta inmunológica que generan las vacunas conjugadas en comparación con las vacunas de polisacáridos, es la que marca la pauta para preferir una u otra en las poblaciones a vacunar.

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Revista Puertorriqueña de Medicina y Salud Pública

Recomendaciones actuales según los CDC para el uso de vacunas antineumocócicas La vacuna PCV13 se recomienda para: Todos los niños menores de 2 años en series de 4 dosis (2 meses, 4 meses, 6 meses y 12 a 15 meses) Personas entre los 19 y 64 años con afecciones que debilitan su sistema inmune Adultos de 65 años o mayores inmunocompetentes pueden discutir y decidir, junto con su médico la aplicación de la vacuna (Primero recibirían 1 dosis de PCV13 y luego, la PPSV23 como mínimo 1 año después / Si ya recibió la PPSV23, aplicar la PCV13 1 año después) La vacuna PPSV23 está indicada en: • Todos los pacientes adultos de 65 años o más • Personas entre los 19 y 64 años con afecciones que debilitan su sistema inmune • Adultos de 19 a 64 años que sean fumadores

ADULTOS DE 65 AÑOS O MAYORES INMUNOCOMPETENTES PUEDEN DISCUTIR Y DECIDIR, JUNTO CON SU MÉDICO LA APLICACIÓN DE LA VACUNA.

Referencias Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vac cine among adults aged /= 65 years: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report.

2014:63(37);822-825.

Preado V. Conceptos microbiológicos de Streptococcus pneumoniae. Rev. chil. infectol. vol.18, s.1. Santiago, 2001.

Blamey R. Vacunas anti-neumocóccicas en adultos: actualización.

Rev. chil. infectol. vol.31, no.5. Santiago, oct. 2014.

Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices. ACIP presentation slides: June 2019 meeting. https://www.cdc.gov/vaccines/acip/meetings/slides2019-06.html Biagini L, Pezzani M, Rojas R, Fuentealba F. Cost-Utility study of PCV13 versus PPSV23 in adults in Chile. Value in Health Regional Issues, vol. 17. (2018 Dec), pp. 194-201 Shah A, Wallace M, Fields H. Shared Decision-Making for Administering PCV13 in Older Adults. Am Fam Physician. 2020 Feb 1;101(3):134-135.

Revista Puertorriqueña de Medicina y Salud Pública

71

As soon as you diagnose mCSPC or nmCRPC...

INDICATION ERLEADA® (apalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with: • Metastatic castration-sensitive prostate cancer (mCSPC) • Non-metastatic castration-resistant prostate cancer (nmCRPC) IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA® and 3% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA® and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within 6 months of randomization were excluded from the SPARTAN and TITAN studies.

Ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA®. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA® for Grade 3 and 4 events.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2020 08/20 cp-145357v2

Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA® and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA® and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA® compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA® with increased frequency in the elderly.

Evaluate patients for fall risk.

Seizure — In 2 randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA®. Advise patients of the risk of developing a seizure while receiving ERLEADA® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA® have not been established in females. Based on its mechanism of action, ERLEADA® can cause fetal harm and loss of pregnancy when administered to a pregnant female.

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA® [see Use in Specific Populations (8.1, 8.3)].

ADVERSE REACTIONS Adverse Reactions — The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

Laboratory Abnormalities — All Grades (Grade 3-4) • Hematology — In the TITAN study: white blood cell decreased ERLEADA® 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA® 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA® 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA® 41% (2%), placebo 21% (2%) • Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA® 17% (3%), placebo 12% (2%). In the SPARTAN study: hypercholesterolemia ERLEADA® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA® 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA® 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA® 32% (2%), placebo 22% (0.5%)

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(2.2)]. vs 8% vs 8% withwith placebo. placebo. *Study *Study Design: Design: TITAN TITAN waswas a phase a phase 3, multicenter, 3, multicenter, randomized, randomized, double-blind, double-blind, ® ® ® ® placebo-controlled placebo-controlled trialtrial of patients of patients withwith mCSPC mCSPC (N=1052).

(N=1052).

Patients Patients hadhad newly newly Grade Grade 3 rashes 3 rashes (defi (defi nedned as covering as covering >30% >30% body body surface surface areaarea EffEff ectect of of ERLEADA ERLEADA onon Other Other Drugs Drugs —— ERLEADA ERLEADA ® ® diagnosed diagnosed mCSPC mCSPC or relapsed or relapsed metastatic metastatic disease disease after after an initial an initial diagnosis diagnosis of of [BSA]) [BSA]) were were reported reported withwith ERLEADA ERLEADAtreatment treatment (6%) (6%) vs vs is aisstrong a strong inducer inducer of CYP3A4 of CYP3A4 andand CYP2C19, CYP2C19, andand a weak a weak localized localized disease. disease.

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(0.5%). inducer inducer of CYP2C9 of CYP2C9 in humans. in humans.

Concomitant Concomitant useuse of ERLEADA of ERLEADA sitessites of metastases of metastases werewere excluded. excluded.

Patients Patients werewere randomized randomized 1:1 to 1:1receive to receive ® ® ERLEADA 240240 mg orally mg orally onceonce dailydaily or placebo or placebo orally orally onceonce daily.daily.

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Rash Rash withwith medications medications thatthat areare primarily primarily metabolized metabolized

by CYP3A4,

by CYP3A4, ERLEADA in the in TITAN the TITAN trialtrial received received a concomitant a concomitant GnRH GnRH analog analog or had or had a prior a prior bilateral bilateral resolved resolved in 78% in 78% of patients of patients within within a median a median of 78 of 78 days days CYP2C19, CYP2C19, or CYP2C9 or CYP2C9 cancan result result in lower in lower exposure exposure to to 1,2 1,2 orchiectomy. orchiectomy.

The The dualdual primary primary endpoints endpoints werewere overall overall survival survival andand rPFS.rPFS. from from onset onset of rash. of rash.

Rash Rash waswas commonly commonly managed managed withwith oraloral these these medications. medications.

Substitution Substitution for for these these medications medications is is † † All patients All patients whowho enrolled enrolled in the in TITAN the TITAN studystudy started started ADTADT for mCSPC for mCSPC ≤6 months ≤6 months 2 2 to randomization. to randomization. antihistamines, antihistamines, topical topical corticosteroids, corticosteroids, andand 19%19% of patients of patients recommended recommended when when possible possible or evaluate or evaluate for for lossloss of activity of activity priorprior ‡ ‡ Study Study Design: Design: SPARTAN SPARTAN waswas a phase a phase 3, multicenter, 3, multicenter, randomized, randomized, doubledoublereceived received systemic systemic corticosteroids. corticosteroids.

Dose Dose reduction reduction or dose or dose if medication if medication is continued. is continued.

Concomitant Concomitant administration administration of of blind, blind, placebo-controlled placebo-controlled trialtrial of patients of patients withwith nmCRPC nmCRPC (N=1207).

(N=1207).

Patients Patients hadhad ® ® interruption interruption occurred occurred in 14% in 14% andand 28%28% of patients, of patients, respectively. respectively.ERLEADA ERLEADA withwith medications medications thatthat areare substrates substrates of UDPof UDPa PSA a PSA doubling doubling timetime ≤10≤10 months months andand serum serum testosterone testosterone levels levels <50<50 ng/dL. ng/dL. Of the Of the patients patients whowho hadhad dose dose interruption, interruption, 59%59% experienced experienced glucuronosyl glucuronosyl transferase transferase (UGT) (UGT) cancan result result in decreased in decreased All patients All patients enrolled enrolled werewere conficonfi rmed rmed to betonon-metastatic be non-metastatic by blinded by blinded central central ® ® imaging imaging review.Patients review.Patients withwith a history a history of seizure, of seizure, predisposing predisposing factors factors for seizure, for seizure, recurrence recurrence of rash of rash upon upon reintroduction reintroduction of ERLEADA of ERLEADA exposure. exposure.

UseUse caution caution if substrates if substrates of UGT of UGT must must be be co-co. . receiving or receiving drugs drugs known known to decrease to decrease the seizure the seizure threshold threshold or toorinduce to induce seizure seizure ® ® administered administered withwith ERLEADA ERLEADA andand evaluate evaluate for for lossloss of activity. of activity. or Hypothyroidism Hypothyroidism —— In 2Inrandomized 2 randomized studies, studies, ® ® werewere excluded. excluded.

Patients Patients werewere randomized randomized 2:1 to 2:1receive to receive ERLEADA ERLEADA mg orally mg orally onceonce dailydaily or placebo or placebo orally orally onceonce daily.daily.

All patients All patients in the in SPARTAN the SPARTAN hypothyroidism hypothyroidism waswas reported reported for for 8%8% of patients of patients treated treated withwith P-gp, P-gp, BCRP, BCRP, or or OATP1B1 OATP1B1 Substrates Substrates —— Apalutamide Apalutamide 240240 ® ® trialtrial received received a concomitant a concomitant GnRH GnRH analog analog or had or had a bilateral a bilateral orchiectomy. orchiectomy.

The The ERLEADA ERLEADA a weak inducer inducer of P-glycoprotein of P-glycoprotein (P-gp), (P-gp), breast breast cancer cancer andand 2%2% of patients of patients treated treated withwith placebo placebo based based is aisweak primary primary endpoint endpoint waswas metastasis-free metastasis-free survival survival (MFS), (MFS), defidefi nedned as the as time the time fromfrom resistance protein protein (BCRP), (BCRP), andand organic organic anion anion transporting transporting on on assessments assessments of thyroid-stimulating of thyroid-stimulating hormone hormone (TSH) (TSH) every every resistance randomization randomization to the to time the time of fiof rstfievidence rst evidence of blinded of blinded independent independent central central review-confi review-confi rmed rmed distant distant metastasis, metastasis, defidefi nedned as new as new bonebone or soft or soft tissue tissue lesions lesions polypeptide 1B11B1 (OATP1B1) (OATP1B1) clinically. clinically.

Concomitant Concomitant useuse of of 4 months.

4 months.

Elevated Elevated TSHTSH occurred occurred in 25% in 25% of patients of patients treated treated polypeptide ® ® ® ® or enlarged or enlarged lymph lymph nodes nodes above above the iliac the iliac bifurcation, bifurcation, or death or death duedue to any to any ERLEADA withwith ERLEADA ERLEADA andand 7%7% of patients of patients treated treated withwith placebo. placebo.

TheThe ERLEADA withwith medications medications thatthat areare substrates substrates of P-gp, of P-gp, cause, cause, whichever whichever occurred occurred first.fiSecondary rst. Secondary endpoints endpoints werewere timetime to metastasis, to metastasis, median median onset onset waswas at the at the firstfirst scheduled scheduled assessment. assessment.

There There BCRP, BCRP, or OATP1B1 or OATP1B1 cancan result result in lower in lower exposure exposure of these of these progression-free progression-free survival, survival, timetime to symptomatic to symptomatic progression, progression, overall overall survival, survival, andand 1,3 1,3 timetime to initiation to initiation of cytotoxic of cytotoxic chemotherapy. chemotherapy. were were no no Grade Grade 3 or3 4oradverse 4 adverse reactions. reactions.

Thyroid Thyroid replacement replacement medications. medications.

UseUse caution caution if substrates if substrates of P-gp, of P-gp, BCRP, BCRP, or or § § ® ® In the In SPARTAN the SPARTAN study, study, conventional conventional imaging imaging (technetium-99m (technetium-99m bonebone scans scans andand therapy, therapy, when when clinically clinically indicated, indicated, should should be be initiated initiated or or OATP1B1 OATP1B1 must must be be co-administered co-administered withwith ERLEADA ERLEADA andand CT scans) CT scans) waswas usedused to confi to confi rm that rm that patients patients werewere non-metastatic non-metastatic at screening at screening dose-adjusted. dose-adjusted. evaluate evaluate for for lossloss of activity of activity if medication if medication is continued. is continued. for inclusion. for inclusion.

Patients Patients withwith pelvic pelvic lymph lymph nodes nodes <2 cm <2 in cmshort in short axisaxis (N1)(N1) located located below the iliac the iliac bifurcation bifurcation at screening at screening werewere allowed allowed in the in study. the study.

All patients All patients in in DRUG DRUG INTERACTIONS INTERACTIONS ADTADT = androgen = androgen deprivation deprivation therapy; therapy; AR =ARandrogen = androgen receptor; receptor; CI =CIconfi = confi dence dence below 1,3 1,3 SPARTAN SPARTAN had had a PSA a PSA doubling doubling time time ≤10 ≤10 months months at study at study entry. entry. ® ® interval; interval; CT =CTcomputed = computed tomography; tomography; GnRH GnRH = gonadotropin-releasing = gonadotropin-releasing hormone; hormone; EffEff ectect of of Other Other Drugs Drugs onon ERLEADA ERLEADA —— HR =HRhazard = hazard ratio;ratio; mCSPC mCSPC = metastatic = metastatic castration-sensitive castration-sensitive prostate prostate cancer; cancer; Co-administration Co-administration of aofstrong a strong CYP2C8 CYP2C8 or CYP3A4 or CYP3A4 inhibitor inhibitor is is MFSMFS = metastasis-free = metastasis-free survival; survival; nmCRPC nmCRPC = non-metastatic = non-metastatic castration-resistant castration-resistant prostate cancer; cancer; PSAPSA = prostate-specifi = prostate-specifi c antigen; c antigen; rPFSrPFS = radiographic = radiographic progressionprogressionpredicted predicted to increase to increase thethe steady-state steady-state exposure exposure of the of the active active prostate ® ® Please Please seesee Brief Brief Summary Summary of of fullfull Prescribing Prescribing Information Information forfor ERLEADA ERLEADA onon subsequent subsequent pages. pages. ® ® References: References: 1. ERLEADA 1. ERLEADA [Prescribing [Prescribing Information].

Information].

Horsham, Horsham, PA: PA: Janssen Janssen Biotech, Biotech, Inc. Inc. 2. Chi 2. Chi KN, KN, Agarwal Agarwal N, Bjartell N, Bjartell A, etA,al;etfor al; the for the TITAN TITAN Investigators.

Investigators.

Apalutamide Apalutamide for metastatic, for metastatic, castration-sensitive castration-sensitive prostate prostate cancer. cancer.

N Engl N Engl J Med. J Med. 2019;381(1):13-24.

2019;381(1):13-24.

3. Smith 3. Smith MR,MR, SaadSaad F, Chowdhury F, Chowdhury S, etS,al;etfor al; the for the SPARTAN SPARTAN Investigators.

Investigators.

Apalutamide Apalutamide treatment treatment andand metastasis-free metastasis-free survival survival in prostate in prostate cancer. cancer.

N Engl N Engl J Med. J Med. 2018;378(15):1408-1418.

