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for moderate to severe rheumatoid arthritis (RA) in adult MTX-IR patients1

EXPECTATIONS CHALLENGE TREATMENT GOALS IN RA RINVOQ is a new once-daily oral JAK inhibitor that met all primary (ACR20 or ACR50 at Week 12 or 14) and ranked secondary endpoints in 5 clinical trials.1,2,a,b Head-to-Head Trial Results

Remission, Even Without MTX

Radiographic Inhibition, Even Without MTX

Superiority data evaluating ACR50, HAQ-DI, and pain reduction in RINVOQ + MTX vs a TNFi + MTX at Week 12

DAS28-CRP<2.6 evaluated at Week 12 or 14

ΔmTSS measured at Week 24 or 26

[ranked secondary endpoint in SELECT-COMPARE and SELECT-EARLY]1,2,a,b

[ranked secondary endpoint in SELECTCOMPARE, SELECT-MONOTHERAPY, and SELECT-NEXT]1,2,a,b

[ranked secondary endpoints in SELECTCOMPARE]3,4,a,b

Safety Data From a Large Registrational Program in RA 5 phase 3 trials, >4350 patients across treatment arms, >3400 patient-years of exposure to RINVOQ 15 mg1,5,6,a-d

RINVOQ is not indicated for MTX-naïve patients.

All with the commitment to exceptional access and patient support from AbbVie.

Explore study results, including superiority data, at RinvoqHCP.com aStudied in adult patients with moderate to severe RA. bSELECT-EARLY (RA-I; MTX-naïve) [primary endpoint at Week 12: ACR50 response vs MTX, select ranked secondary

endpoint at Week 24: ΔmTSS vs MTX]; SELECT-MONOTHERAPY (RA-II; MTX-IR) [primary endpoint at Week 14: ACR20 response vs MTX, select ranked secondary endpoint at Week 14: DAS28-CRP<2.6 vs MTX]; SELECT-NEXT (RA-III; csDMARD-IR) [RINVOQ + csDMARD; primary endpoint at Week 12: ACR20 response vs placebo + csDMARD, select ranked secondary endpoint at Week 12: DAS28-CRP<2.6 vs placebo + csDMARD]; SELECT-COMPARE (RA-IV; MTX-IR) [RINVOQ + MTX; primary endpoint at Week 12: ACR20 response vs placebo + MTX, select ranked secondary endpoints at Week 12: DAS28-CRP<2.6 vs placebo + MTX, HAQ-DI vs placebo + MTX, ACR50 response vs a TNFi + MTX, HAQ-DI vs a TNFi + MTX, pain reduction vs a TNFi + MTX; ΔmTSS vs placebo + MTX at Week 26]; SELECT-BEYOND (RA-V; bDMARDIR) [RINVOQ + csDMARD; primary endpoint at Week 12: ACR20 response vs placebo + csDMARD]. cRINVOQ 15 mg; upadacitinib 30 mg; methotrexate; TNFi, placebo. dLong-term data as of 11/14/18.

ACR=American College of Rheumatology; bDMARD-IR=inadequate response or intolerance to biologic disease-modifying antirheumatic drug; csDMARD=conventional synthetic disease-modifying antirheumatic drug; csDMARD-IR=inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drug; DAS28-CRP=Disease Activity Score 28 joints, c-reactive protein; HAQ-DI=Health Assessment Questionnaire-Disability Index; JAK=Janus kinase; mTSS=modified total Sharp score; MTX=methotrexate; MTX-IR=inadequate response or intolerance to methotrexate; TNFi=tumor necrosis factor inhibitor.

INDICATION1 RINVOQ is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

Limitation of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

SAFETY CONSIDERATIONS1 SERIOUS INFECTIONS Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

MALIGNANCY Lymphoma and other malignancies have been observed in RINVOQ-treated patients.

THROMBOSIS Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.

OTHER SERIOUS ADVERSE REACTIONS Patients treated with RINVOQ also may be at risk for other serious adverse reactions, including gastrointestinal perforations, neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations, and embryo-fetal toxicity.

Please see additional Important Safety Information, including BOXED WARNING on Serious Infections, Malignancy, and Thrombosis, on the previous page of this advertisement.

Please see Brief Summary of full Prescribing Information on previous pages of this advertisement.

IMPORTANT SAFETY INFORMATION1 SERIOUS INFECTIONS Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include: • Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before RINVOQ use and during therapy. Consider treatment for latent infection prior to RINVOQ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Anemia Decreases in hemoglobin levels to <8 g/dL were reported in RINVOQ clinical studies. Treatment should not be initiated or should be interrupted in patients with hemoglobin levels <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Lipids Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Manage patients according to clinical guidelines for the management of hyperlipidemia. Evaluate 12 weeks after initiation of treatment and thereafter according to the clinical guidelines for hyperlipidemia.

Liver enzyme elevations Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo. Evaluate at baseline and thereafter according to routine patient management.

Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

MALIGNANCY Lymphoma and other malignancies have been observed in patients treated with RINVOQ. Consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or in patients who develop a malignancy. NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

EMBRYO-FETAL TOXICITY Based on animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ.

THROMBOSIS Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death. Consider the risks and benefits prior to treating patients who may be at increased risk. Patients with symptoms of thrombosis should be promptly evaluated.

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in clinical studies with RINVOQ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). RINVOQ should be used with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.

LABORATORY ABNORMALITIES Neutropenia Treatment with RINVOQ was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm3).

Treatment with RINVOQ is not recommended in patients with an ANC <1000 cells/mm3. Evaluate neutrophil counts at baseline and thereafter according to routine patient management.

Lymphopenia Absolute lymphocyte counts (ALC) <500 cells/mm3 were reported in RINVOQ clinical studies. Treatment with RINVOQ is not recommended in patients with an ALC <500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management.

VACCINATION Use of live, attenuated vaccines during, or immediately prior to, RINVOQ therapy is not recommended. Prior to initiating RINVOQ, patients should be brought up to date on all immunizations, including prophylactic zoster vaccinations, in agreement with current immunization guidelines.

LACTATION There are no data on the presence of RINVOQ in human milk, the effects on the breastfed infant, or the effects on milk production.

Available data in animals have shown the excretion of RINVOQ in milk. Advise patients that breastfeeding is not recommended during treatment with RINVOQ and for 6 days after the last dose.

HEPATIC IMPAIRMENT RINVOQ is not recommended in patients with severe hepatic impairment.

ADVERSE REACTIONS The most common adverse reactions in RINVOQ clinical trials (≥1%) were: upper respiratory tract infection, nausea, cough, and pyrexia.

References: 1. RINVOQ [package insert]. North Chicago, IL: AbbVie Inc; 2019.