2018;378(15):1408-1418.

Visit Visiterleadahcp.com erleadahcp.com

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Brief Summary of Prescribing Information for ERLEADA® (apalutamide) ERLEADA® (apalutamide) tablets, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE ERLEADA is indicated for the treatment of patients with • Metastatic castration-sensitive prostate cancer (mCSPC) • Non-metastatic castration-resistant prostate cancer (nmCRPC) CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Ischemic Cardiovascular Events Ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA for Grade 3 and 4 events.

In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 3% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within six months of randomization were excluded from the SPARTAN and TITAN studies.

Fractures Fractures occurred in patients receiving ERLEADA. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

In a randomized study (SPARTAN) of patients with non-metastatic castrationresistant prostate cancer, fractures occurred in 12% of patients treated with ERLEADA and in 7% of patients treated with placebo. Grade 3-4 fractures occurred in 3% of patients treated with ERLEADA and in 1% of patients treated with placebo. The median time to onset of fracture was 314 days (range: 20 to 953 days) for patients treated with ERLEADA. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the SPARTAN study.

In a randomized study (TITAN) of patients with metastatic castrationsensitive prostate cancer, fractures occurred in 9% of patients treated with ERLEADA and in 6% of patients treated with placebo. Grade 3-4 fractures were similar in both arms at 2%. The median time to onset of fracture was 56 days (range: 2 to 111 days) for patients treated with ERLEADA. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the TITAN study.

Falls Falls occurred in patients receiving ERLEADA with increased frequency in the elderly [see Use in Specific Populations]. Evaluate patients for fall risk.

In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA compared to 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure.

Seizure Seizure occurred in patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

In two randomized studies (SPARTAN and TITAN), five patients (0.4%) treated with ERLEADA and one patient treated with placebo (0.1%) experienced a seizure. Seizure occurred from 159 to 650 days after initiation of ERLEADA. Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizure were excluded. There is no clinical experience in re-administering ERLEADA to patients who experienced a seizure.

Embryo-Fetal Toxicity The safety and efficacy of ERLEADA have not been established in females.

Based on its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1) in full Prescribing Information]. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Ischemic Cardiovascular Events [see Warnings and Precautions].

• Fractures [see Warnings and Precautions].

• Falls [see Warnings and Precautions].

• Seizure [see Warnings and Precautions].

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ERLEADA® (apalutamide) tablets

E

The most common adverse reactions (≥ 10%) that occurred more frequently in the ERLEADA-treated patients (≥ 2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

Metastatic Castration-sensitive Prostate Cancer (mCSPC) TITAN, a randomized (1:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had mCSPC. In this study, patients received either ERLEADA at a dose of 240 mg daily or placebo. All patients in the TITAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. The median duration of exposure was 20 months (range: 0 to 34 months) in patients who received ERLEADA and 18 months (range: 0.1 to 34 months) in patients who received placebo.

Ten patients (2%) who were treated with ERLEADA died from adverse reactions. The reasons for death were ischemic cardiovascular events (n=3), acute kidney injury (n=2), cardio-respiratory arrest (n=1), sudden cardiac death (n=1), respiratory failure (n=1), cerebrovascular accident (n=1), and large intestinal ulcer perforation (n=1). ERLEADA was discontinued due to adverse reactions in 8% of patients, most commonly from rash (2%). Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 23% of patients; the most frequent (>1%) were rash, fatigue, and hypertension.

Serious adverse reactions occurred in 20% of ERLEADA-treated patients and 20% in patients receiving placebo.

Table 1 shows adverse reactions occurring in ≥10% on the ERLEADA arm in TITAN that occurred with a ≥2% absolute increase in frequency compared to placebo. Table 2 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the ERLEADA arm compared to placebo.

E T c a d A i v i T E T S t p

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Table 1: Adverse Reactions in TITAN (mCSPC) ERLEADA Placebo N=524 N=527 All Grades Grade 3-4 All Grades Grade 3-4 % % % %

System/Organ Class Adverse reaction General disorders and administration site conditions Fatigue1,3 Musculoskeletal and connective tissue disorders Arthralgia3 Skin and subcutaneous tissue disorders Rash2 Pruritus Vascular disorders Hot flush Hypertension 1 2

3

26

3

25

2

17

0.4

15

0.9

28 11

6 <1

9 5

0.6 <1

23 18

0 8

16 16

0 9

Includes fatigue and asthenia Includes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular Per the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3

1

2

3

Additional adverse reactions of interest occurring in 2%, but less than 10% of patients treated with ERLEADA included diarrhea (9% versus 6% on placebo), muscle spasm (3% versus 2% on placebo), dysgeusia (3% versus 1% on placebo), and hypothyroidism (4% versus 1% on placebo).

Table 2: Laboratory Abnormalities Occurring in ≥ 15% of ERLEADA-Treated Patients and at a Higher Incidence than Placebo (Between Arm Difference > 5% All Grades) in TITAN (mCSPC) ERLEADA N=524 Laboratory Abnormality

4

5

All Grades %

Grade 3-4 %

All Grades %

Grade 3-4 %

27

0.4

19

0.6

17

3

12

2

Hematology White blood cell decreased Chemistry Hypertriglyceridemia1 1

Placebo N=527

Does not reflect fasting values

Non-metastatic Castration-resistant Prostate Cancer (nmCRPC) SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had nmCRPC. In this study, patients received either ERLEADA at a dose of 240 mg daily or a placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 16.9 months (range: 0.1 to 42 months) in patients who received ERLEADA and 11.2 months (range: 0.1 to 37 months) in patients who received placebo.

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Eight patients (1%) who were treated with ERLEADA died from adverse reactions.

The reasons for death were infection (n=4), myocardial infarction (n=3), and cerebral hemorrhage (n=1). One patient (0.3%) treated with placebo died from an adverse reaction of cardiopulmonary arrest (n=1). ERLEADA was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3%).

Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of ERLEADA-treated patients and 23% in patients receiving placebo.

The most frequent serious adverse reactions (>2%) were fracture (3%) in the ERLEADA arm and urinary retention (4%) in the placebo arm.

Table 3 shows adverse reactions occurring in ≥10% on the ERLEADA arm in SPARTAN that occurred with a ≥2% absolute increase in frequency compared to placebo. Table 4 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the ERLEADA arm compared to placebo.

Table 4: Laboratory Abnormalities Occurring in ≥ 15% of ERLEADA-Treated Patients and at a Higher Incidence than Placebo (Between Arm Difference > 5% All Grades) in SPARTAN (nmCRPC)

Table 3: Adverse Reactions in SPARTAN (nmCRPC) System/Organ Class Adverse reaction General disorders and administration site conditions Fatigue1,4 Musculoskeletal and connective tissue disorders Arthralgia4 Skin and subcutaneous tissue disorders Rash2 Metabolism and nutrition disorders Decreased appetite5 Peripheral edema6 Injury, poisoning and procedural complications Fall4 Fracture3 Investigations Weight decreased4 Vascular disorders Hypertension Hot flush Gastrointestinal disorders Diarrhea Nausea 1

h r, n, n,

2

e

3

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d m

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4 5 6

ERLEADA Placebo N=803 N=398 All Grades Grade 3-4 All Grades Grade 3-4 % % % % 39

1

28

0.3

16

0

8

0

25

5

6

0.3

12 11

0.1 0

9 9

0 0

16 12

2 3

9 7

0.8 0.8

16

1

6

0.3

25 14

14 0

20 9

12 0

20 18

1 0

15 16

0.5 0

Includes fatigue and asthenia Includes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular Includes rib fracture, lumbar vertebral fracture, spinal compression fracture, spinal fracture, foot fracture, hip fracture, humerus fracture, thoracic vertebral fracture, upper limb fracture, fractured sacrum, hand fracture, pubis fracture, acetabulum fracture, ankle fracture, compression fracture, costal cartilage fracture, facial bones fracture, lower limb fracture, osteoporotic fracture, wrist fracture, avulsion fracture, fibula fracture, fractured coccyx, pelvic fracture, radius fracture, sternal fracture, stress fracture, traumatic fracture, cervical vertebral fracture, femoral neck fracture, and tibia fracture Per the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3 Includes appetite disorder, decreased appetite, early satiety, and hypophagia Includes peripheral edema, generalized edema, edema, edema genital, penile edema, peripheral swelling, scrotal edema, lymphedema, swelling, and localized edema

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ERLEADA included hypothyroidism (8.1% versus 2% on placebo), pruritus (6.2% versus 2% on placebo), and heart failure (2.2% versus 1% on placebo).

ERLEADA N=803 Laboratory Abnormality Hematology Anemia Leukopenia Lymphopenia Chemistry Hypercholesterolemia1 Hyperglycemia1 Hypertriglyceridemia1 Hyperkalemia

Placebo N=398

All Grades %

Grade 3-4 %

All Grades %

Grade 3-4 %

70 47 41

0.4 0.3 2

64 29 21

0.5 0 2

76 70 67 32

0.1 2 2 2

46 59 49 22

0 1 0.8 0.5

Does not reflect fasting values Rash In the combined data of two randomized, placebo-controlled clinical studies, rash associated with ERLEADA was most commonly described as macular or maculo-papular. Adverse reactions of rash were reported for 26% of patients treated with ERLEADA versus 8% of patients treated with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (6%) versus placebo (0.5%).

The onset of rash occurred at a median of 83 days of ERLEADA treatment.

Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids.

Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA. Hypothyroidism In the combined data of two randomized, placebo-controlled clinical studies, hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroidstimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 5% of patients treated with ERLEADA. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted [see Drug Interactions].

Post-Marketing Experience The following additional adverse reactions have been identified during postapproval use of ERLEADA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease DRUG INTERACTIONS Effect of Other Drugs on ERLEADA Strong CYP2C8 or CYP3A4 Inhibitors Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl-apalutamide).

No initial dose adjustment is necessary however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2) in full Prescribing Information]. Mild or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect the exposure of apalutamide.

Effect of ERLEADA on Other Drugs CYP3A4, CYP2C9, CYP2C19 and UGT Substrates ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity [see Clinical Pharmacology (12.3) in full Prescribing Information].

1

T:8” S:6.75”

ERLEADA® (apalutamide) tablets

ERLEADA® (apalutamide) tablets

P-gp, BCRP or OATP1B1 Substrates Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. At steady-state, apalutamide reduced the plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a BCRP/OATP1B1 substrate). Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The safety and efficacy of ERLEADA have not been established in females.

Based on its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy [see Clinical Pharmacology (12.1) in full Prescribing Information].

There are no human data on the use of ERLEADA in pregnant women. ERLEADA is not indicated for use in females, so animal embryo-fetal developmental toxicology studies were not conducted with apalutamide.

Lactation Risk Summary The safety and efficacy of ERLEADA have not been established in females.

There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production.

Females and Males of Reproductive Potential Contraception Males Based on the mechanism of action and findings in an animal reproduction study, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. [see Use in Specific Populations].

Infertility Males Based on animal studies, ERLEADA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) in full Prescribing Information].

Pediatric Use Safety and effectiveness of ERLEADA in pediatric patients have not been established.

Geriatric Use Of the 1327 patients who received ERLEADA in clinical studies, 19% of patients were less than 65 years, 41% of patients were 65 years to 74 years, and 40% were 75 years and over.

No overall differences in effectiveness were observed between older and younger patients.

Of patients treated with ERLEADA (n=1073), Grade 3-4 adverse reactions occurred in 39% of patients younger than 65 years, 41% of patients 65-74 years, and 49% of patients 75 years or older. Falls in patients receiving ERLEADA with androgen deprivation therapy was elevated in the elderly, occurring in 8% of patients younger than 65 years, 10% of patients 65-74 years, and 19% of patients 75 years or older.

OVERDOSAGE There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop ERLEADA, undertake general supportive measures until clinical toxicity has been diminished or resolved.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Ischemic Cardiovascular Events • Inform patients that ERLEADA has been associated with ischemic cardiovascular events. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular event occur [see Warnings and Precautions].

Falls and Fractures • Inform patients that ERLEADA is associated with an increased incidence of falls and fractures [see Warnings and Precautions].

Seizures • Inform patients that ERLEADA has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they experience a seizure [see Warnings and Precautions].

Rash • Inform patients that ERLEADA is associated with rashes and to inform their healthcare provider if they develop a rash [see Adverse Reactions].

Dosage and Administration • Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with ERLEADA. • Instruct patients to take their dose at the same time each day (once daily). ERLEADA can be taken with or without food. Each tablet should be swallowed whole.

• Inform patients that in the event of a missed daily dose of ERLEADA, they should take their normal dose as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose [see Dosage and Administration (2.1) in full Prescribing Information].

• Instruct patients who have difficulty swallowing tablets whole to mix the recommended dose of ERLEADA tablets with applesauce. Do not crush tablets [see Dosage and Administration (2.3) in full Prescribing Information].

Embryo-Fetal Toxicity • Inform patients that ERLEADA can be harmful to a developing fetus.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. Advise male patients to use a condom if having sex with a pregnant woman [see Warnings and Precautions].

Infertility • Advise male patients that ERLEADA may impair fertility and not to donate sperm during therapy and for 3 months following the last dose of ERLEADA [see Use in Specific Populations].

Manufactured by: Janssen Ortho LLC Gurabo, PR 00778 Manufactured for: Janssen Products, LP Horsham, PA 19044 © 2019 Janssen Pharmaceutical Companies cp-50509v3

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CORRECCIÓN QUIRÚRGICA DE LA ARTERIA CARÓTIDA INTERNA TORTUOSA

El Comité Editorial de la Revista Puertorriqueña de Medicina y Salud Pública, su editor Fundador, Juan Carlos Orengo Valverde, su Editor Alberto Santiago Cornier, y los que hacemos posible cada número de esta revista, lamentamos sensiblemente el fallecimiento del distinguido Raúl García-Rinaldi.

Gracias, por su amistad, su magisterio, su legado.

Publicamos el último artículo sometido por el ilustre compañero.

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MSP ARTÍCULO / CASO CLÍNICO

Raúl García-Rinaldi MD, PhD

Isabel Becerra-Román MD

División de cirugía cardiovascular Mayagüez Medical Center Mayagüez, Puerto Rico

División de cirugía cardiovascular Mayagüez Medical Center Mayagüez, Puerto Rico

RESUMEN Las tortuosidades de la arteria carótida internas son relativamente comunes, frecuentemente asociadas con la estenosis de arteria carótida y pueden causar insuficiencia cerebrovascular.

Se han descrito muchas técnicas de reparación, incluyendo el uso de varios materiales de parche para complementar las técnicas de resección.