2. Data on file, AbbVie Inc. ABVRRTI68885. 3. Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase 3, double-blind, randomized controlled trial [published online July 9, 2019]. Arthritis Rheumatol. doi:10.1002/art.41032 4. Supplement to: Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase 3, double-blind, randomized controlled trial [published online July 9, 2019]. Arthritis Rheumatol. doi:10.1002/art.41032 5. Cohen SB, van Vollenhoven R, Winthrop K, et al. Safety Profile of Upadacitinib in Rheumatoid Arthritis: Integrated Analysis From the SELECT Phase 3 Clinical Program. Presented at: EULAR Annual Meeting; June 12–15, 2019; Madrid, Spain.

6. Data on file, AbbVie Inc. ABVRRTI68550.

Please see Brief Summary of full Prescribing Information on previous pages of this advertisement.

RINVOQ is a registered trademark owned or licensed by AbbVie Biotechnology, LTD, its subsidiaries and affiliates. ©2019 AbbVie Inc. North Chicago, IL 60064 US-RNQR-190422 September 2019 Printed in U.S.A.

RINVOQ™ ( upadacitinib) extended-release tablets, for oral use WARNING: SERIOUS INFECTIONS, MALIGNANCY, AND THROMBOSIS SERIOUS INFECTIONS Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions, Adverse Reactions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before RINVOQ use and during therapy. Treatment for latent infection should be considered prior to RINVOQ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with RINVOQ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions].

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with RINVOQ [see Warnings and Precautions].

THROMBOSIS Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.

Many of these adverse events were serious and some resulted in death. Consider the risks and benefits prior to treating patients who may be at increased risk. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately [see Warnings and Precautions].

INDICATIONS AND USAGE Rheumatoid Arthritis RINVOQ™ (upadacitinib) is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

Limitation of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections have been reported in patients receiving RINVOQ. The most frequent serious infections reported with RINVOQ included pneumonia and cellulitis [see Adverse Reactions]. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis, were reported with RINVOQ. Avoid use of RINVOQ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating RINVOQ in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ. Interrupt RINVOQ if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with RINVOQ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and RINVOQ should be interrupted if the patient is not responding to antimicrobial therapy.

RINVOQ may be resumed once the infection is controlled.

Tuberculosis Patients should be screened for tuberculosis (TB) before starting RINVOQ therapy. RINVOQ should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of RINVOQ in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, were reported in clinical studies with RINVOQ [see Adverse Reactions]. If a patient develops herpes zoster, consider temporarily interrupting RINVOQ until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed in accordance with clinical guidelines before starting and during therapy with RINVOQ. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA, were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. However, cases of hepatitis B reactivation were still reported in patients enrolled in the Phase 3 studies of RINVOQ. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted.

Malignancy Malignancies were observed in clinical studies of RINVOQ [see Adverse Reactions]. Consider the risks and benefits of RINVOQ treatment prior to initiating therapy in patients with a known malignancy other than

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing RINVOQ in patients who develop a malignancy.

Non-Melanoma Skin Cancer NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Thrombosis Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

Consider the risks and benefits of RINVOQ treatment prior to treating patients who may be at increased risk of thrombosis. If symptoms of thrombosis occur, patients should be evaluated promptly and treated appropriately.

Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with RINVOQ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

RINVOQ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Laboratory Parameters Neutropenia Treatment with RINVOQ was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3).

Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid initiation of or interrupt RINVOQ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3).

Lymphopenia ALC less than 500 cells/mm3 were reported in RINVOQ clinical studies.

Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid initiation of or interrupt RINVOQ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3).

Anemia Decreases in hemoglobin levels to less than 8 g/dL were reported in RINVOQ clinical studies.

Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid initiation of or interrupt RINVOQ treatment in patients with a low hemoglobin level (i.e., less than 8 g/dL).

Lipids Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol [see Adverse Reactions].

Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Patients should be monitored 12 weeks after initiation of treatment, and thereafter according to the clinical guidelines for hyperlipidemia.

Manage patients according to clinical guidelines for the management of hyperlipidemia.

Liver Enzyme Elevations Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo.

Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury.

If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

Embryo-Fetal Toxicity Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in fetal malformations.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks following completion of therapy [see Use in Specific Populations].

Vaccination Use of live, attenuated vaccines during, or immediately prior to, RINVOQ therapy is not recommended. Prior to initiating RINVOQ, it is recommended that patients be brought up to date with all immunizations, including prophylactic zoster vaccinations, in agreement with current immunization guidelines.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions] • Malignancy [see Warnings and Precautions] • Thrombosis [see Warnings and Precautions] • Gastrointestinal Perforations [see Warnings and Precautions] • Laboratory Parameters [see 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 practice.

A total of 3833 patients with rheumatoid arthritis were treated with upadacitinib in the Phase 3 clinical studies of whom 2806 were exposed for at least one year.

Patients could advance or switch to RINVOQ 15 mg from placebo, or be rescued to RINVOQ from active comparator or placebo from as early as Week 12 depending on the study design.

A total of 2630 patients received at least 1 dose of RINVOQ 15 mg, of whom 1860 were exposed for at least one year. In studies RA-I, RA-II, RA-III and RA-V, 1213 patients received at least 1 dose of RINVOQ 15 mg, of which 986 patients were exposed for at least one year, and 1203 patients received at least 1 dose of upadacitinib 30 mg, of which 946 were exposed for at least one year.

Table 2: Adverse Reactions Reported in greater than or equal to 1% of Rheumatoid Arthritis Patients Treated with RINVOQ 15 mg in Placebo-controlled Studies Adverse Reaction

Placebo n=1042 (%)

RINVOQ 15 mg n=1035 (%)

Upper respiratory tract infection 9.5 13.5 (URTI)* Nausea 2.2 3.5 Cough 1.0 2.2 Pyrexia 0 1.2 * URTI includes: acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, viral upper respiratory tract infection Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg group and at a higher rate than in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (includes oral herpes), and oral candidiasis.

Four integrated datasets are presented in the Specific Adverse Reaction section: Placebo-controlled Studies: Studies RA-III, RA-IV, and RA-V were integrated to represent safety through 12/14 weeks for placebo (n=1042) and RINVOQ 15 mg (n=1035). Studies RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), RINVOQ 15 mg (n=385), upadacitinib 30 mg (n=384). Study RA-IV did not include the 30 mg dose and, therefore, safety data for upadacitinib 30 mg can only be compared with placebo and RINVOQ 15 mg rates from pooling studies RA-III and RA-V. MTX-controlled Studies: Studies RA-I and RA-II were integrated to represent safety through 12/14 weeks for MTX (n=530), RINVOQ 15 mg (n=534), and upadacitinib 30 mg (n=529).

12-Month Exposure Dataset: Studies RA-I, II, III, and V were integrated to represent the long-term safety of RINVOQ 15 mg (n=1213) and upadacitinib 30 mg (n=1203).

Exposure adjusted incidence rates were adjusted by study for all the adverse events reported in this section.

Specific Adverse Reactions Infections Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, infections were reported in 218 patients (95.7 per 100 patient-years) treated with placebo and 284 patients (127.8 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, infections were reported in 99 patients (136.5 per 100 patient-years) treated with placebo, 118 patients (164.5 per 100 patient-years) treated with RINVOQ 15 mg, and 126 patients (180.3 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Studies: Infections were reported in 127 patients (119.5 per 100 patient-years) treated with MTX monotherapy, 104 patients (91.8 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 128 patients (115.1 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Infections were reported in 615 patients (83.8 per 100 patient-years) treated with RINVOQ 15 mg and 674 patients (99.7 per 100 patient-years) treated with upadacitinib 30 mg.

Serious Infections Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, serious infections were reported in 6 patients (2.3 per 100 patient-years) treated with placebo, and 12 patients (4.6 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, serious infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 7 patients (8.2 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Studies: Serious infections were reported in 2 patients (1.6 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 8 patients (6.4 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Serious infections were reported in 38 patients (3.5 per 100 patient-years) treated with RINVOQ 15 mg and 59 patients (5.6 per 100 patient-years) treated with upadacitinib 30 mg.

The most frequently reported serious infections were pneumonia and cellulitis.

Tuberculosis Placebo-controlled Studies and MTX-controlled Studies: In the placebo-controlled period, there were no active cases of tuberculosis reported in the placebo, RINVOQ 15 mg, and upadacitinib 30 mg groups.

In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, RINVOQ 15 mg monotherapy, and upadacitinib 30 mg monotherapy groups.

12-Month Exposure Dataset: Active tuberculosis was reported for 2 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg. Cases of extra-pulmonary tuberculosis were reported.

Opportunistic Infections (excluding tuberculosis) Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, opportunistic infections were reported in 3 patients (1.2 per 100 patient-years) treated with placebo, and 5 patients (1.9 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, opportunistic infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 6 patients (7.1 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Studies: Opportunistic infections were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 0 patients treated with RINVOQ 15 mg monotherapy, and 4 patients (3.2 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Opportunistic infections were reported in 7 patients (0.6 per 100 patient-years) treated with RINVOQ 15 mg and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg.

Malignancy Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, malignancies excluding NMSC were reported in 1 patient (0.4 per 100 patient-years) treated with placebo, and 1 patient (0.4 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, malignancies excluding NMSC were reported in 0 patients treated with placebo, 1 patient (1.1 per 100 patient-years) treated with RINVOQ 15 mg, and 3 patients (3.5 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Studies: Malignancies excluding NMSC were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 0 patients treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Malignancies excluding NMSC were reported in 13 patients (1.2 per 100 patient-years) treated with RINVOQ 15 mg and 14 patients (1.3 per 100 patient-years) treated with upadacitinib 30 mg.

Gastrointestinal Perforations Placebo-controlled Studies: There were no gastrointestinal perforations (based on medical review) reported in patients treated with placebo, RINVOQ 15 mg, and upadacitinib 30 mg.

MTX-controlled Studies: There were no cases of gastrointestinal perforations reported in the MTX and RINVOQ 15 mg group through 12/14 weeks. Two cases of gastrointestinal perforations were observed in the upadacitinib 30 mg group.

12-Month Exposure Dataset: Gastrointestinal perforations were reported in 1 patient treated with RINVOQ 15 mg and 4 patients treated with upadacitinib 30 mg.

Thrombosis Placebo-controlled Studies: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in 1 patient treated with placebo and 1 patient treated with RINVOQ 15 mg. In RA-V, venous thrombosis was observed in 1 patient treated with RINVOQ 15 mg. There were no observed cases of venous thrombosis reported in RA-III. No cases of arterial thrombosis were observed through 12/14 weeks.

MTX-controlled Studies: In RA-II, venous thrombosis was observed in 0 patients treated with MTX monotherapy, 1 patient treated with RINVOQ 15 mg monotherapy and 0 patients treated with upadacitinib 30 mg monotherapy through Week 14. In RA-II, no cases of arterial thrombosis were observed through 12/14 weeks. In RA-I, venous thrombosis was observed in 1 patient treated with MTX, 0 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg through Week 24. In RA-I, arterial thrombosis was observed in 1 patient treated with upadacitinib 30 mg through Week 24.

12-Month Exposure Dataset: Venous thrombosis events were reported in 5 patients (0.5 per 100 patient-years) treated with RINVOQ 15 mg and 4 patients (0.4 per 100 patient-years) treated with upadacitinib 30 mg. Arterial thrombosis events were reported in 0 patients treated with RINVOQ 15 mg and 2 patients (0.2 per 100 patient-years) treated with upadacitinib 30 mg.

Laboratory Abnormalities Hepatic Transaminase Elevations In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ 15 mg, and in 1.5% and 0.7% of patients treated with placebo, respectively. In RA-III and RA-V, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 1.0% of patients treated with RINVOQ 15 mg, 1.0% and 0% of patients treated with upadacitinib 30 mg and in 1.3% and 1.0% of patients treated with placebo, respectively.

In MTX-controlled studies, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with RINVOQ 15 mg, 1.7% and 1.3% of patients treated with upadacitinib 30 mg and in 1.9% and 0.9% of patients treated with MTX, respectively.

Lipid Elevations Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Elevations in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In controlled studies, for up to 12/14 weeks, changes from baseline in lipid parameters in patients treated with RINVOQ 15 mg and upadacitinib 30 mg, respectively, are summarized below: • Mean LDL cholesterol increased by 14.81 mg/dL and 17.17 mg/dL. • Mean HDL cholesterol increased by 8.16 mg/dL and 9.01 mg/dL. • The mean LDL/HDL ratio remained stable.

• Mean triglycerides increased by 13.55 mg/dL and 14.44 mg/dL. Creatine Phosphokinase Elevations In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the RINVOQ 15 mg and placebo groups, respectively. Most elevations >5 x ULN were transient and did not require treatment discontinuation.

In RA-III and RA-V, CPK elevations > 5 x ULN were observed in 0.3% of patients treated with placebo, 1.6% of patients treated with RINVOQ 15 mg, and none in patients treated with upadacitinib 30 mg.

Neutropenia In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in neutrophil counts, below 1000 cells/mm3 in at least one measurement occurred in 1.1% and <0.1% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in neutrophil counts below 1000 cells/mm3 in at least one measurement occurred in 0.3% of patients treated with placebo, 1.3% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical studies, treatment was interrupted in response to ANC less than 500 cells/mm3.

Lymphopenia In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.9% and 0.7% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.5% of patients treated with placebo, 0.5% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg.

Anemia In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in <0.1% of patients in both the RINVOQ 15 mg and placebo groups. In RA-III and RA-V, hemoglobin decreases below 8 g/dL in at least one measurement were observed in 0.3% of patients treated with placebo, and none in patients treated with RINVOQ 15 mg and upadacitinib 30 mg.

DRUG INTERACTIONS Strong CYP3A4 Inhibitors Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole). RINVOQ should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors.