Objetivo: evaluar retrospectivamente la seguridad y los resultados de la reparación quirúrgica y la angioplastia con parche en pacientes con arteria carótida interna tortuosa. Métodos: ahora reportamos nuestros resultados en 90 pacientes tratados con resección parcial de la arteria carótida interna, endarterectomía carotídea si está indicada, y angioplastia con parche de Dacron®. No se observó ninguna muerte perioperatoria.

Resultados: el seguimiento medio fue de 11 meses. Dos (2%) de los pacientes tuvieron déficit neurológico transitorio.

Conclusión: la técnica empleada es segura y efectiva y podría ser utilizada en pacientes con esta condición.

ABSTRACT Tortuosities of the internal carotid artery are relatively common, frequently associated with carotid artery stenosis and can cause cerebrovascular insufficiency. Many techniques of repair have been described, including the use of various patch materials to complement resectional techniques.

Objective: To retrospectively evaluate safety and outcomes of surgical repair and patch angiopasty for patients with tortuous internal carotid artery.

Methods: We now report our results in 90 patients treated by partial resection of the internal carotid artery, carotid endarterectomy if indicated, and Dacron®patch angioplasty. No perioperative death was observed.

Results: The mean follow-up was 11 months. Two (2%) patients had transient neurological deficit.

Conclusion: The technique employed is safe and effective, and could be utilized in patients with these conditions.

PALABRAS CLAVES Cirugía de carótida, arteria carótida interna, endarterectomía carotídea, tortuosidad carotídea KEYWORDS Carotid surgery, internal carotid artery, carotid endarterectomy, carotid tortuosity Revista Puertorriqueña de Medicina y Salud Pública

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INTRODUCCIÓN El alargamiento de la arteria carótida interna (ACI) puede resultar en el enrollamiento o torsión de la arteria. La torsión se define como una angulación aguda de un segmento de la ACI, frecuentemente asociada a la estenosis funcional de la porción afectada[1,2]. El enrollamiento es la redundancia de la ACI que resulta en una angulación exagerada en forma de C o S o una configuración circular de la arteria carótida interna[1]. Estas tortuosidades pueden ocurrir en el 10 al 25% de la población[3-5].

Las malformaciones embrionarias que resultan en enrollamientos y torsiones rara vez se observan en niños.

La ACI se deriva del tercer arco aórtico de la raíz aórtica dorsal. En la mayoría de los casos, una torcedura que ocurre normalmente se endereza a medida que desciende el corazón y los grandes vasos[6-8].

El envejecimiento causa una pérdida en la elasticidad de la pared arterial. Esto, en combinación con tensiones laterales, causa el alargamiento de la ACI entre dos puntos fijos: el cráneo y la entrada torácica [8]. Las torsiones de la ACI pueden causar síntomas neurológicos en algunas posiciones y movimientos de la cabeza en algunos pacientes[7,8]. El enrollamiento es sintomático solo en algunos pacientes[9].

El tratamiento de una torsión carotídea con estenosis carotídea debe ser concomitante. Fearn y McCollum demostraron que la reparación simultánea puede ser realizada sin mortalidad o morbilidad adicional en

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comparación con la endarterectomía carotídea aislada (CEA por sus siglas en inglés)[10].

La tortuosidad de la ACI ha sido tratada usando varias técnicas. El tratamiento fue descrito por primera vez en 1951, cuando Riser et al. suturaron el margen de una arteria carótida interna retorcida al músculo esternocleidomastoideo [11].

Las técnicas seccionales tales como (a) resección de una arteria carótida interna redundante con anastomosis de extremo a extremo, (b) división de la ACI con reimplantación en la arteria carótida común proximal y (c) se ha empleado exitosamente la resección de un segmento de la arteria carótida común[8].

El uso de material de parche para complementar las técnicas reseccionales ha variado significativamente desde su aplicación inicial. Materiales como: espuma de acrilato [12], vena safena autóloga o aloinjerto[3,4,7,13-16], porción resecada de la arteria carótida [17], politetrafluoroetileno (PFTE) [4,16] y Dacron®[10,13] han sido utilizados con éxito como material de parche. Rosenthal et al. no describieron ninguna ventaja del uso de ningún tipo de parche en particular en su estudio comparativo [18].

Sin embargo, otros autores han concluido que no hay suficientes datos disponibles para establecer un tipo de parche óptimo[19].

Ahora reportamos nuestra experiencia clínic en la reparación del alargamiento de la arteria carótida, tratada con una resección parcial de la ACi redundante,

MSP ARTÍCULO / CASO CLÍNICO

con el uso concomitante de CEA si está indicado y el uso de un parche de Dacron®, una de las técnicas descritas por primera vez por Collins et al.[9].

MÉTODOS Noventa pacientes tratados entre 2001 y 2019 se sometieron a una resección parcial de la ACI y una angioplastia con parche de Dacron, 92% de los pacientes tuvieron una endarterectomía carotídea asociada. El estudio fue aprobado por la Junta de Revisión Institucional de la Universidad de Ciencias Médicas de Ponce. Los registros de la oficina y el hospital fueron revisados y se obtuvo información de la demografía de los pacientes, enfermedades comórbidas, estudios vasculares y cirugías, síntomas preoperatorios y duración de la hospitalización.

La población de pacientes consistió en 40 hombres y 50 mujeres. La edad media de este grupo fue de 73 (54-88 años). La tabla 1 resume las condiciones preexistentes de los pacientes, un número significativo de pacientes eran diabéticos e hipertensos y un 57% de ellos tenía una enfermedad arterial coronaria. Veintinueve (32%) de los pacientes se había sometido a intervenciones vasculares previas (Tabla 2).

Se identificó tortuosidad de la arteria carótida unilateral en 77 pacientes (86%) y trece (14%) tuvieron tortuosidad carótida bilateral. Ochenta y tres (92%) de los pacientes tuvieron enfermedad oclusiva de la carótida asociada.

Estos pacientes fueron sometidos a CEA con acortamiento

concomitante y reimplantación de la ACI y angioplastia con parche Dacron®. Un paciente se sometió a una cirugía concomitante de injerto de bypass de la arteria coronaria (CABG) (Tabla 3). Dos pacientes se sometieron a la reparación de la torsión y se realizó CEA seguido de una cirugía de bypass coronaria en la misma admisión.

Se reparó la torsión y se realizó CEA en cuatro pacientes y en una admisión posterior se realizó un bypass arterial coronario.

Las indicaciones para la corrección quirúrgica fueron síntomas cerebrovasculares focales o globales asociados con una tortuosidad de la ACI o pacientes asintomáticos con estenosis carotídea y >60% de estenosis de la ACI torsionada, demostrados por una arteriografía o examen con ultrasonido de doppler (DUS).

La tabla 4 ilustra los síntomas que se presentan en esta serie. Todos los pacientes fueron diagnosticados inicialmente con DUS carotídeo, veinte pacientes tuvieron ambos, DUS y arteriografía.

TÉCNICA QUIRÚRGICA Todas las operaciones fueron realizadas usando anestesia general, hicimos énfasis en el mantenimiento de una presión sanguínea estable en todo momento. Después de la anticoagulación con heparina, se aplicaron gentilmente abrazaderas vasculares en los vasos carótidos. La ACI proximal es resecada (0,5 a 1 cm) (Figura 1, A y B), seguido de una endarterectomía de las arterias carótidas

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comunes y las arterias carótidas externas (Figura 1, C y D). La pared posterior del ACI fue anastomosada a la cara posterior de la arteria carótida común (ACC) con una sutura de monofilamento 7-0 (Figura 1, E y F). Se aplica un parche de Dacron® con una sutura de monofilamento 6-0 y ambas suturas atadas a cada lado (Figura 1G). Se restableció el flujo sanguíneo, la hemostasia fue absoluta. Se realizó un examen doppler intraoperatorio.

RESULTADOS El seguimiento varió de 0,2 meses a 108 meses (media de 11 meses). No hubo muertes perioperatorias. El periodo promedio de hospitalización fue de cinco días (rango entre 1 y 35 días), aunque la mayoría de los pacientes estuvieron en el hospital por dos días. La tabla 3 resume los procedimientos quirúrgicos realizados en esta serie.

Dos pacientes (2%) tuvieron déficits neurológicos transitorios, ambos pacientes recuperaron la función sin discapacidad a largo plazo.

Cinco pacientes informaron de una debilidad facial ipsilateral transitoria que se resolvió en su totalidad.

Un paciente desarrolló un hematoma que requirió drenaje. Dos pacientes tuvieron disfagia leve transitoria que se resolvió.

Catorce meses después de la reparación, un paciente presentó mareo y tuvo una oclusión de la ACI reparada por DUS, también se identificó una nueva lesión oclusiva de la arteria común intratorácica. La paciente fue tratada exitosamente con un bypass de carótida subclavicular común, actualmente es asintomática.

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Veintisiete (30%) de los pacientes se sometieron a procedimientos vasculares posteriores después de la reparación. Quince pacientes se sometieron a CEA contralateral, 5 CABG, 2 a una fístula arteriovenosa, una resección abierta de un aneurisma aórtico abdominal y un reemplazo de válvula aórtica en otro.

Un paciente se sometió a un bypass aortofemoral y a un CEA contralateral, otro paciente a un bypass aortofemoral y más tarde a un CABG. Un paciente se sometió a una resección abierta de un AAA con una reconstrucción aortofemoral y más tarde una fístula arteriovenosa para hemodiálisis.

DISCUSIÓN Existe una fuerte relación entre el alargamiento de la ACI y los episodios cerebrovasculares locales o globales [3,7,9,11,16] . Es poco probable que el enrollamiento carotídeo sin ateroma asociado cause cambios hemodinámicos[9].

Recomendamos la reparación de las espirales de la ACI solo si son sintomáticas o están asociadas a la estenosis carotídea. La torsión, por otro lado, puede causar insuficiencia cerebrovascular particularmente con la extensión del cuello o el doblar o voltear la cabeza. Una torcedura puede ser lo suficientemente severa como para causar el

“El enrrollamiento o la torsión severa puede ser un hallazgo sonográfico o radiológico presente hasta en el 20% de los pacientes con insuficiencia cerebrovascular y constituye un hallazgo significativo”

MSP ARTÍCULO / CASO CLÍNICO

cese total del flujo sanguíneo de la carótida[4,9].

El enrollamiento o la torsión severa puede ser un hallazgo sonográfico o radiológico presente hasta en el 20% de los pacientes con insuficiencia cerebrovascular y constituye un hallazgo significativo [3]. Los estudios que comparan a los pacientes operados con los controles sin operar han confirmado que la tortuosidad de la ACI puede ser responsable de un alto riesgo de derrame[20]. Estamos de acuerdo con otros autores en que la reparación quirúrgica está indicada en los pacientes sintomáticos con torcedura de la ACI y estenosis carotídea[4,7]. Este acercamiento también se recomienda a los pacientes asintomáticos con oclusión contralateral de la ACI [16].

La endarterectomía de la carótida puede proporcionar una protección duradera contra los síntomas recurrentes y previene el derrame cerebral mejor que el tratamiento médico [13,20]. Nuestros datos confirman los hallazgos de que la corrección del alargamiento de la carótida y la enfermedad oclusiva carotídea pueden ser tratadas de forma segura con la técnica que empleamos, descrita por primera vez por Collin et al.[13]. Nuestra serie ilustra que estos pacientes usualmente habían tenido intervenciones vasculares, esta asociación con otras placas ateroscleróticas continuas durante el seguimiento indica la severidad del proceso de la enfermedad aterosclerótica.

Las metas del tratamiento quirúrgico en pacientes con ACI tortuosa son: (1) lograr una reparación permanente sin comprometer el calibre de los vasos, (2) remover cualquier placa estenótica, si se presenta, y (3) restaurar el flujo carotídeo normal [9].

La angioplastia de parche carotídeo ha demostrado disminuir el riesgo de accidente cerebrovascular perioperatorio en comparación con el cierre primario [19,21,22]. Esto fue enfatizado por Archie, quien demostró que el parche reduce significativamente la reestenosis de la carótida en comparación con el cierre primario [21]. El material del parche es cuestión de preferencia individual. Nuestra elección es un parche de Dacron®, que es fácil de usar, sangra menos que un parche de PTFE y evita una incisión separada para la recolección de la vena safena.

No utilizamos derivaciones intraoperatorias y no medimos la presión de la carótida. El mantenimiento de una presión arterial estable es obligatorio [23]. Aunque la cuestión del uso de las derivaciones sigue siendo objeto de debate [22-27] , nuestra elección ha sido no utilizarlas.

CONCLUSIÓN Nuestra revisión retrospectiva muestra que los pacientes que presentan tortuosidad ACI han sido sometidos a intervenciones vasculares previas y frecuentemente requieren más intervenciones. Estamos de acuerdo con muchos autores en que la reparación quirúrgica de la tortuosidad importante de la ACI, particularmente asociada con la estenosis carotídea, debe ser tratada

“La angioplastia de parche carotídeo ha demostrado disminuir el riesgo de accidente cerebrovascular perioperatorio en comparación con el cierre primario”

agresivamente. Aunque hay varias técnicas disponibles para tratar esta patología, preferimos la resección parcial y la reimplantación de la ICA con angioplastia de parche Dacron®. Esta técnica se ha empleado con éxito para corregir la flexión de la carótida y restablecer el flujo sanguíneo cerebral normal y prevenir la insuficiencia cerebrovascular.

REFERENCIAS 1. Weibel J, Fields WS. Tortuosity, Coiling, and Kinking of the Internal Carotid Artery. II. Relationship of Morphological Variation to Cerebrovascular Insufficiency. Neurology.

1965;15:462- 8. https://doi.org/10.1212/ WNL.15.5.462.

2. Metz H, Murray-Leslie RM, Bannister RG, et al. Kinking of the internal carotid artery in relation to cerebrovascular disease. Lancet.

1961;1:424 - 6. ht tps://doi.org/10.1016/ S0140-6736(61)90004-6.

3. Vollmar J, Nadjafi AS, Stalker CG. Surgical treatment of kinked internal carotid arteries.

Br J Surg. 1976;63:847-50. https://doi. org/10.1002/bjs.1800631103.

4. Illuminati G, Calio FG, Papaspyropoulos V, et al. Revascularization of the internal carotid artery for isolated, stenotic, and symptomatic kinking. Arch Surg. 2003;138:192-7.https://doi. org/10.1001/archsurg.138.2.192.

5. Yu J, Qu L, Xu B, et al. Current Understanding

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of Dolichoarteriopathies of the Internal Carotid Artery: A Review. Int J Med Sci. 2017;14:772–84. https://doi.org/10.7150/ijms.19229.

6. Desai B, Toole JF. Kinks, coils and carotids: a review. Stroke. 1975;6:649- 653. https://doi. org/10.1161/01.STR.6.6.649.