Strong CYP3A4 Inducers Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampin), which may lead to reduced therapeutic effect of RINVOQ. Coadministration of RINVOQ with strong CYP3A4 inducers is not recommended.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The limited human data on use of RINVOQ in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. Based on animal studies, upadacitinib has the potential to adversely affect a developing fetus.

In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the maximum recommended human dose (MRHD), respectively, resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib during organogenesis at approximately 0.3 and 2 times the exposure at the MRHD. In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 3 times the MRHD resulted in no maternal or developmental toxicity [see Animal Data].

The estimated background risks of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages are 2-4% and 15-20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data Animal Data In an oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 5, 25, and 75 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that consisted of misshapen humerus and bent scapula) at exposures equal to or greater than approximately 1.7 times the MRHD (on an AUC basis at maternal oral doses of 5 mg/kg/day and higher). Additional skeletal malformations (bent forelimbs/hindlimbs and rib/vertebral defects) and decreased fetal body weights were observed in the absence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at a maternal oral dose of 75 mg/kg/day).

In a second oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 1.5 and 4 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that included bent humerus and scapula) at exposures approximately 1.6 times the MRHD (on an AUC basis at maternal oral doses of 4 mg/kg/day). No developmental toxicity was observed in rats at an exposure approximately 0.3 times the MRHD (on an AUC basis at a maternal oral dose of 1.5 mg/kg/day).

In an oral embryo-fetal developmental study, pregnant rabbits received upadacitinib at doses of 2.5, 10, and 25 mg/kg/day during the period of organogenesis from gestation day 7 to 19. Embryolethality, decreased fetal body weights, and cardiovascular malformations were observed in the presence of maternal toxicity at an exposure approximately 15 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both total and early resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 2 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

In an oral pre- and post-natal development study, pregnant female rats received upadacitinib at doses of 2.5, 5, and 10 mg/kg/day from gestation day 6 through lactation day 20. No maternal or developmental toxicity was observed in either mothers or offspring, respectively, at an exposure approximately 3 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

Lactation Risk Summary There are no data on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with upadacitinib, and for 6 days (approximately 10 half-lives) after the last dose.

Data Animal Data A single oral dose of 10 mg/kg radiolabeled upadacitinib was administered to lactating female Sprague-Dawley rats on post-partum days 7-8. Drug exposure was approximately 30-fold greater in milk than in maternal plasma based on AUC0-t values. Approximately 97% of drug-related material in milk was parent drug.

Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ [see Use in Specific Populations].

Contraception Females Based on animal studies, upadacitinib may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations]. Advise female patients of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose.

Pediatric Use The safety and efficacy of RINVOQ in children and adolescents aged 0 to 18 years have not yet been established. No data are available.

Geriatric Use Of the 4381 patients treated in the five Phase 3 clinical studies, a total of 906 rheumatoid arthritis patients were 65 years of age or older, including 146 patients 75 years and older. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of overall adverse events in the elderly.

Renal Impairment No dose adjustment is required in patients with mild, moderate or severe renal impairment. The use of RINVOQ has not been studied in subjects with end stage renal disease.

Hepatic Impairment No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. RINVOQ is not recommended for use in patients with severe hepatic impairment (Child Pugh C).

OVERDOSAGE Upadacitinib was administered in clinical trials up to doses equivalent in daily AUC to 60 mg extended-release once daily. Adverse events were comparable to those seen at lower doses and no specific toxicities were identified. Approximately 90% of upadacitinib in the systemic circulation is eliminated within 24 hours of dosing (within the range of doses evaluated in clinical studies). In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

Patients who develop adverse reactions should receive appropriate treatment.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of upadacitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received upadacitinib for up to 101 weeks at oral doses up to 15 or 20 mg/kg/day, respectively (approximately 4 and 10 times the MRHD on an AUC basis, respectively).

No evidence of tumorigenicity was observed in male or female Tg.rasH2 mice that received upadacitinib for 26 weeks at oral doses up to 20 mg/kg/day.

Mutagenesis Upadacitinib tested negatively in the following genotoxicity assays: the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay.

Impairment of Fertility Upadacitinib had no effect on fertility in male or female rats at oral doses up to 50 mg/kg/day in males and 75 mg/kg/day in females (approximately 42 and 84 times the MRHD in males and females, respectively, on an AUC basis). However, maintenance of pregnancy was adversely affected at oral doses of 25 mg/kg/day and 75 mg/kg/day based upon dose-related findings of increased post-implantation losses (increased resorptions) and decreased numbers of mean viable embryos per litter (approximately 22 and 84 times the MRHD on an AUC basis, respectively). The number of viable embryos was unaffected in female rats that received upadacitinib at an oral dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 2 times the MRHD on an AUC basis).

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Infections Inform patients that they may be more likely to develop infections when taking RINVOQ. Instruct patients to contact their healthcare provider immediately during treatment if they develop any signs or symptoms of an infection [see Warnings and Precautions].

Advise patients that the risk of herpes zoster is increased in patients taking RINVOQ and in some cases can be serious [see Warnings and Precautions].

Malignancies Inform patients that RINVOQ may increase their risk of certain cancers.

Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions].

Thrombosis Advise patients that events of DVT and PE have been reported in clinical studies with RINVOQ. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions].

Laboratory Abnormalities Inform patients that RINVOQ may affect certain lab tests, and that blood tests are required before and during RINVOQ treatment [see Warnings and Precautions].

Pregnancy Advise pregnant women and females of reproductive potential that exposure to RINVOQ during pregnancy may result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions and Use in Specific Populations]. Advise females of reproductive potential that effective contraception should be used during treatment and for 4 weeks following the final dose of upadacitinib [see Use in Specific Populations].

Lactation Advise women not to breastfeed during treatment with RINVOQ [see Use in Specific Populations].

Administration Advise patients not to chew, crush, or split RINVOQ tablets.

Manufactured by: AbbVie Ireland NL B.V., Sligo, Ireland Packed and Distributed by: AbbVie Inc., North Chicago, IL 60064 RINVOQ is a trademark of AbbVie Biotechnology Ltd. ©2019 AbbVie Inc. Ref: 03-B725 Revised: August, 2019 LAB-2721 MASTER

US-RNQR-190422

Una mirada al cáncer de próstata en Puerto Rico TRATAMIENTO PARA EL CÁNCER DE PRÓSTATA Por Ricardo Sánchez Ortiz, MD FACS

Un diagnóstico temprano puede alargar considerablemente la vida del paciente.

Especialista en Urología Oncológica Director de Cirugía Robótica, Hospital HIMA San Pablo Bayamón Catedrático Auxiliar de Urología de la Universidad de Puerto Rico Adjunct Assistant Profesor of Urology, MD Anderson Cancer Center

El riesgo de desarrollar cáncer de próstata se puede reducir bajando de peso e implementando una dieta baja en grasa.

Robotic Urologic Oncology Institute, San Juan

Estadísticas actuales reportan una tasa de supervivencia del 99% tras 5 años de la enfermedad.

Expertos creen que el cáncer de próstata, que se manifiesta en hombres puertorriqueños, es mucho más agresivo que el desarrollado por la población masculina estadounidense.

ETAPA 1

ETAPA 2

El factor más importante es la detección temprana con visitas anuales al urólogo desde los 40 años.

Sometidos o no a tratamiento, luego de 10 años, el 98% de afectados siguen con vida casi que normal.

El 95% logra sobrevivir complicaciones de salud asociadas más de 15 años, sin a la enfermedad.

ETAPA 3

ETAPA 4

Si el paciente afectado fue diagnosticado con cáncer a temprana edad, los riesgos aumentan en el caso de sus familiares.

PREVALENCIA DE LA CONDICIÓN EN PUERTO RICO De los casos detectados, 6 de cada 10 son diagnostica dos a hombres mayores de 65 años, siendo los 50 años la edad más común de detección de la anomalía.

AGENTES INFECCIOSOS

Bacteria

Virus

Hongos

CAUSANTES DEL CÁNCER DE PRÓSTATA La causa del cáncer de próstata se desconoce, pero hay factores que se asocian con su padecimiento:

Determinados virus

Agentes infecciosos

Hongos

Diagnóstico de esta patología

En estos pacientes, la detección solo se realiza cuando se manifiestas síntomas contundentes como:

Sangrado al orinar

Dificultad para conseguir una erección

Pérdida total del control de esfínteres

Necesidad de orinar con mayor frecuencia

Factores genéticos

Pacientes con un familiar de primer grado afectado (padre, hijo o hermano) tienen de un 18 a 40% de probabilidad de desarrollar cáncer en su vida.

Dolor / ardor al orinar o eyacular

EDITORIAL CRUZANDO FRONTERAS EN LOS AVANCES DE LA MEDICINA ONCOLÓGICA

Robert Hunter Mellado MD MSc FACP Director Cancer Medicine and Clinical Medicine Hospital del Centro Comprensivo de Cáncer

El diagnóstico de cáncer representa una condición respetada por algunos y temidos por todos. Su impacto en las múltiples dimensiones del ser humano es bien conocido y experimentado por cerca de 17,000 puertorriqueños todos los años. La evaluación del cáncer cada día es más compleja, ya que requiere un esfuerzo cooperativo de múltiples profesionales de la salud, está asociada a una creciente complejidad en definición patológica con un incremento en la necesidad de estudios moleculares.

El estadio apropiado de la condición, requiere de estudios más complejos e invasivos para entender la dimensión de la condición. El tratamiento de la malignidad comienza con diseñar la terapia óptima, elaborar la logística de la implementación del mismo, atender los elementos

8

Revista Puertorriqueña de Medicina y Salud Pública

que regulan y autorizan la disponibilidad de los tratamientos y finalmente dialogar y consentir al paciente sobre el diagnóstico, el tratamiento recomendado, las opciones disponibles, los beneficios y riesgos. La demografía de nuestros pacientes revela que la mayoría de los sujetos con un diagnóstico de cáncer son envejecientes.

Atender las necesidades peculiares de esta población con sus condiciones de comorbilidad representa un reto continuo.

El complemento de las alternativas para manejar el cáncer se expande continuamente, y con estas nuevas avenidas de terapia se abren y crean una evolución constante en la estrategia de tratamientos a usarse al igual que las secuelas del mismo. Parte de este paradigma, es la necesidad de atender aspectos especiales del paciente con cáncer que se van presentando a la medida que las opciones viables de terapia se incrementan y los efectos nocivos de estos tratamientos se le asigne su peso correspondiente en la calidad de vida del paciente. En esta edición tres médicos expertos en sus respectivas áreas de la oncología del Hospital del Centro Comprensivo de Cáncer presentan áreas de la medicina que están en las fronteras de los avances en la medicina oncológica.

Se estima que por lo menos entre un 2-3% de los sobrevivientes de cáncer en Puerto Rico se le diagnosticó el cáncer en la edad pediátrica. Los avances en la terapia oncológica pediátrica están asociados a la posibilidad de cura en más de un 70% de los casos. En esta edición, la Dra. Saisha Muñiz presenta un perfil de las necesidades de este grupo de sobrevivientes de cáncer.

El Dr. José Rivera del Río y la Dra. Elsa Pedro introducen un nuevo capítulo en la evolución de la patología del sistema cardiovascular con la oncología cardíaca y el Dr.Yamil Castillo presenta la re-introducción de la cirugía para los tumores de orofaringe y los aspectos de prevención primaria relevante a esta población.

El futuro del Hospital del Centro Comprensivo de Cáncer es prometedor. Nuestra tarea de facilitar acceso a medicamentos de vanguardia, proveer la medicina de mañana, HOY, por conducto de estudios clínicos y el manejo multidisciplinario es nuestro norte. Nuestra más sagrada misión es servir de recurso a todos los pacientes de nuestra Isla con esta temible condición.

venetoclax tablets

10mg, 50mg,100mg

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is a registered trademark ofAbeie Inc.

and marketed by Abeie Inc.,1 North Waukegan Road, North Chicago, IL60064 ©2019 Abeie US-VEN-‘I90028/May 2019

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tablets

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Somos todo lo que necesitas

FOR ADULTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS

TALTZ DATA ON COMPLETE CLEARANCE IN CHALLENGING BODY AREAS Taltz is an interleukin-17A (IL-17A) antagonist indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

SCALP PSORIASIS

71% PSSI 100 by week 12 2

Taltz is the first and only FDA-approved medication for moderate to severe plaque psoriasis with data on efficacy in genital psoriasis included in the Prescribing Information.1

NAIL PSORIASIS

56% NAPSI 0 by week 603

GENITAL PSORIASIS

Discover more Taltz efficacy data in challenging body areas by visiting taltz.com/challengingareas Subgroup analyses presented for nail, scalp, and palmoplantar psoriasis are post hoc. The UNCOVER studies were not powered for these subgroup analyses, nor were analyses error-controlled. Therefore, treatment differences observed in these subgroups cannot be regarded as statistically significant. Data presented for nail are from the UNCOVER-3 open-label extension period.

56% sPGA-G 0 by week 124

PALMOPLANTAR PSORIASIS

52% PPASI 100 by week 12 5

PSSI=Psoriasis Scalp Severity Index; NAPSI=Nail Psoriasis Severity Index; sPGA-G=static Physician’s Global Assessment of Genitalia; PPASI=Palmoplantar Psoriasis Area Severity Index.