7. Vannix RS, Joergenson EJ, Carter R. Kinking of the internal carotid artery: clinical significance and surgical management. Am J Surg. 1977;134:82-9. https://doi.org/10.1016/0002-9610(77)90288-4.

8. Moore WS, Quinones-Baldrich WJ. Extracranial cerebrovascular disease. In: Moore WS, editor.

Vascular surgery: A comprehensive review. New York: Grune & Stratton;1983.p.493-545.

9. Poindexter JM Jr, Patel KR, Clauss RH. Management of kinked extracranial cerebral arteries. J Vasc Surg. 1987;6:127-33. https://doi.org/10.1067/ mva.1987.avs0060127.

10. Fearn SJ, McCollum CN. Shortening and reimplantation for tortuous internal carotid artery. J Vasc Surg. 1998;27:936-9. https://doi.org/10.1016/ S0741-5214(98)70275-7.

11. Riser MM, Geraud J, Ducoudray J, et al. Dolicho-carotide interne avec syndrome vertigineux [Long internal carotid artery with vertiginous syndrome].

Rev Neurol. 1951;85:145-7.

12. Henly WS, Cooley DA, Gordon WB, et al.

Tortuosity of the internal carotid artery: Report of seven cases treated surgically. Postgrad Med. 1962;31:133-42. https://doi.org/10.1080/003254 81.1962.11694547.

13. Collins PS, Orecchia P, Gomez E. A technique for correction of carotid kinks and coils following endarterectomy. Ann Vasc Surg. 1991;5:116-20. https://doi.org/10.1007/BF02016742.

14. Bakst A A. A New Operative Procedure for Correction of Kinked Carotid Arter y.

Vascular Surgery. 1990;24:54–9.https://doi. org/10.1177/153857449002400110.

15. Poorthuis MH, Brand EC, Toorop RJ, et al. Posterior transverse plication of the internal carotid artery to correct for kinking. J Vasc Surg. 2014;59:968-77. https://doi.org/10.1016/j.jvs.2013.10.053.

16. Ballotta E, Abbruzzese E, Thiene G, et al. The elongation of the internal carotid artery: early and long-term results of patients having surgery compared with unoperated controls. Ann Vasc Surg. 1997;11:120-8. https://doi.org/10.1007/ s100169900021.

17. Smith BM, Stans VA, Maggart MA. Operative

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management of the kinked carotid artery. Surg Gynecol Obstet 1986; 162:70-2 18. Rosenthal D, Archie JP, Garcia-Rinaldi R, et al.

Carotid patch angioplasty:Immediate and long-term results. J Vasc Surg. 1990;12:326-33. https://doi. org/10.1016/0741-5214(90)90156-5.

19. Bond R, Rerkasem K, Naylor AR, et al. Systematic review of randomized controlled trials of patch angioplasty versus primary closure and different types of patch materials during carotid endarterectomy. J Vasc Surg. 2004;40:1126-35. https://doi. org/10.1016/j.jvs.2004.08.048.

20. Ballotta E, Thiene G, Baracchini C, et al. Surgical vs medical treatment for isolated for isolated internal carotid artery elongation with coiling and kinking in symptomatic patients: a prospective randomized clinical study. J Vasc Surg. 2005;42:838-46. https://doi.org/10.1016/j.jvs.2005.07.034.

21. Archie JP. Carotid endarterectomy outcome with vein or Dacron graft patch angioplasty and internal carotid artery shortening. J Vasc Surg. 1999;29:654-64.https://doi.org/10.1016/ S0741-5214(99)70311-3.

22. AbuRahma AF. Process of care for carotid endarterctomy: Surgical and anesthesia considerations. J Vasc Surg. 2009;50:921-33.https://doi. org/10.1016/j.jvs.2009.04.071.

23. Boontje AH. Carotid endarterectomy without temporary indwelling shunt: results and analysis of back pressure measurements. Cardiovasc Surg.

1994;2:549-54 24. AbuRahma AF, Mousa AY, Stone PA. Shunting during carotid endarterectomy. J Vasc Surg.

2011;54:1502-10.ht t ps://doi.org/10.1016/j. jvs.2011.06.020.

25. AbuRahma AF, Stone PA, Hass SM, et al. Prospective randomized trial of routine versus selective shunting in carotid endarterectomy based on stump pressure. J Vasc Surg. 2010;51:1133-8. https://doi. org/10.1016/j.jvs.2009.12.046.

26. Ott DA, Cooley DA, Chapa L, et al. Carotid endarterectomy without temporary intraluminal shunt. Study of 309 consecutive operations.

A nn Surg. 1980;191:708 –14.ht t ps://d oi. org/10.1097/00000658-198006000-00008.

27. Halsey JH Jr. Risks and benefits of shunting in carotid endarterectomy. The International Transcranial Doppler Collaborators. Stoke. 1992; 23:1583-7. https://doi.org/10.1161/01.STR.23.11.1583.

BECAUSE A THROMBOTIC EVENT DOESN’T ALWAYS COME WITH A WARNING CHOOSE XARELTO® TO HELP PROTECT THEM FROM THE UNEXPECTED The DOAC with the most FDA-approved indications to treat and help protect against thrombotic events APPROVED in acutely ill medical patients*

INDICATIONS XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

XARELTO® is indicated for the treatment of deep vein thrombosis (DVT). XARELTO® is indicated for the treatment of pulmonary embolism (PE).

XARELTO® is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

*XARELTO® is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE-related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE, and not at high risk of bleeding.

XARELTO® is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

XARELTO® is indicated, in combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular [CV] death, myocardial infarction [MI], and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

IMPORTANT SAFETY INFORMATION WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of XARELTO® increases the risk of thrombotic events

procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

B. Spinal/epidural hematoma

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Premature discontinuation of any oral anticoagulant, including XARELTO®, increases the risk of thrombotic events. If anticoagulation with XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal

CONTRAINDICATIONS • Active pathological bleeding • Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS • Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

• Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue in patients with active pathological hemorrhage.

– An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable.

– Concomitant use of other drugs that impair hemostasis increases risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents,

• Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery • Optimal timing between the administration of XARELTO® and neuraxial procedures is not known

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).

– Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding: Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO® for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage; active cancer (ie, undergoing acute, in-hospital cancer treatment); active gastroduodenal ulcer or history of bleeding in the three months prior to treatment; or dual antiplatelet therapy. XARELTO® is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.

• Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with concurrent use of XARELTO® and epidural or spinal anesthesia/ analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO®. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO® is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be

DOAC = direct oral anticoagulant.

Please read accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS for XARELTO®.

IMPORTANT SAFETY INFORMATION (cont’d)

cp-62551v6

• Patients with Prosthetic Heart Valves: Use of XARELTO® is not recommended in patients who have had transcatheter aortic valve replacement (TAVR), based on the results of WARNINGS AND PRECAUTIONS (cont’d) the GALILEO study, which reported higher rates of death and bleeding in patients randomized • Spinal/Epidural Anesthesia or Puncture (cont'd): removed before at least 2 half-lives to XARELTO® compared to those randomized to an antiplatelet regimen. Safety and efficacy have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly of XARELTO® have not been studied in patients with other prosthetic heart valves or other patients aged 60 to 76 years), after the last administration of XARELTO®. The next dose should valve procedures. Use of XARELTO® is not recommended in patients with prosthetic heart not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture valves. occurs, delay the administration of XARELTO® for 24 hours. Monitor frequently to detect signs • Acute PE in Hemodynamically Unstable Patients/Patients Who Require or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO® is not (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct recommended acutely as an alternative to unfractionated heparin in patients with pulmonary patients to immediately report any of the above signs or symptoms. If signs or symptoms embolism who present with hemodynamic instability or who may receive thrombolysis or of spinal hematoma are suspected, initiate urgent diagnosis and treatment including pulmonary embolectomy. consideration for spinal cord decompression even though such treatment may not prevent or • Increased Risk of Thrombosis in Patients with Antiphospholipid Syndrome: reverse neurological sequelae.

Direct-acting oral anticoagulants (DOACs), including XARELTO®, are not recommended for • Use in Patients with Renal Impairment: use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS – Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, (ie, more frequently in situations in which renal function may decline) and adjust therapy and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with accordingly. Consider dose adjustment or discontinuation in patients who develop acute increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. ® ® renal failure while on XARELTO . Clinical efficacy and safety studies with XARELTO did not enroll patients with CrCl <30 mL/min or end-stage renal disease (ESRD) on dialysis.

DRUG INTERACTIONS – Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and • Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may Reduction in the Risk of Recurrence of DVT and of PE: In patients with CrCl increase risk of bleeding. <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared • Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may to patients with normal renal function. There are limited clinical data in patients with CrCl increase risk of thromboembolic events.

15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or • XARELTO® should not be used in patients with CrCl 15 to <80 mL/min who are receiving symptoms of blood loss in these patients. There are no clinical data in patients with CrCl concomitant combined P-gp and moderate CYP3A inhibitors (eg, erythromycin) unless the <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these potential benefit justifies the potential risk. patients. Discontinue XARELTO® in patients who develop acute renal failure while on • Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may treatment. increase risk of bleeding.

– Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement • Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, Surgery: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic unless benefit outweighs risk. Promptly evaluate signs or symptoms of blood loss if patients effects are increased compared to patients with normal renal function. There are limited are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate signs or symptoms of blood loss in these patients. There are no clinical USE IN SPECIFIC POPULATIONS data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the • Pregnancy: The limited available data on XARELTO® in pregnant women are insufficient ® ® use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO® with renal failure while on treatment. caution in pregnant patients because of the potential for pregnancy-related hemorrhage – Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients and/or emergent delivery. The anticoagulant effect of XARELTO® cannot be reliably at Risk for Thromboembolic Complications Not at High Risk of Bleeding: In monitored with standard laboratory testing. Consider the benefits and risks of XARELTO® for patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are the mother and possible risks to the fetus when prescribing to a pregnant woman. increased compared to patients with normal renal function. There are limited clinical data in – Fetal/Neonatal adverse reactions: Based on the pharmacologic activity of Factor Xa patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any inhibitors and the potential to cross the placenta, bleeding may occur at any site in the signs or symptoms of blood loss in these patients. There are no clinical data in patients with fetus and/or neonate.

CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in – Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic ® these patients. Discontinue XARELTO in patients who develop acute renal failure while on events when considering use in this setting. treatment.

– There are no adequate or well-controlled studies of XARELTO® in pregnant women, – Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD and dosing for pregnant women has not been established. Post-marketing experience is or PAD: For patients with CrCl <15 mL/min, no data are available, and limited data currently insufficient to determine a rivaroxaban-associated risk for major birth defects or are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/ miscarriage. min, a dose of 2.5 mg XARELTO® twice daily is expected to give an exposure similar to • Lactation: Rivaroxaban has been detected in human milk. There are insufficient data to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min), whose efficacy determine the effects of rivaroxaban on the breastfed child or on milk production. Consider and safety outcomes were similar to those with preserved renal function. Clinical the developmental and health benefits of breastfeeding along with the mother’s clinical need efficacy and safety studies with XARELTO® did not enroll patients with end-stage renal for XARELTO® and any potential adverse effects on the breastfed infant from XARELTO® or disease (ESRD) on dialysis. from the underlying maternal condition.

• Use in Patients with Hepatic Impairment: No clinical data are available for patients with • Females and Males of Reproductive Potential: Females of reproductive potential severe hepatic impairment. Avoid use in patients with moderate (Child-Pugh B) and severe requiring anticoagulation should discuss pregnancy planning with their physician.

(Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, • Pediatric Use: Safety and effectiveness in pediatric patients have not been established. since drug exposure and bleeding risk may be increased.

• Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of OVERDOSAGE XARELTO® with known combined P-gp and strong CYP3A inhibitors or inducers.

• Overdose of XARELTO® may lead to hemorrhage. Discontinue XARELTO® and initiate ® • Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO should be appropriate therapy if bleeding complications associated with overdosage occur. An used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® agent to reverse the anti-factor Xa activity of rivaroxaban is available. dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing. Promptly evaluate signs or symptoms suggesting ADVERSE REACTIONS IN CLINICAL STUDIES blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

• Most common adverse reactions with XARELTO® were bleeding complications.

Please read accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS for XARELTO®.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2020 April 2020 cp-108829v4

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.3) in Full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in Full Prescribing Information].

B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery • optimal timing between the administration of XARELTO and neuraxial procedures is not known [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1) in Full Prescribing Information].

Treatment of Deep Vein Thrombosis XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

Treatment of Pulmonary Embolism XARELTO is indicated for the treatment of pulmonary embolism (PE).

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding [see Warnings and Precautions and Clinical Studies (14.1) in Full Prescribing Information].

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD) XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular (CV) death, myocardial infarction (MI) and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions]

XARELTO® (rivaroxaban) tablets WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.3) and Clinical Studies (14.1) in Full Prescribing Information].

Risk of Bleeding XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal antiinflammatory drugs (NSAIDs) [see Drug Interactions], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy.

XARELTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.

Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.1) in Full Prescribing Information]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations].

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations].

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function.

There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations].

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function.

There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Population].

Use in Patients with Hepatic Impairment No clinical data are available for patients with severe hepatic impairment.

Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations].

Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions].

Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions].

Risk of Pregnancy-Related Hemorrhage In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions and Use in Specific Populations].

Patients with Prosthetic Heart Valves On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves.

Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including XARELTO, are not recommended for use in patients with triple-positive antiphospholipid

syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: • Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and Warnings and Precautions] • Bleeding Risk [see Warnings and Precautions] • Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 31,691 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3); 3997 patients who received 10 mg orally once daily for prophylaxis of VTE and VTE-related death in acutely ill medical patients (MAGELLAN) and 9134 patients who received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily, for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).

Hemorrhage The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.

Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days Parameter Major Bleeding†

XARELTO Warfarin N=7111 N=7125 n (%/year) n (%/year) 395 (3.6) 386 (3.5)

XARELTO vs. Warfarin HR (95% CI) 1.04 (0.90, 1.20)

55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) Intracranial Hemorrhage (ICH)‡ Hemorrhagic Stroke§ 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96) Other ICH 19 (0.2) 26 (0.2) 0.74 (0.41, 1.34) Gastrointestinal (GI)¶ 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99) 27 (0.2) 55 (0.5) 0.50 (0.31, 0.79) Fatal Bleeding# ICH 24 (0.2) 42 (0.4) 0.58 (0.35, 0.96) Non-intracranial 3 (0.0) 13 (0.1) 0.23 (0.07, 0.82) Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. ‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. § Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. ¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. # Fatal bleeding is adjudicated death with the primary cause of death from bleeding.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Figure 1 shows the risk of major bleeding events across major subgroups.

Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.

Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

Table 3: Bleeding Events* in EINSTEIN CHOICE XARELTO† 10 mg N=1127 n (%) 5 (0.4) 0 2 (0.2) 3 (0.3) 22 (2.0)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN DVT and EINSTEIN PE Studies In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/ Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively.

The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.

Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Enoxaparin/ VKA† XARELTO† N=4130 N=4116 Parameter n (%) n (%) Major bleeding event 40 (1.0) 72 (1.7) Fatal bleeding 3 (<0.1) 8 (0.2) Intracranial 2 (<0.1) 4 (<0.1) Non-fatal critical organ bleeding 10 (0.2) 29 (0.7) Intracranial‡ 3 (<0.1) 10 (0.2) Retroperitoneal‡ 1 (<0.1) 8 (0.2) Intraocular‡ 3 (<0.1) 2 (<0.1) Intra-articular‡ 0 4 (<0.1) Non-fatal non-critical organ bleeding§ 27 (0.7) 37 (0.9) Decrease in Hb ≥ 2 g/dL 28 (0.7) 42 (1.0) Transfusion of ≥2 units of whole blood or 18 (0.4) 25 (0.6) packed red blood cells Clinically relevant non-major bleeding 357 (8.6) 357 (8.7) Any bleeding 1169 (28.3) 1153 (28.0) * Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/ VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells

Acetylsalicylic Acid (aspirin)† 100 mg N=1131 n (%) 3 (0.3) 1 (<0.1) 1 (<0.1) 1 (<0.1) 20 (1.8)

Parameter Major bleeding event Fatal bleeding Non-fatal critical organ bleeding Non-fatal non-critical organ bleeding§ Clinically relevant non-major (CRNM) bleeding¶ Any bleeding 151 (13.4) 138 (12.2) * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily. § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. ¶ Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

Total treated patients Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event‡ Hip Surgery Studies Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event‡

XARELTO 10 mg N=4487 n (%) 14 (0.3) 1 (<0.1) 2 (<0.1) 7 (0.2) 4 (0.1)

Enoxaparin†

261 (5.8) N=3281 n (%) 7 (0.2) 1 (<0.1) 1 (<0.1) 2 (0.1) 3 (0.1)

251 (5.6) N=3298 n (%) 3 (0.1) 0 1 (<0.1) 1 (<0.1) 1 (<0.1)

201 (6.1)

191 (5.8)

N=4524 n (%) 9 (0.2) 0 3 (0.1) 5 (0.1) 1 (<0.1)

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3) (continued)

Table 6: Major Bleeding Events* in COMPASS - On Treatment Plus 2 days

Knee Surgery Study

XARELTO 10 mg N=1206 n (%) 7 (0.6) 0 1 (0.1) 5 (0.4) 1 (0.1)

Enoxaparin† N=1226 n (%) 6 (0.5) 0 2 (0.2) 4 (0.3) 0

Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 60 (5.0) 60 (4.9) Any bleeding event‡ * Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication.

Patients may have more than one event. † Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) ‡ Includes major bleeding events Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events. Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Patients with bronchiectasis/pulmonary cavitation, active cancer (i.e., undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 5. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo.

Table 5 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study.

Table 5: Bleeding Events in MAGELLAN* Study–Safety Analysis Set - On Treatment Plus 2 Days Enoxaparin 40 mg / MAGELLAN Study¶ XARELTO 10 mg placebo N=3218 N=3229 n (%) n (%) Major bleeding‡† 22 (0.7) 15 (0.5) Critical site bleeding 7 (0.2) 4 (0.1) 3 (<0.1) 1 (<0.1) Fatal bleeding§ Clinically relevant non-major 93 (2.9) 34 (1.1) bleeding events (CRNM) * Patients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. † Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. ‡ Defined as clinically overt bleeding associated with a drop in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. § Fatal bleeding is adjudicated death with the primary cause of death from bleeding. ¶ Patients received either XARELTO or placebo once daily for 35 ±4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 ±4 days in the hospital.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD In the COMPASS trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily in combination with aspirin 100 mg once daily vs. 1.2% for aspirin 100 mg once daily.

Table 6 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

Parameter Modified ISTH Major Bleeding‡

XARELTO plus Aspirin alone† XARELTO plus aspirin† N=9107 aspirin vs.

N=9134 Aspirin alone n (%/year) n (%/year) HR (95 % CI) 263 (1.6)

144 (0.9)

1.84 (1.50, 2.26)

12 (<0.1)

8 (<0.1)

1.51 (0.62, 3.69)

6 (<0.1) 6 (<0.1)

3 (<0.1) 5 (<0.1)

2.01 (0.50, 8.03) 1.21 (0.37, 3.96)

58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1)

43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1)

1.36 (0.91, 2.01) 1.09 (0.61, 1.98) 1.38 (0.68, 2.82) 0.67 (0.24, 1.88)

- Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ)

7 (<0.1)

6 (<0.1)

1.17 (0.39, 3.48)

- Bleeding leading to hospitalization (nonfatal, not in critical organ, not requiring reoperation)

188 (1.1)

91 (0.5)

2.08 (1.62, 2.67)

117 (0.7)

49 (0.3)

2.40 (1.72, 3.35)

- Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial - Symptomatic bleeding in critical organ (non-fatal) ICH Hemorrhagic Stroke Other ICH

Major GI bleeding

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. † Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or aspirin 100 mg once daily ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization.

CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Figure 2 shows the risk of modified ISTH major bleeding events across major subgroups.

Figure 2: Risk of Modified ISTH Major Bleeding Events by Baseline Characteristics in COMPASS – On Treatment Plus 2 Days

Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 7.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Table 7: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System Adverse Reaction XARELTO 20 mg Enoxaparin/VKA EINSTEIN DVT Study N=1718 N=1711 n (%) n (%) Gastrointestinal disorders Abdominal pain 46 (2.7) 25 (1.5) General disorders and administration site conditions Fatigue 24 (1.4) 15 (0.9) Musculoskeletal and connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle spasm 23 (1.3) 13 (0.8) Nervous system disorders Dizziness 38 (2.2) 22 (1.3) Psychiatric disorders Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) XARELTO 20 mg Enoxaparin/VKA EINSTEIN PE Study N=2412 N=2405 n (%) n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator

DRUG INTERACTIONS General Inhibition and Induction Properties Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATPbinding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman [see Warnings and Precautions].

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal Adverse Reactions Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

Data Human Data There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 8.

Table 8: Other Adverse Drug Reactions* Reported by ≥1% of XARELTOTreated Patients in RECORD 1-3 Studies XARELTO 10 mg N=4487 n (%)

Enoxaparin† Body System N=4524 Adverse Reaction n (%) Injury, poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.0) Musculoskeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) * Adverse reaction occurring any time following the first dose of doubleblind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) Postmarketing Experience The following adverse reactions have been identified during post-approval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Animal Data Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Lactation Risk Summary Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).

Data Animal Data Following a single oral administration of 3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

Females and Males of Reproductive Potential Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Geriatric Use Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years.

In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In the MAGELLAN study, approximately 67% were 65 years and over and about 37% were >75 years. In the COMPASS study, approximately 76% were 65 years and over and about 17% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3) and Clinical Studies (14) in Full Prescribing Information].

Renal Impairment In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Nonvalvular Atrial Fibrillation Patients with Chronic Kidney Disease not on Dialysis In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Patients with End-Stage Renal Disease on Dialysis Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF. Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. In the RECORD 1-3 trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding Patients with CrCl values <30 mL/min at screening were excluded from the MAGELLAN study. In patients with CrCl <30 mL/min a dose of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid use of XARELTO in patients with CrCl <15 mL/min.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD Patients with Chronic Kidney Disease not on Dialysis Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information], whose efficacy and safety outcomes were similar to those with preserved renal function.

Patients with End-Stage Renal Disease on Dialysis No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS. Hepatic Impairment In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Product of Germany Finished Product Manufactured by: Janssen Ortho LLC or Gurabo, PR 00778

Bayer AG 51368 Leverkusen, Germany

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

© 2011-2019 Janssen Pharmaceutical Companies cp-62544v7

INSTITUTO INSTITUTO INSTITUTO INSTITUTO CARDIOVASCULAR CARDIOVASCULAR CARDIOVASCULAR CARDIOVASCULAR SAN SAN LUCAS SAN SANLUCAS LUCAS LUCAS

Los Los especialistas que necesita corazón Los Losespecialistas especialistas especialistasque que quenecesita necesita necesitatu tutu tucorazón corazón corazón

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PROCEDIMIENTOS PROCEDIMIENTOS PROCEDIMIENTOS PROCEDIMIENTOS INNOVADORES INNOVADORES INNOVADORES INNOVADORES

INSTITUTO INSTITUTO INSTITUTO INSTITUTO CARDIOVASCULAR CARDIOVASCULAR CARDIOVASCULAR CARDIOVASCULAR

El Centro El Centro Médico Médico Episcopal Episcopal SanSan Lucas Lucas es el es el El Centro El Centro Médico Médico San esen el esen el primer primer hospital hospital en Episcopal Puerto en Episcopal Puerto Rico Rico y San elLucas yCaribe elLucas Caribe primer primer hospital hospital enprocedimiento Puerto en Puerto Rico Rico yde elyde Caribe el Caribe en en practicar practicar el el procedimiento implante implante practicar practicar el que el procedimiento procedimiento de implante implante “Watchman” “Watchman” que evita evita queque losde los coágulos coágulos de de “Watchman” “Watchman” que evita evita que que los los coágulos de de sangre sangre entren entren alque flujo al flujo sanguíneo sanguíneo ycoágulos puedan y puedan sangre sangre entren entren al flujo alcerebrovascular. flujo sanguíneo sanguíneo y También puedan y También puedan causar causar un accidente un accidente cerebrovascular. causar causar uncon accidente uncon accidente cerebrovascular. cerebrovascular.

También También cuenta cuenta el elprimer primer electrofisiólogo electrofisiólogo cuenta cuenta con con elrealizarlo.“Watchman” elrealizarlo.“Watchman” primer primerelectrofisiólogo electrofisiólogo adiestrado adiestrado para para es un es un adiestrado adiestrado para para esuna un esuna un procedimiento procedimiento derealizarlo.“Watchman” avanzada derealizarlo.“Watchman” avanzada queque presenta presenta procedimiento procedimiento avanzada de avanzada quepara que presenta presenta unauna alternativa alternativaa de alargo largo plazo plazo para algunos algunos alternativa alternativa acon alargo largoplazo plazo para para algunos pacientes pacientes con fibrilación fibrilación auricular auricular no algunos no valvular valvular pacientes con con fibrilación fibrilación auricular auricular no no valvular valvular quepacientes que utilizan utilizan Warfarina.

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OFRECEMOS: OFRECEMOS: OFRECEMOS: OFRECEMOS: Cardiólogos Cardiólogos disponibles disponibles 24/7 24/7 Cardiólogos disponibles disponibles 24/7 24/7 en Cardiólogos en Sala Sala de de Emergencia Emergencia para para atender atender en en Sala Sala demiocardio de Emergencia Emergencia para para atender atender infarto infarto al al miocardio (STEMI) (STEMI) infarto infarto al miocardio al miocardio (STEMI) (STEMI) Angioplastía Angioplastía compleja compleja concon Angioplastía Angioplastía compleja compleja con con oclusión oclusión total total crónica crónica (CTO) (CTO) oclusión oclusión total total crónica crónica (CTO) (CTO) Angioplastía Angioplastía coronaria coronaria y periferovascular y periferovascular Angioplastía Angioplastía coronaria coronaria y periferovascular y periferovascular

Crio Crio ablación ablación y ablación y ablación para para arritmias arritmias Crio Crio ablación ablación y ablación y ablación para para arritmias arritmias Ecocardiograma Ecocardiograma transtorácico transtorácico 3D3D Ecocardiograma Ecocardiograma transtorácico transtorácico 3D3D Ecocardiograma Ecocardiograma Transesofágico Transesofágico (TEE) (TEE) Ecocardiograma Ecocardiograma Transesofágico Transesofágico (TEE) (TEE) Pruebas Pruebas de de esfuerzo esfuerzo (Stress (Stress Test) Test) Pruebas Pruebas de de esfuerzo esfuerzo (Stress (Stress Test) Test) Monitoreo Monitoreo cardíaco cardíaco 24 24 horas horas (Holter) (Holter) Monitoreo Monitoreo cardíaco cardíaco 24 24 horas horas (Holter) (Holter)

787.844.2080 787.844.2080 | sanlucaspr.org | sanlucaspr.org 787.844.2080 787.844.2080 | sanlucaspr.org | sanlucaspr.org centromedicoepiscopalsanlucas centromedicoepiscopalsanlucas centromedicoepiscopalsanlucas centromedicoepiscopalsanlucas

EL AÑO QUE PUSO A PRUEBA A LA CIENCIA

MEDICINA EN TIEMPOS DE PANDEMIA

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La pandemia está generando cambios significativos en los procesos de publicación científica. En muchos lugares, el tiempo entre la presentación y la publicación de un manuscrito se ha reducido de manera significativa. En Puerto Rico, estos acontecimientos ponen a prueba la relevancia de las investigaciones, los hallazgos y su importancia para el mundo académico.

BELINDA Z. BURGOS GONZÁLEZ AGENCIA LATINA DE NOTICIAS MEDICINA Y SALUD PÚBLICA

COVID-19 DEBUTA CON PANCREATITIS EN PACIENTE PUERTORRIQUEÑO No tuvo fiebre, tos, dolor de garganta, sarpullido, dificultad respiratoria, ni otros síntomas asociados dentro del cuadro clínico del infeccioso coronavirus. Presentó pancreatitis.

Este fue el caso de un hombre que se presentó a la sala de emergencias con dolor abdominal que se irradiaba a la espalda, y los niveles de triglicéridos y enzimas hepáticas reflejaron niveles un poco altos, según el Dr. Lorenzo Ortíz Román, médico interno del Hospital Auxilio Mutuo.

“Aunque los doctores de sala de emergencias no hallaban explicación alguna para el origen de la pancreatitis ya que hay bastantes (cuadros clínicos que pudieran provocarla). Al realizarle la prueba de COVID19, salió positiva. Al paciente se le colocó en aislamiento y se le ordenó un examen (radiológico) “CT” de abdomen donde se le vió la inflamación en el páncreas, pero también se vieron que las bases pulmonares con opacidades (cambios en la parénquima del pulmón) como hallazgo incidental”, relató a Medicina y Salud Pública (MSP).