Primary endpoints from UNCOVER-1, -2, and -3 trials at week 121 In UNCOVER-2 (Taltz n=351; placebo n=168), 90% of Taltz patients achieved PASI 75 vs 2% for placebo, 40% of Taltz patients achieved PASI 100 vs 1% for placebo, and 83% of Taltz patients achieved sPGA 0,1 vs 2% for placebo. In UNCOVER-1 (Taltz n=433; placebo n=431) and UNCOVER-3 (Taltz n=385; placebo n=193), Taltz patients achieved similar results: 89% and 87% of Taltz patients achieved PASI 75 vs 4% and 7% for placebo. Additionally, 35% and 38% achieved PASI 100 vs 0% and 0% for placebo. Also, 82% and 81% of Taltz patients achieved sPGA 0,1 vs 3% and 7% for placebo.

UNCOVER-1, -2, and -3 trial designs1

The Taltz plaque psoriasis clinical program included 3 randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of Taltz. All patients were ≥18 years of age and had plaque psoriasis with a body surface area involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score ≥3, and a Psoriasis Area Severity Index (PASI) score ≥12, and were candidates for phototherapy or systemic therapy. Participants were randomized to receive placebo or Taltz 80 mg every 2 weeks following a 160 mg starting dose. In UNCOVER-2 and -3, an additional arm of US-approved Enbrel® (etanercept) (50 mg twice weekly) was included. Co-primary efficacy endpoints were proportion of patients with an sPGA 0,1 and at least a 2-point improvement from baseline and proportion of patients achieving PASI 75 (at least a 75% reduction in the PASI composite score) at week 12.

Nonresponder imputation (NRI) methods were used for categorical efficacy analyses.

Patients originally randomized to Taltz who were responders at week 12 (ie, sPGA 0,1) in UNCOVER-1 and -2 were re-randomized to either Taltz 80 mg every 4 weeks or placebo for an additional 48 weeks. Patients who relapsed (sPGA ≥3) at any time during the maintenance period were classified as nonresponders at week 60.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS

Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.

WARNINGS AND PRECAUTIONS

Infections Taltz may increase the risk of infection. In clinical trials of patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%). A similar increase in risk of infection was seen in placebo-controlled trials of patients with psoriatic arthritis. Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Pre-Treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Closely monitor patients receiving Taltz for signs and symptoms of active TB during and after treatment.

Hypersensitivity Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease During Taltz treatment, monitor patients for onset or exacerbations of inflammatory bowel disease. Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than in the placebo group (0%) during clinical trials in patients with plaque psoriasis.

ADDITIONAL RESULTS IN CHALLENGING BODY AREAS Post hoc subgroup analyses of patients with scalp psoriasis*

sPGA of Genitalia 0,1 response rates at week 12, NRI8,9

PSSI 100 response rates at weeks 12 and 60 (induction period and open-label extension), nonresponder imputation (NRI)2

In IXORA-Q, 73% of patients receiving Taltz (n=75) achieved sPGA-G 0,1 (clear or almost clear genital skin) at week 12 vs 8% of patients receiving placebo (n=74).

The sPGA-G is designed to specifically evaluate plaque lesion severity in the genital area rather than the entire body; erythema is the dominant feature influencing the sPGA-G rating. At baseline, patients had a minimum BSA ≥1% and sPGA-G ≥3.

In UNCOVER-3, 71% of patients receiving Taltz (132 out of 185) achieved PSSI 100 vs 4% receiving placebo (3 out of 82) at week 12. At week 60, 78% of patients receiving Taltz (132 out of 169) achieved PSSI 100.

ADDITIONAL RESULTS: In UNCOVER-1 (Taltz n=210; placebo n=215) and UNCOVER-2 (Taltz n=144; placebo n=77), 68% and 71% of patients who received Taltz 80 mg every 2 weeks, respectively, achieved PSSI 100 at week 12 vs 3% and 3% for placebo. *A subset of patients from UNCOVER-3 with moderate to severe plaque psoriasis and scalp psoriasis (defined as PSSI score ≥15 and scalp involvement ≥30%) at baseline. The mean baseline PSSI score was 30 for Taltz and 29 for placebo.

Post hoc subgroup analyses of patients with nail psoriasis† NAPSI 0 response rates at weeks 12 and 60 (induction period and open-label extension), NRI3 In UNCOVER-3, 6% of patients receiving Taltz (8 out of 138) achieved NAPSI 0 vs 0% receiving placebo (0 out of 71) at week 12. At week 60, 56% of patients receiving Taltz (77 out of 138) achieved NAPSI 0.

The mean number of fingernails involved at baseline was 9.2 for Taltz and 9.1 for placebo. Only patients’ fingernails were observed.3,6 ADDITIONAL RESULTS: In UNCOVER-1 (Taltz n=172; placebo n=168) and UNCOVER-2 (Taltz n=131; placebo n=72), 7% and 8%, respectively, of patients who received Taltz 80 mg every 2 weeks achieved NAPSI 0 at week 12 vs 0% and 4% for placebo.3 A subset of patients from UNCOVER-3 with moderate to severe plaque psoriasis who had nail psoriasis (defined as NAPSI ≥16 with ≥4 fingernails involved) at baseline. The mean baseline NAPSI scores were 39 for Taltz and 37 for placebo.3 NAPSI is based on a score of 0-80. Only patients’ fingernails were observed.6

†

Post hoc subgroup analyses of patients with palmoplantar psoriasis‡ PPASI 100 response rate at week 12 (induction period), NRI5,7 In UNCOVER-1, -2, and -3, 52% of patients receiving Taltz (59 out of 114) achieved PPASI 100 vs 8% of patients receiving placebo (7 out of 85) at week 12.5 ADDITIONAL RESULTS: In UNCOVER-1 (Taltz n=45; placebo n=47), UNCOVER-2 (Taltz n=31; placebo n=18), and UNCOVER-3 (Taltz n=38; placebo n=20), 53%, 52%, and 50%, respectively, of patients who received Taltz 80 mg every 2 weeks achieved PPASI 100 at week 12 vs 9%, 6%, and 10% for placebo.5 ‡

A subset of patients from UNCOVER-1, -2, and -3 with moderate to severe plaque psoriasis and palmoplantar psoriasis (defined as PPASI ≥8) at baseline. The mean baseline PPASI score was 19 for Taltz patients and 23 for placebo.5 PPASI is based on a score of 0-72.7

80 mg/mL

BSA=body surface area.

More than half of patients achieved sPGA-G 0 by week 124 In IXORA-Q, 42 out of 75 Taltz-treated patients achieved sPGA-G 0 (completely clear genital skin) at week 12. 56% of patients receiving Taltz (n=75) achieved sPGA-G 0 at week 12 vs 5% of patients receiving placebo (n=74).10 sPGA-G 0 was a prespecified, exploratory endpoint. It was not controlled for multiplicity; therefore, treatment differences between Taltz and placebo cannot be regarded as statistically significant.