“Al paciente se le comenzó a tratar bajo los protocolos clínicos para el COVID19 del Dr. Fernando Cababillas, con esteroides, y comenzaron a bajar los marcadores inflamatorios. Este paciente no tenía tos, no

tenía fiebre ni los síntomas comunes asociados a COVID19. Las indicaciones además del radiólogo concurrían con una neumonía viral.”, puntualizó.

Enfatizó que dado el caso, durante la pandemia los médicos han dado indicaciones de que todo paciente que arribe a la sala de emergencias con pancreatitis y no se le halle las causas más comúnes que propendan al desarrollo de este tipo de cuadro, se le realice la prueba de COVID19.

“El paciente fue dado de alta, pero es importante recalcar que en distintos estudios se ha hablado ya de que se han encontrado partículas del virus en el tejido pancreático.

De hecho, el páncreas tiene un receptor en los pulmones que es el mismo que utiliza el virus para invadir las células en los pulmones . Se conoce la patofisiología de cómo el virus invade las células y por lo tanto es importante que si no se le haya causa común de pancreatitis a un paciente, se le haga prueba para COVID19”, afirmó.

Una pancreatitis es una inflamación del páncreas síntomas comunes son dolor intenso en la parte superior del abdomen, náuseas y vómito. Esta puede desarrollarse como secuela tales como: alcoholismo, cirugía abdominal, fibrosis quística, infecciones, obesidad, cáncer de páncreas y otros.

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EL AÑO QUE PUSO A PRUEBA A LA CIENCIA

EL AÑO DE LA TELEMEDICINA

EN ENTREVISTA CON LA REVISTA MEDICINA Y SALUD PÚBLICA (MSP), EL DR. VÍCTOR RAMOS, PRESIDENTE DEL COLEGIO DE MÉDICOS CIRUJANOS DE PUERTO RICO, INVITÓ A LOS ESPECIALISTAS A REGISTRARSE Y HACE PARTE DEL GRUPO DE CASI 3,500 ESPECIALISTAS QUE RECIBIERON LA CERTIFICACIÓN.

En el 2020

la entonces gobernadora Wanda Vázquez Garced firmó una medida que flexibiliza los requisitos para que los médicos puedan practicar la telemedicina en momentos en que el país estaba bajo un toque de queda más estricto por el coronavirus (COVID-19).

De esta manera, se autorizó a los médicos a enviar una receta, referido u orden médica por fotografía o cualquier otro método electrónico a los proveedores de servicio, quienes deberán aceptarlas y despacharlas.

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EDICIÓN ESPECIAL

EL DOCTOR CARLOS MELLADO ES NOMINADO PARA DIRIGIR EL DEPARTAMENTO DE SALUD

“Lo más triste que vimos fue un de 20 años con una úlcera en el cuello, con fallo renal e infección bastante severa”.

El Dr. Carlos Mellado asume una de las sillas más importantes del gobierno, en momentos en que la Isla y el mundo sigue buscando como manejar la emergencia sanitaria por la pandemia del covid-19.

El galeno fue Procurador del Paciente y ganó la simpatía, respeto y agradecimiento de puertorriqueños y caribeños por su trabajo con la Fundación “Haití se pone de Pie”.

El médico boricua que protege a la comunidad latina en desastres naturales En el 2019, encabezó un equipo médico que atendió la emergencia en las Bahamas ocasionada por un fuerte huracán. Anteriormente lo había hecho en Puerto Rico. Y todos conocen su

conmovedora ayuda a los hermanos haitianos. “ La mayoría de los pacientes después del huracán en Bahamas no tenían sus medicamentos para tratar la presión alta, diabetes, cáncer y otras condiciones crónicas u sigo inmunes”, dijo el galeno a MSP que lo entrevistó en aquella ocasión.

El grupo estuvo conformado por médicos generales, ortopedas, cardiólogos pediatras, fisiatras, entre otros. En su viaje llevaron 268 cajas de medicamentos para la población.

También realizaron desbridamiento, cuidado local, inyecciones intraarticulares y demás procedimientos no invasivos pues, aunque estaban dispuestos a operar, no había espacio.

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EL AÑO QUE PUSO A PRUEBA A LA CIENCIA

FORO POR LA SALUD MSP

a Junta Editorial de La Revista Puertorriqueña Medicina y Salud Pública en alianza con MSP Broadcasting realizaron el único Foro por la Salud en tiempos de pandemia y año electoral donde lograron reunir a los 6 candidatos a la gobernación de Puerto Rico.

El panel de líderes del sector de salud contó con el acompañamiento y asesoría reconocidas entidades y

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representantes del país como el presidente del Colegio de Médicos Cirujanos de Puerto Rico, el Dr. Víctor Ramos; el director ejecutivo de Puerto Rico Public Health Trust, el Dr. José Rodríguez Orengo; el presidente de la Sociedad de Enfermedades Infecciosas de Puerto Rico, el Dr. Lemuel Martínez; y la Licda. Liliam Rodríguez y Licda. Linette Sánchez, de la Alianza Los Pacientes Primero.

UNA VEZ MÁS, LA IMPORTANCIA DEL CUIDADO DE LA SALUD FUE PIEDRA ANGULAR EN LA CAMPAÑA POLÍTICA A LA GOBERNACIÓN DE PUERTO RICO CÓMO SE EVIDENCIÓ EN EL ÚNICO FORO CELEBRADO CON LA ASISTENCIA PERFECTA DE LOS SEIS CANDIDATOS A LA GOBERNACIÓN. EL FORO FUE ORGANIZADO POR LA REVISTA PUERTORRIQUEÑA DE MEDICINA Y SALUD PÚBLICA Y TRANSMITIDO A TODO EL PAÍS POR LAS REDES SOCIALES Y DOS IMPORTANTES CANALES DE TELEVISIÓN.

“En conmemoración de nuestro decimoquinto aniversario, logramos cumplir con el objetivo de presentarle a la ciudadanía los postulados de los candidatos a la gobernación en el área de salud, siendo esta una prioridad dentro de la realidad en la que vivimos hoy día. Siempre nos hemos destacado por presentar trabajos originales en una plataforma de multimedios de 360 grados para darle

visibilidad a nuestros investigadores y científicos, y así lo continuaremos haciendo,” expresó Pedro Carlos Lugo III, Principal Oficial Ejecutivo de MSP Broadcasting.

La junta editorial de la Revista de Medicina y Salud Pública agradece a sus aliados por hacerlo posible y se enorgullece de presentar y contribuir al país con este trabajo especial.

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EL AÑO QUE PUSO A PRUEBA A LA CIENCIA

EN EL FRENTE DE UNA CRISIS GLOBAL: PREVENIR Y DETENER LA PROPAGACIÓN

Pedro Carlos Lugo III, CEO MSP Broadcasting, Hon. Pedro Pierluisi, Gobernador de Puerto Rico, Dr. Alberto Santiago Cornier, Editor en Jefe MSP.

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uerto Rico merece una respuesta urgente, sensible y profesional a la creciente crisis de salud pública causada por el brote de coronavirus (COVID-19). Por ello, el Editor de la Revista Puertorriqueña de Medicina y Salud Pública, Dr. Alberto Santiago Cornier y el Principal Oficial Ejecutivo de MSP Broadcasting, Pedro Carlos Lugo III, conversaron con el Gobernador, Pedro Pierluisi en torno al rol del gobierno para atender la crisis.

El Dr. Santiago Cornier a nombre del Comité Editorial Científico de la Revista Medicina y Salud Pública planteó los siguientes puntos: • Escuchar a la ciencia • Garantizar que las decisiones de salud pública estén informadas por los profesionales de la salud pública.

• Asegurar que todos los estadounidenses tengan acceso a pruebas frecuentes, confiables y gratuitas.

• Solucionar los problemas con el equipo de protección personal para los profesionales de la salud.

• Garantizar la disponibilidad de mascarillas, protectores faciales y otros EPP. • Trabajar para desarrollar una capacidad de manufactura flexible.

• Ofrecer una orientación clara, coherente y basada en la evidencia sobre cómo las comunidades deben lidiar con la pandemia y los recursos para que las

escuelas, los pequeños negocios y las familias salgan adelante.

• El distanciamiento social. Respetar la posición de la ciencia y permitir que provean orientación específica basada en la evidencia sobre cómo subir o bajar el indicador en relación con el nivel de riesgo y el grado de propagación viral en una comunidad, incluyendo cuándo abrir o cerrar ciertos negocios, bares, restaurantes y otros espacios; cuándo abrir o cerrar escuelas, y qué pasos deben tomar para que las aulas y las instalaciones sean seguras; restricciones apropiadas sobre el tamaño de las reuniones; cuándo emitir restricciones de quedarse en casa.

“ESTO NO SE TRATA DE POLÍTICA, MUCHO MENOS DE PREFERENCIAS PARTIDISTAS, SE TR ATA DE SALVAR LAS VIDAS DE NUESTROS PACIENTES.” DR. ALBERTO SANTIAGO CORNIER • Planificar la distribución efectiva y equitativa de los tratamientos y vacunas.

Porque el desarrollo de vacunas no es suficiente si no se distribuyen eficazmente.

• Proteger a los adultos mayores y a otras personas en alto riesgo.

• Ampliar las defensas para predecir, prevenir y mitigar las amenazas pandémicas, incluidas las procedentes de otros países.

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INDICATION FOR CYRAMZA INDICATION FOR CYRAMZA CYRAMZA, combination with docetaxel, is indicated CYRAMZA, in in combination with docetaxel, is indicated treatment patients with metastatic non-small forfor thethe treatment of of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression cell lung cancer (NSCLC) with disease progression after platinum-based chemotherapy.

Patients onon or or after platinum-based chemotherapy.

Patients with epidermal growth factor receptor (EGFR) with epidermal growth factor receptor (EGFR) or or anaplastic lymphoma kinase (ALK) genomic tumor anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression aberrations should have disease progression onon FDA-approved therapy these aberrations prior FDA-approved therapy forfor these aberrations prior to to receiving CYRAMZA. receiving CYRAMZA. For safety and dosing guidelines CYRAMZA, For safety and dosing guidelines forfor CYRAMZA, see respective Important Safety Information and see respective Important Safety Information and Brief Summary Prescribing Information Brief Summary of of Prescribing Information onon thethe following pages. following pages.

SELECT IMPORTANT SAFETY INFORMATION FOR CYRAMZA SELECT IMPORTANT SAFETY INFORMATION FOR CYRAMZA HEMORRHAGE HEMORRHAGE • CYRAMZA increased risk hemorrhage and gastrointestinal • CYRAMZA increased thethe risk of of hemorrhage and gastrointestinal hemorrhage, including Grade hemorrhagic events.

2137 hemorrhage, including Grade ≥3≥3 hemorrhagic events.

In In 2137 patients with various cancers treated with CYRAMZA, patients with various cancers treated with CYRAMZA, thethe incidence Grade hemorrhage ranged from 13-55%. incidence of of allall Grade hemorrhage ranged from 13-55%.

Grade 3-5 hemorrhage incidence ranged from 2-5%.

Grade 3-5 hemorrhage incidence ranged from 2-5%.

• Patients with NSCLC receiving therapeutic anticoagulation with • Patients with NSCLC receiving therapeutic anticoagulation or or with evidence of major airway invasion cancer were excluded from evidence of major airway invasion byby cancer were excluded from REVEL. addition, patients with NSCLC with a recent history REVEL. In In addition, patients with NSCLC with a recent history of of gross hemoptysis, those receiving chronic therapy with NSAIDs gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin with or other anti-platelet therapy other than once daily aspirin or or with radiographic evidence major airway blood vessel invasion radiographic evidence of of major airway or or blood vessel invasion or or intratumor cavitation were excluded from REVEL and RELAY; intratumor cavitation were excluded from REVEL and RELAY; therefore risk pulmonary hemorrhage these groups therefore thethe risk of of pulmonary hemorrhage in in these groups of of patients is unknown. patients is unknown.

• Permanently discontinue CYRAMZA patients who experience • Permanently discontinue CYRAMZA in in patients who experience severe (Grade 3 or bleeding. severe (Grade 3 or 4) 4) bleeding.

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WeWe are committed totodelivering options for are committed delivering options formetastatic metastatic We are committed to delivering options for metastatic non-small lung cancer (mNSCLC) non-small cell lung cancer (mNSCLC) soyou youcan canchoose choose non-small cellcell lung cancer (mNSCLC) so so you can choose right therapy atatthe time patients. the right therapy theright right time foryour your patients. thethe right therapy at the right time forfor your patients. catch advancements To catch upwith with ourlatest latest advancements To To catch upup with ourour latest advancements ininthoracic cancer care, visit: thoracic cancer care, visit: in thoracic cancer care, visit: CYRAMZA.com ALIMTA.com Lilly.com CYRAMZA.com ALIMTA.com Lilly.com CYRAMZA.com ALIMTA.com Lilly.com

INDICATION FOR ALIMTA INDICATION FOR ALIMTA INDICATION FOR ALIMTA ALIMTA is indicated in combination with pembrolizumab (pembro) ALIMTA is indicated in combination with pembrolizumab (pembro) ALIMTA is indicated in combination with pembrolizumab (pembro) platinum chemotherapy initial treatment of patients andand platinum chemotherapy forfor thethe initial treatment of patients andwith platinum chemotherapy for thenon-small initial treatment of cancer patients with nonsquamous metastatic non-small lung cancer nonsquamous metastatic cellcell lung with(mNSCLC) nonsquamous metastatic non-small cell lung cancer (mNSCLC) with EGFR or ALK genomic tumor aberrations. with no no EGFR or ALK genomic tumor aberrations. (mNSCLC) with no EGFR or ALK genomic tumor aberrations.

Limitation of Use: ALIMTA is not indicated treatment Limitation of Use: ALIMTA is not indicated forfor thethe treatment of of Limitation of Use: ALIMTA is not indicated for the treatment of patients with squamous non-small lung cancer. patients with squamous cellcell non-small cellcell lung cancer. patients with squamous cell non-small cell lung cancer.

SELECT IMPORTANT SAFETY INFORMATION FOR ALIMTA SELECT IMPORTANT SAFETY INFORMATION FOR ALIMTA SELECT IMPORTANT SAFETY INFORMATION FOR ALIMTA Contraindication Contraindication Contraindication ALIMTA is contraindicated patients who have a history ALIMTA is contraindicated in in patients who have a history ALIMTA contraindicated in patients who have a history ofissevere hypersensitivity reaction pemetrexed. of severe hypersensitivity reaction to to pemetrexed. of severe hypersensitivity reaction to pemetrexed. safety and dosing guidelines ALIMTA, see respective ForFor safety and dosing guidelines forfor ALIMTA, see respective For safety and dosing guidelines for ALIMTA, see respective Important Safety Information and Brief Summary Important Safety Information and Brief Summary of of Important Safety Information and Brief Summary of Prescribing Information following pages.