NRI of intent-to-treat population through week 12; primary endpoint=sPGA-G 0,1 at week 12.10

IXORA-Q trial design11 IXORA-Q is a placebo-controlled, randomized, double-blind study comparing efficacy and safety of Taltz vs placebo in patients with moderate to severe genital psoriasis as measured by the proportion of patients achieving sPGA-G 0,1 at week 12 (primary endpoint).

The study enrolled 149 adult patients with plaque psoriasis who had minimum BSA of ≥1%, sPGA ≥3 (moderate psoriasis) and sPGA-G of ≥3 (moderate genital psoriasis), who failed to respond to or were intolerant of at least one topical therapy used for treatment of psoriasis affecting the genital area (corticosteroids, calcineurin inhibitors, and/or vitamin D analogues), and who were candidates for phototherapy and/or systemic therapy. Patients were randomized to receive placebo or Taltz 80 mg every 2 weeks after a 160 mg starting dose. Nonresponder imputation (NRI) methods were used for categorical efficacy analyses.

Secondary efficacy endpoints included the proportion of patients at week 12 achieving overall sPGA 0,1 and a ≥4-point improvement in Genital Psoriasis Itch Numeric Rating Scale (NRS) within the Genital Psoriasis Symptoms Scale (GPSS) (in patients with a baseline score of at least 4) and proportion of patients achieving Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item 2 score of 0 or 1 at week 12 (sexual frequency “never” or “rarely” limited by genital psoriasis).

Discover more Taltz efficacy data in challenging body areas by visiting taltz.com/challengingareas

IMPORTANT SAFETY INFORMATION (cont’d) Immunizations Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz.

ADVERSE REACTIONS Most common adverse reactions (≥1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. Overall, the safety profile observed in patients with psoriatic arthritis was consistent with the safety profile in patients with plaque psoriasis, with the exception of influenza and conjunctivitis.

Please see Brief Summary of Prescribing Information on the following pages. Please see Instructions for Use included with the device.

IX HCP ISI 01DEC2017 References: 1. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018. 2. Data on file. Lilly USA, LLC. TAL20170829F. 3. Data on file. Lilly USA, LLC. TAL20170829B. 4. Ryan C, Menter A, Guenther L, et al; IXORA-Q Study Group. Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis. Br J Dermatol. 2018;179:844-852. 5. Data on file. Lilly USA, LLC. TAL20170829D. 6. Dennehy EB, Zhang L, Amato D, Goldblum O, Rich P. Ixekizumab is effective in subjects with moderate to severe plaque psoriasis with significant nail involvement: results from UNCOVER 3.

J Drugs Dermatol. 2016;15:958-961. 7. Menter A, Warren RB, Langley RG, et al. Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate-to-severe plaque psoriasis and non-pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2 and UNCOVER-3). J Eur Acad Dermatol Venereol. 2017;31:1686-1692. 8. Ryan C, Menter A, Guenther L, et al. Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled, phase 3b clinical trial in patients with moderate-to-severe genital psoriasis. Presented at the 18th Annual Fall Scientific Meeting of the Sexual Medicine Society of North America; October 27, 2017; San Antonio, TX. Abstract 012. http://smsna.org/V1/index.php?option=com_content&view=article&id=419&abstract_id=221. 9. Data on file. Lilly USA, LLC. TAL20171219A. 10. Data on file. Lilly USA, LLC. DOF-IX-US-0014. 11. Data on file. Lilly USA, LLC. TAL01242018A. Taltz® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries and affiliates.

Other company and product names are trademarks of their respective owners.

PP-IX-US-2360 01/2019 ©LILLY USA, LLC 2019. ALL RIGHTS RESERVED.

Taltz® (ixekizumab) injection Brief Summary: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE Plaque Psoriasis—Taltz is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Psoriatic Arthritis— Taltz is indicated for the treatment of adult patients with active psoriatic arthritis.

CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients (Warnings and Precautions).

WARNINGS AND PRECAUTIONS Infections—Taltz may increase the risk of infection. In clinical trials in patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the Taltz group than in the placebo group. A similar increase in risk of infection was seen in placebo-controlled trials in patients with psoriatic arthritis (Adverse Reactions). Instruct patients treated with Taltz to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Taltz until the infection resolves.

Pre-treatment Evaluation for Tuberculosis—Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Consider anti-TB therapy prior to initiating Taltz in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving Taltz should be monitored closely for signs and symptoms of active TB during and after treatment.

Hypersensitivity—Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz (Adverse Reactions). If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease— During Taltz treatment, monitor for onset or exacerbation of inflammatory bowel disease. Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than in the placebo group (0%) during the 12-week, placebocontrolled period in clinical trials in patients with plaque psoriasis.

Immunizations—Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz. No data are available on the response to live vaccines.

ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: t *OGFDUJPOT (Warnings and Precautions) t )ZQFSTFOTJUJWJUZ 3FBDUJPOT (Contraindications and Warnings and Precautions) t *OþBNNBUPSZ #PXFM %JTFBTF (Warnings and Precautions) Clinical Trials Experience—Because clinical trials are conducted under widely varying and controlled 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.

Plaque Psoriasis Weeks 0 to 12 : Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of Taltz compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received Taltz (160 mg at Week 0, 80 mg every 2 weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of Taltz (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept.

In the 12-week, placebo-controlled period, adverse events occurred in 58% of the Taltz Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up).

Serious adverse events occurred in 2% of the Taltz group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up).

Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Taltz group than the placebo group during the 12-week placebo-controlled period of the pooled clinical trials.

Table 1: Adverse Reactions Occurring in ≥1% of the Taltz Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 Adverse Reactions Injection site reactions Upper respiratory tract infectionsa Nausea Tinea infections a b

Taltz 80 mg Q2W (N=1167) (n%) 196 (17)

Etanerceptb (N=287) (n%) 32 (11)

Placebo (N=791) (n%) 26 (3)

163 (14)

23 (8)

101 (13)

23 (2) 17 (2)

1 (<1) 0

5 (1) 1 (<1)

Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.

U.S. approved etanercept.

Adverse reactions that occurred at rates less than 1% in the Taltz group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema.

Weeks 13 to 60 : A total of 332 subjects received the recommended maintenance regimen of Taltz 80 mg dosed every 4 weeks.

During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with Taltz (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with Taltz (0.05 per subject-year of follow-up) and none in the subjects treated with placebo.

Weeks 0 to 60 : Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with Taltz (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with Taltz (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up).

Specific Adverse Drug Reactions: Injection Site Reactions : The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Taltz. ® Taltz14 (ixekizumab) injection

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IX HCP BS 01DEC2017

Infections : In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with Taltz (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with Taltz (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) (Warnings and Precautions).

During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with Taltz (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with Taltz (0.01 per subject-year of follow-up) and none in the subjects treated with placebo.

Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with Taltz (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with Taltz (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up).

Laboratory Assessment of Cytopenia: Neutropenia—Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with Taltz (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with Taltz, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12.

In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the Taltz group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subjectyear of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for Taltz 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for Taltz 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to <2,000 cells/mm3). Neutropenia in the Taltz group was not associated with an increased rate of infection compared to the placebo group.