Prescribing Information onon thethe following pages.

Prescribing Information on the following pages.

® ® PP-PM-US-1154 08/2020 ©Lilly USA, 2020. rights reserved.

ALIMTA CYRAMZA registered PP-PM-US-1154 08/2020 ©Lilly USA, LLCLLC 2020.

All All rights reserved.

ALIMTA andand CYRAMZA areare registered ® PP-PM-US-1154 08/2020 ©Lilly USA, LLC 2020.

All rights reserved.

ALIMTA® andorCYRAMZA are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, affiliates. trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. ®

®

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5%.

Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.

Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding.

Gastrointestinal Perforations CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing CYRAMZA has the potential to adversely affect wound healing.

CYRAMZA has not been studied in patients with serious or non-healing wounds.

Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing.

The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events (ATEs) Serious, sometimes fatal, ATEs, including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2%.

Permanently discontinue CYRAMZA in patients who experience an ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%. In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib.

Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled.

Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRR) RR, including severe and life-threatening IRR, occurred in CYRAMZA clinical trials. Symptoms of IRR included rigors/ tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.

In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. In 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR ranged from <1- 9%. Grade 3-5 IRR incidence was <1%.

Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3- 4 IRR. Worsening of Pre-existing Hepatic Impairment Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%).

Posterior Reversible Encephalopathy Syndrome (PRES) PRES (also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in <0.1% of 2137 patients with various cancers treated with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.

Permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34%.

Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%.

Monitor for proteinuria. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours.

Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours.

Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction In 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism.

Monitor thyroid function during treatment with CYRAMZA. Embryo-Fetal Toxicity CYRAMZA can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

Lactation Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.

Adverse Reactions REVEL: The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with docetaxel at a rate of ≥5% and ≥2% higher than placebo with docetaxel were neutropenia (55% vs 46%), fatigue/asthenia (55% vs 50%), stomatitis/mucosal inflammation (37% vs 19%), epistaxis (19% vs 7%), febrile neutropenia (16% vs 10%), peripheral edema (16% vs 9%), thrombocytopenia (13% vs 5%), lacrimation increased (13% vs 5%), and hypertension (11% vs 5%).

The most common serious adverse reactions with CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel- treated patients versus 37% in patients who received placebo with docetaxel.

Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxeltreated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis≈(0.3%).

For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were hyponatremia (4.8%) and proteinuria (3.3%).

RELAY: The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with erlotinib at a rate of ≥5% and ≥2% higher than placebo with erlotinib were infections (81% vs 76%), diarrhea (70% vs 71%), hypertension (45% vs 12%), stomatitis (42% vs 36%), alopecia (34% vs 20%), epistaxis (34% vs 12%), proteinuria (34% vs 8%), peripheral edema (23% vs 4%), headache (15% vs 7%), gastrointestinal hemorrhage (10% vs 3%), gingival bleeding (9% vs 1%), and pulmonary hemorrhage (7% vs 2%).

The most common serious adverse reactions with CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo.

Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinibtreated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%).

Of the 221 patients who received CYRAMZA with erlotinib, 119 (54%) were 65 and over, while 29 (13%) were 75 and over.

Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%), and weight loss (19% versus 6%).

Please see Brief Summary of Prescribing Information for CYRAMZA on subsequent pages.

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IMPORTANT SAFETY INFORMATION FOR ALIMTA CONTRAINDICATION

Bullous and Exfoliative Skin Toxicity

ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/toxic epidermal necrolysis, can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering, or exfoliating skin toxicity.

WARNINGS AND PRECAUTIONS Myelosuppression and Increased Risk of Myelosuppression Without Vitamin Supplementation ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.

Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid.

Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles.

In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.

Renal Failure ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA. The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI).

Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.

Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA. Radiation Recall Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall.

Increased Risk of Toxicity With Ibuprofen in Patients With Renal Impairment Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.

Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

DRUG INTERACTIONS Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

ADVERSE REACTIONS Severe adverse reactions (Grade 3-4) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were fatigue (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%).

Common adverse reactions (all grades) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite (28% vs 30%); rash (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%).

USE IN SPECIFIC PATIENT POPULATIONS Lactation: There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.

Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after the last dose.

Males of Reproductive Potential: ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.

Pediatric Use: The safety and effectiveness of ALIMTA in pediatric patients have not been established. Adverse reactions observed in pediatric patients studied were similar to those observed in adults.

Patients with Renal Impairment: ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min.

Geriatric: The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.

For safety and dosing guidelines, see Brief Summary of Prescribing Information for ALIMTA on the following pages.

PM_HCP_ISI_NSCLC1L_Combo_30 JAN2019

CYRAMZA® (ramucirumab) injection, for intravenous use Brief Summary: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with erlotinib, is indicated for the treatment of patients with first-line metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.

CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy.

Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5%. Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding.

Gastrointestinal Perforations CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF or VEGFR pathway. CYRAMZA, a VEGFR2 antagonist, has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.

Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2%. Permanently discontinue CYRAMZA in patients who experience an ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%. In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib. Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled.

Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Infusion-related reactions (IRR) including severe and life threatening IRR occurred in CYRAMZA clinical trials. The majority of IRR across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRR included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.

In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade CYRAMZA® (ramucirumab) injection, for intravenous use

RB-L HCP BS 01JUN2020

IRR ranged from <1-9%. Grade 3-5 IRR incidence was <1%. Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRR. Worsening of Pre-existing Hepatic Impairment Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%).

Posterior Reversible Encephalopathy Syndrome Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 2137 patients enrolled in six clinical studies with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/ vomiting, blindness, or altered consciousness, with or without associated hypertension. Confirm the diagnosis of PRES with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the result of the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA. Embryo-Fetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CYRAMZA Administered in Combination with Erlotinib The safety of CYRAMZA was evaluated in RELAY. Patients had previously untreated EGFR exon 19 deletion or exon 21 (L858R) substitution mutation-positive metastatic NSCLC. Patients had ECOG PS 0 or 1. RELAY excluded patients with bilirubin greater than the ULN, central nervous system (CNS) metastases, clinically active interstitial lung disease (ILD), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major blood vessel invasion or encasement by cancer or intra-tumor cavitation, or gross hemoptysis within the preceding 2 months. The study also excluded patients receiving chronic nonsteroidal anti-inflammatory agents (NSAIDs) or anti-platelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously every two weeks in combination with erlotinib 150 mg taken orally once daily. Patients randomized to CYRAMZA received a median of 21 doses; the median duration of exposure was 11 months, and 90 (41% of 221) patients received CYRAMZA for at least 12 months.

The most common serious adverse reactions in patients who received CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo. Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%). The most common adverse reactions (all grades) observed in CYRAMZA with erlotinib-treated patients at a rate of ≥30% of patients and ≥2% higher than placebo with erlotinib-treated patients were infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities ≥30% and ≥2% higher than the placebo were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. Table 4 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 5 provides the incidence and severity of laboratory abnormalities in RELAY. CYRAMZA® (ramucirumab) injection, for intravenous use

RB-L HCP BS 01JUN2020

Table 1: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in RELAY CYRAMZA + Erlotinib Placebo + Erlotinib (N=221) (N=225) Adverse Reactions All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Infections Infectionsa,b 81 17 76 7 Vascular Hypertension 45 24 12 5 Gastrointestinal Diarrhea 70 7 71 1 Stomatitis 42 2 36 1 Gastrointestinal 10 1 3 <1 hemorrhagec Gingival bleeding 9 0 1 0 Renal and Urinary Proteinuriac 34 3 8 0 Skin and Subcutaneous Tissue Alopecia 34 N/Ad 20 N/Ad Respiratory, Thoracic, and Mediastinal Epistaxis 34 0 12 0 Pulmonary hemorrhagec,e 7 <1 2 <1 General Peripheral edema 23 <1 4 0 Nervous System Headache 15 <1 7 0 Abbreviations: N/A = not applicable. a Includes all preferred terms that are part of the System Organ Class Infections and Infestations. Most common (≥1%) Grade ≥3 infections and frequencies for CYRAMZA with erlotinib compared to placebo with erlotinib, respectively, include pneumonia (3% versus 0%), cellulitis (1% versus 0%), paronychia (4% versus 3%), skin infection (1% versus 0%), and urinary tract infection (1% versus 0%). b Includes 3 fatal events in the CYRAMZA arm. c Gastrointestinal hemorrhage, proteinuria, and pulmonary hemorrhage are consolidated terms. d Grade ≥3 does not exist in CTCAE. e Includes 1 fatal event in the CYRAMZA arm.

Table 2: Laboratory Abnormalities Worsening from Baseline in ≥20% (All Grades) of Patients Receiving CYRAMZA with Erlotinib with a Difference Between Arms of ≥2% in RELAY CYRAMZA + Erlotiniba Placebo + Erlotiniba Laboratory Abnormality All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Chemistry Alanine aminotransferase 74 11 60 13 increased Aspartate aminotransferase 71 6 47 4 increased Alkaline phosphatase 25 <1 16 1 increased Hypokalemia 24 5 18 2 Hematology Anemia 42 5 25 2 Thrombocytopenia 41 3 12 3 Neutropenia 33 7 21 4 a The denominator used to calculate the incidence varied based on the number of patients with a baseline and at least one on-study laboratory measurement: CYRAMZA-treated patients (range 215-218 patients) and placebo-treated patients (range 224-225 patients).

CYRAMZA Administered in Combination with Docetaxel The safety of CYRAMZA was evaluated in REVEL. Patients had NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease and ECOG PS 0 or 1. REVEL excluded patients with bilirubin greater than the ULN, uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic antiplatelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously in combination with docetaxel 75 mg/m2 intravenously every 21 days. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, REVEL was amended and 24 patients (11 patients receiving CYRAMZA with docetaxel, 13 patients receiving placebo with docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every three weeks. Patients randomized to CYRAMZA received a median of 4.5 doses; the median duration of exposure CYRAMZA® (ramucirumab) injection, for intravenous use

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was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months.

The most common serious adverse reactions in patients who received CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel-treated patients versus 37% in patients who received placebo with docetaxel. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions (all grades) observed in CYRAMZA with docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Table 3 provides the frequency and severity of adverse reactions (NCI CTCAE, version 4.0) in REVEL. Table3: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in REVEL CYRAMZA + Docetaxel Placebo + Docetaxel (N=627) (N=618) Adverse Reactions All Grades Grade 3-4 All Grades Grade 3-4 (%) (%) (%) (%) Hematology Neutropeniaa 55 49 46 40 Febrile neutropenia 16 16 10 10 Thrombocytopeniaa 13 3 5 <1 General Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Gastrointestinal Stomatitis/Mucosal 37 7 19 2 inflammation Respiratory, Thoracic, and Mediastinal Epistaxis 19 <1 7 <1 Eye Lacrimation increased 13 <1 5 0 Vascular Hypertensiona 11 6 5 2 a Neutropenia, thrombocytopenia, and hypertension are consolidated terms.

Clinically relevant adverse drug reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were hyponatremia (4.8%) and proteinuria (3.3%).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzymelinked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

Postmarketing Experience The following adverse reactions have been identified during postapproval use of CYRAMZA. Because such reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Blood and lymphatic system: Thrombotic microangiopathy • Neoplasms benign, malignant and unspecified: Hemangioma • Respiratory, thoracic, and mediastinal: Dysphonia • Vascular: Arterial (including aortic) aneurysms, dissections, and rupture USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman. There are no available data on CYRAMZA use in pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal CYRAMZA® (ramucirumab) injection, for intravenous use

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development, and postnatal development. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise a pregnant woman of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryo-fetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk or its effects on the breastfed child or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.

Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating CYRAMZA. Contraception Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman.

Females Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established.

Juvenile Animal Toxicity Data In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 221 patients in RELAY, 119 (54%) were 65 and over, while 29 (13%) were 75 and over. Overall, no clinically meaningful differences in effectiveness were observed between these patients and younger patients. Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%) and weight loss (19% versus 6%).

Of the 1253 patients in REVEL, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA with docetaxel in REVEL, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of REVEL, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years and over was 1.10 (95% CI: 0.89, 1.36).

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within ULN and aspartate aminotransferase [AST] >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Rx only Additional information can be found at www.cyramza.com

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright ©2019, Eli Lilly and Company. All rights reserved.

RB-L HCP BS 01JUN2020 CYRAMZA® (ramucirumab) injection, for intravenous use

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ALIMTA® (pemetrexed for injection), for Intravenous Use Initial U.S. Approval: 2004 BRIEF SUMMARY: Consult the package insert for complete prescribing information.

at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

INDICATIONS AND USAGE

ADVERSE REACTIONS

Nonsquamous Non-Small Cell Lung Cancer (NSCLC) ALIMTA (pemetrexed) is indicated: • in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

• in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC).

• as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

• as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

CONTRAINDICATIONS: ALIMTA is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed.

WARNINGS AND PRECAUTIONS Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.

Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid.

Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles.

In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.

Renal Failure ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA. The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI).

Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.

Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of StevensJohnson Syndrome/Toxic epidermal necrolysis can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA. Radiation Recall Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall.

Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.

Embryo-Fetal Toxicity

Non-Squamous NSCLC First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy The safety of ALIMTA in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received ALIMTA, pembrolizumab, and platinum every 3 weeks for 4 cycles followed

by ALIMTA and pembrolizumab (n=405), or placebo, ALIMTA, and platinum every 3 weeks for 4 cycles followed by placebo and ALIMTA (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to ALIMTA was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

ALIMTA was discontinued for adverse reactions in 23% of patients in the ALIMTA, pembrolizumab, and platinum arm.

The most common adverse reactions resulting in discontinuation of ALIMTA in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of ALIMTA occurred in 49% of patients in the ALIMTA, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of ALIMTA in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).

Below summarizes the adverse reactions and laboratory abnormalities that worsened from baseline (graded per NCI CTCAE v4.03) that occurred in ≥20% of patients treated with ALIMTA, pembrolizumab and platinum.

Adverse Reactions • Grade 3-4 Adverse Reactions occurring in ≥20% patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were fatigue* (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash† (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%).

• All Grades Adverse Reactions occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue* (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite ( 28% vs 30%); rash† (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%). *Includes asthenia and fatigue Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular

†

Laboratory Abnormalities that Worsened from Baseline Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: ALIMTA/pembrolizumab/platinum chemotherapy (range 381-401 patients) and placebo/ ALIMTA/platinum chemotherapy (range 184 to 197 patients).

• Grade 3-4 Laboratory Abnormalities that Worsened from Baseline in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were lymphopenia (22% vs 25%); neutropenia (20% vs 19%); anemia (17% vs 18%); thrombocytopenia (12% vs 8%); hypophosphatemia (10% vs 14%); hyperglycemia (9% vs 7%); hyponatremia (7% vs 6%); hypokalemia (5% vs 5%); increased creatinine (4.2% vs 1%); increased ALT (3.8% vs 2.6%); increased AST (2.8% vs 1%); hypoalbuminemia (2.8% vs 1.1%); hypocalcemia (2.8% vs 1.7%); hyperkalemia (2.8% vs 3.1%) and increased alkaline phosphatase (1.8% vs 2.1%).

• All Grades Laboratory Abnormalities that Worsened from Baseline in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were anemia (85% vs 81%); lymphopenia (64% vs 64%); hyperglycemia (63% vs 60%); neutropenia (48% vs 41%); increased ALT (47% vs 42%); increased AST (47% vs 40%); hypoalbuminemia (39% vs 39%); increased creatinine (37% vs 25%); hyponatremia (32% vs 23%); hypophosphatemia (30% vs 28%); thrombocytopenia (30% vs 29%); increased alkaline phosphatase (26% vs 29%); hypocalcemia (24% vs 17%); hyperkalemia (24% vs 19%); and hypokalemia (21% vs 20%).

Initial Treatment in Combination with Cisplatin The safety of ALIMTA was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either ALIMTA 500 mg/ m2 intravenously and cisplatin 75 mg/ m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 and cisplatin 75 mg/ m2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12.

Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations

Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

ALIMTA® (pemetrexed for injection), for Intravenous Use

ALIMTA® (pemetrexed for injection), for Intravenous Use

PM HCP BS ALLNSCLC 12MAR2019

PM HCP BS ALLNSCLC 12MAR2019

The data described below reflect exposure to ALIMTA plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White,16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of ALIMTA. Below shows the frequency and severity of adverse reactions (NCI CTCAE version 2.0) that occurred in ≥5% of 839 patients receiving ALIMTA in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for ALIMTA, as compared to the control arm, for any specified adverse reaction listed below.

• Grade 3-4 Adverse Reactions occurring in ≥5% fully vitamin supplemented patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB), respectively, were neutropenia (15% vs 27%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anemia (6% vs 10%); thrombocytopenia (4% vs 13%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); diarrhea (1% vs 2%); stomatitis/pharyngitis (1% vs 0%); constipation (1% vs 0%), sensory neuropathy (0% vs 1%), alopecia (0% vs 1%) and rash/desquamation (0% vs 1%).

• All Grades Adverse Reactions occurring in ≥5% fully vitamin supplemented patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB), respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); creatinine elevation (10% vs 7%), sensory neuropathy (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); and dyspepsia/heartburn (5% vs 6%).

The following additional adverse reactions of ALIMTA were observed: • Incidence 1% to <5%: febrile neutropenia, infection, pyrexia, dehydration, increased AST, increased ALT, renal failure, conjunctivitis • Incidence <1%: arrhythmia, chest pain, increased GGT, motor neuropathy Maintenance Treatment Following First-Line Non-ALIMTA Containing Platinum-Based Chemotherapy In Study JMEN, the safety of ALIMTA was evaluated in a randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either ALIMTA 500 mg/m2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to ALIMTA in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of ALIMTA and a relative dose intensity of ALIMTA of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of ALIMTA. Below shows the frequency and severity of adverse reactions (NCI CTCAE version 3.0) reported in ≥5% of the 438 ALIMTA-treated patients in Study JMEN. The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the ALIMTA arm compared to the placebo arm.

• Grade 3-4 Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); infection (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); and sensory neuropathy (1% vs 0%).

• All Grades Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-ALIMTA containing platinum-based induction therapy were fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); anemia (15% vs 6%); increased rash/desquamation (10% vs 3%); ALT (10% vs 4%); sensory neuropathy (9% vs 4%); vomiting (9% vs 1%); increased AST (8% vs 4%); mucositis/stomatitis (7% vs 2%); neutropenia (6% vs 0%); diarrhea (5% vs 3%); and infection (5% vs 2%).

The following additional adverse reactions were observed in patients who received ALIMTA. • Incidence 1% to <5%: alopecia, pruritus/itching, constipation, edema, fever, thrombocytopenia, ocular surface disease (including conjunctivitis), increased lacrimation • Incidence <1%: supraventricular arrhythmia, erythema multiforme, febrile neutropenia, allergic reaction/ hypersensitivity, motor neuropathy, renal failure Maintenance Treatment Following First-line ALIMTA Plus Platinum-Based Chemotherapy The safety of ALIMTA was evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of ALIMTA in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive ALIMTA 500 mg/m2 or matching placebo intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both study arms received folic acid and vitamin B12 supplementation.

The data described below reflect exposure to ALIMTA in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for ALIMTA and placebo arms.

Dose reductions for adverse reactions occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm.

Dose delays for adverse reactions occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm.

Below shows the frequency and severity of adverse reactions (graded per NCI CTCAE version 3.0) reported in ≥5% of the 333 ALIMTA-treated patients in PARAMOUNT. The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the ALIMTA arm compared to the placebo arm.

• Grade 3-4 Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (PARAMOUNT), respectively, following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); fatigue (4.5% vs 0.6%); neutropenia (3.9% vs 0%); nausea (0.3% vs 0%); and mucositis/stomatitis (0.3% vs 0%).

• All Grades Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (PARAMOUNT), respectively, following ALIMTA plus cisplatin induction therapy were fatigue (18% vs 11%); anemia (15% vs 4.8%); nausea (12% vs 2.4%); neutropenia (9% vs 0.6%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm.

• Incidence 1% to <5%: thrombocytopenia, febrile neutropenia • Incidence <1%: ventricular tachycardia, syncope, pain, gastrointestinal obstruction, depression, renal failure, pulmonary embolism Treatment of Recurrent Disease After Prior Chemotherapy The safety of ALIMTA was evaluated in Study JMEI, a randomized (1:1), open-label, active-controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received ALIMTA 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the ALIMTA arm received folic acid and vitamin B12 supplementation.

Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to ALIMTA in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0.

Below shows the frequency and severity of adverse reactions (graded per NCI CTCAE version 2.0) reported in ≥5% of the 265 ALIMTA-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for ALIMTA, as compared to the control arm, for any specified adverse reaction listed below.

• Grade 3-4 Adverse Reactions occurring in ≥5% of fully supplemented patients receiving ALIMTA as a single agent versus docetaxel (JMEI), respectively, were neutropenia (5% vs 40%); fatigue (5% vs 5%); anemia (4% vs 4%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs 1%); thrombocytopenia (2% vs 0%); increased ALT (2% vs 0%); alopecia (1% vs 2%); diarrhea (0% vs 3%); stomatitis/ pharyngitis (1% vs 1%); and increased AST (1% vs 0%).

• All Grades Adverse Reactions of fully supplemented patients receiving ALIMTA as a single agent versus docetaxel (JMEI), respectively, were fatigue (34% vs 36%); nausea (31% vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%); vomiting (16% vs 12%); stomatitis/pharyngitis (15% vs 17%); rash/desquamation (14% vs 6%); diarrhea (13% vs 24%); neutropenia (11% vs 45%); fever (8% vs 8%); thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); pruritis (7% vs 2%); increased AST (7% vs 1%); alopecia (6% vs 38%); and constipation (6% vs 4%).

The following additional adverse reactions were observed in patients assigned to receive ALIMTA. • Incidence 1% to <5%: abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection, erythema multiforme, motor neuropathy, sensory neuropathy • Incidence <1%: supraventricular arrhythmias, renal failure DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

USE IN SPECIFIC POPULATIONS Pregnancy

PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

Risk Summary Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no available data on ALIMTA use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

ALIMTA® (pemetrexed for injection), for Intravenous Use

ALIMTA® (pemetrexed for injection), for Intravenous Use

PM HCP BS ALLNSCLC 12MAR2019

PM HCP BS ALLNSCLC 12MAR2019

PARAMOUNT. Median age was 61 years % were Asian, and <1% were Black or African cycles was 4 for ALIMTA and placebo arms. e ALIMTA arm and 0.6% in the placebo arm.

MTA arm and 16% in the placebo arm.

r NCI CTCAE version 3.0) reported in ≥5% red blood cell (13% versus 4.8%) and nts (12% versus 7%), and granulocyte colony ared to the placebo arm.

h non-progressive locally advanced or receiving ALIMTA as a single agent versus y, following ALIMTA plus cisplatin induction ); neutropenia (3.9% vs 0%); nausea

h non-progressive locally advanced or receiving ALIMTA as a single agent versus y, following ALIMTA plus cisplatin induction nausea (12% vs 2.4%); neutropenia (5% vs 2.4%); and edema (5% vs 3.6%).

more frequently in the ALIMTA arm. a ointestinal obstruction, depression, renal

open-label, active-controlled trial conducted py. Patients received ALIMTA 500 mg/m2 1-day cycle. All patients on the ALIMTA arm

olled third-space fluid retention, inadequate arance less than 45 mL/min. Patients unable r unable to take folic acid, vitamin B12 or

n Study JMEI. Median age was 58 years 4% were Asian, 2.6% were Black or African es; 19% had an ECOG PS 0.

per NCI CTCAE version 2.0) reported in not designed to demonstrate a statistically d to the control arm, for any specified adverse

lemented patients receiving ALIMTA as a openia (5% vs 40%); fatigue (5% vs 5%); %); vomiting (2% vs 1%); thrombocytopenia ); diarrhea (0% vs 3%); stomatitis/

s receiving ALIMTA as a single agent 6%); nausea (31% vs 17%); anorexia %); stomatitis/pharyngitis (15% vs 17%); eutropenia (11% vs 45%); fever (8% vs 8%); pruritis (7% vs 2%); increased AST 4%).

ssigned to receive ALIMTA. ersensitivity, febrile neutropenia, infection,

Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2.

At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/ m2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).

Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after last dose.

Females and Males of Reproductive Potential Contraception Females ALIMTA can cause fetal harm when administered to a pregnant woman. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with ALIMTA for at least 6 months after the final dose of ALIMTA. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

Infertility Males ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.

Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established. The safety and pharmacokinetics of ALIMTA were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors. ALIMTA was administered at doses ranging from 400 to 2480 mg/m2 intravenously over 10 minutes on Day 1 of a 21-day cycle to 32 pediatric patients with recurrent solid tumors in a dose-finding study. The maximum tolerated dose (MTD) was determined to be 1910 mg/m2 (60 mg/kg for patients <12 months old). ALIMTA was administered at the MTD every 21 days in an activity-estimating study enrolling 72 patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone.

No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults.

Single-dose pharmacokinetics of ALIMTA administered at doses ranging from 400 to 2480 mg/m2 were evaluated in 22 patients (13 males and 9 females) age 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. Average clearance (2.30 L/h/m2) and half-life (2.3 hours) were similar in pediatric patients compared to adults.

Geriatric Use Of the 3,946 patients enrolled in clinical studies of ALIMTA, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.

Patients with Renal Impairment ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min.

Additional information can be found at www.Alimta.com

eatinine clearance between 45 mL/min and

, and 2 days following administration and gastrointestinal toxicity, if concomitant

IMTA can cause fetal harm when MTA use in pregnant women. In animal gnant mice during the period of organogenesis at doses lower than the recommended k to a fetus. In the U.S. general population, n clinically recognized pregnancies is 2 to 4% PM HCP BS ALLNSCLC 12MAR2019

Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2004, 2019, Eli Lilly and Company. All rights reserved.

PM HCP BS ALLNSCLC 12MAR2019 ALIMTA® (pemetrexed for injection), for Intravenous Use

PM HCP BS ALLNSCLC 12MAR2019

MSP / SALUD PÚBLICA

PHOTO_TIME / SHUTTERSTOCK

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Revista Puertorriqueña de Medicina y Salud Pública

MSP / SALUD PÚBLICA

¿CUÁL ES LA RELACIÓN ENTRE LOS INCENDIOS FORESTALES Y EL CAMBIO CLIMÁTICO?

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Según ha demostrado la ciencia, el cambio climático ha avivado los incendios más grandes e intensos de todo el oeste de Estados Unidos. El aumento de la temperatura, los cambios en los patrones de lluvia y nieve, los cambios en las comunidades de plantas y otras alteraciones relacionadas con el clima han aumentado enormemente la probabilidad de que se produzcan incendios, y de mayor intensidad y amplitud que en el pasado.

La escala e intensidad de los incendios forestales en el oeste de Estados Unidos tiñó la atmósfera de colores rojizos y elevó la contaminación atmosférica a niveles nunca antes experimentados para el planeta tierra.

En el 2020, la nieve se derritió antes de lo esperado y el calor llegó para quedarse. Muchos estados del oeste registraron los veranos más calurosos de su historia; la temperatura promedio en los EE. UU. superó el promedio registrado para el siglo XX.

Revista Puertorriqueña de Medicina y Salud Pública

121

EL AÑO QUE PUSO A PRUEBA A LA CIENCIA

AHOGADOS EN LA CONTAMINACIÓN

l fotógrafo estadounidense Justin Hofman tenía en la mira a un caballito de mar nadando en aguas de Indonesia... cuando de repente el pez fue invadido por plástico, basura y aguas residuales.

Para luchar contra la corriente, el animal se aferró a un bastoncillo de algodón o hisopo más grande que su propio cuerpo.

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Revista Puertorriqueña de Medicina y Salud Pública

ESTABA DESTINADA A SER UNA FOTO ESPECTACULAR DE LA NATURALEZA. PERO LA MAREA CAMBIÓ EL PAISAJE.

“Las manchas blancas que se ven en el fondo son en realidad bolsas de plástico”, dijo Hofman molesto.

La imagen fue nominada al premio al Mejor Fotógrafo de Vida Silvestre del Año que organiza el Museo de Historia Natural de Londres.

Además de este reconocimiento, la imagen se ha difundido ampliamente en redes sociales y algunos

usuarios la han usado para denunciar la contaminación en los océanos.

“Mientras todo ocurría, sabía que era una escena importante para documentar.

Fue frustrante, asqueroso y triste pero tenía que capturarlo”, dijo Hofman.

Cada año, entre 5 y 13 millones de toneladas de plástico acaban en los océanos del mundo.

H AHTAOT OR ERYE Y|

C | AC GA UG AU SA S|

P| OP N OC N EC E

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Porque Porque Porque nunca nunca nunca nos nos nos daremos daremos daremos por por vencidos ayudando a las personas apor vivir vencidos vencidos vencidos ayudando ayudando ayudando a a las las a personas las personas personas a vivir a vivir sus mejores vidas hoy y mañana. avivir sus sus sus mejores mejores mejores vidas vidas vidas hoy hoy hoy y ymañana. mañana. y mañana.

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