Thrombocytopenia—Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for Taltz 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3). Thrombocytopenia in subjects treated with Taltz was not associated with an increased rate of bleeding compared to subjects treated with placebo.

Active Comparator Trials : In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S.-approved etanercept and 2% for Taltz 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for Taltz 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for Taltz 80 mg Q2W. The rate of serious infections was 0.3% for both Taltz 80 mg Q2W and U.S. approved etanercept.

Psoriatic Arthritis Taltz was studied in two placebo-controlled trials in patients with psoriatic arthritis. A total of 678 patients were studied (454 patients on Taltz and 224 on placebo). A total of 229 patients in these trials received TALTZ 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with psoriatic arthritis treated with Taltz Q4W is consistent with the safety profile in patients with plaque psoriasis with the exception of the frequencies of influenza (1.3%) and conjunctivitis (1.3%).

Immunogenicity—As with all therapeutic proteins there is the potential for immunogenicity with Taltz. The assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated.

Plaque Psoriasis Population

By Week 12, approximately 9% of subjects treated with Taltz every 2 weeks developed antibodies to ixekizumab.

Approximately 22% of subjects treated with Taltz at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.

Of the subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with Taltz at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy.

Psoriatic Arthritis Population For subjects treated with Taltz 80 mg every 4 weeks for up to 52 weeks (PsA1), 11% developed anti-drug antibodies, the majority of which were low titer, and 8% had confirmed neutralizing antibodies.

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 Taltz across indications or with the incidences of antibodies to other products may be misleading.

Postmarketing Experience—The following adverse reactions have been identified during post-approval use of Taltz. Because the 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 Taltz exposure.

Immune system disorders: anaphylaxis (Contraindications and Warnings and Precautions) DRUG INTERACTIONS Live Vaccinations—Avoid use of live vaccines in patients treated with Taltz (Warnings and Precautions).

Cytochrome P450 Substrates—The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFĮ, IFN) during chronic inflammation. Thus, Taltz, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes.

Therefore, upon initiation or discontinuation of Taltz in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary—There are no available data on Taltz use in pregnant women to inform any drug associated risks.

Human IgG is known to cross the placental barrier; therefore, Taltz may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical significance of these nonclinical findings is unknown.

The background risk of major birth defects and 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 to 4% and 15 to 20%, respectively.

Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

Data Animal Data—An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys.

In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.

Lactation Risk Summary—There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Taltz and any potential adverse effects on the breastfed infant from Taltz or from the underlying maternal condition.

Pediatric Use—The safety and effectiveness of Taltz in pediatric patients (<18 years of age) have not been evaluated.

Geriatric Use—Of the 4204 psoriasis subjects exposed to Taltz, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.

OVERDOSAGE—In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.

PATIENT COUNSELING INFORMATION—Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Taltz and each time the prescription is renewed, as there may be new information they need to know.

Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly (Instructions for Use).

Infection: Inform patients that Taltz may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection (Warnings and Precautions).

Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions (Warnings and Precautions).

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

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2016, 2017, Eli Lilly and Company. All rights reserved.

IX HCP BS 01DEC2017 Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

Autor Dr. David Blas Boria Neuro Oncólogo Facultad Médica del Hospital Centro Comprensivo de Cáncer UPR

Credenciales: Residencia en Neurología: Universidad de Puerto Rico Recinto de Ciencias Médicas Fellowship en Neuro-Oncología: University of Texas MD Anderson Cancer Center Boards: American Board of Psychiatry and Neurology: Neurology United Council of Neurological Subspecialties: Neuro Oncology

LA QUIMIOTERAPIA EN EL TRATAMIENTO PARA EL CÁNCER: IMPACTO EN LA FUNCIÓN COGNITIVA

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MSP ARTÍCULO / ORIGINAL PALABRAS CLAVES

KEYWORDS

Quimio cerebro, nebulosidad mental, cambios cognitivos, función cognitiva, disfunción cognitiva

Chemobrain, chemofog, cognitive change, cognitive functioning, cognitive dysfunction

RESUMEN En los últimos 30 años ha aumentado la evidencia que sugiere que los tratamientos para el cáncer sistémico pudieran tener cambios inmediatos a largo plazo en la función cognitiva. Los cambios cognitivos relacionados al cáncer y su tratamiento son frecuentes y de gran preocupación para los pacientes. No hay un tratamiento estándar para el manejo o prevención de los cambios cognitivos que experimentan los pacientes debido a su condición o los efectos secundarios de la quimioterapia.

ABSTRACT In the last 20-30 years, evidence has increased that suggests that treatments for systemic cancer may have immediate or long-term changes in cognitive function. The cognitive changes related to cancer and its treatment is a frequent condition and is of great concern for patients. There is no standard treatment for the management or prevention of cognitive changes that patients experience due to their condition or the side effects of chemotherapy.

INTRODUCCIÓN Existen aproximadamente 16.9 millones de sobrevivientes de cáncer en los Estados Unidos de América y se espera que esa población aumente a 22.1 millones debido al crecimiento y envejecimiento de la población (1). A pesar de esta mejoría, los efectos tardíos de tratamientos, en particular aquellos relacionados a la quimioterapia, son de mucha preocupación para los pacientes, en particular los cambios cognitivos que pueden afectar la calidad de vida de los pacientes.

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MSP ARTÍCULO / ORIGINAL

¿QUÉ ES QUIMIO CEREBRO? Los cambios cognitivos que pueden afectar a los pacientes se conocen como nebulosidad mental (chemofog) o quimiocerebro (chemobrain). Originalmente se conocía que existían cambios cognitivos asociados a los tumores del sistema nervioso central y sus tratamientos, pero no asociados a malignidades sistémicas debido a la premisa que las quimioterapias tradicionales no cruzan la barrera hematoencefalica, pero en los últimos 20 o 30 años ha aumentado la evidencia que sugiere que los tratamientos para el cáncer sistémico pudieran tener cambios inmediatos y a largo plazo en la función cognitiva. La disfunción cognitiva se puede ver en diferentes tipos de cáncer al momento del diagnóstico, el cual puede variar desde un 90% en pacientes con tumores primarios cerebrales, y entre un 17 a un 75% en pacientes con cáncer de seno (2).

Es importante mencionar que los cambios cognitivos relacionados con el cáncer han sido documentados en la ausencia de quimioterapia, lo cual nos lleva a pensar que estos cambios están también relacionados al cáncer como tal, cirugías, y otras terapias que no son quimioterapias (por ejemplo, terapias hormonales) (3). Además, con estilos de vida y comorbilidades médicas, como problemas con fatiga y sueño pueden ser factores de riesgo para un deterioro cognitivo tardío. Cabe destacar que, en algunos casos, los pacientes ya tienen una reserva cognitiva baja, lo cual los hace más susceptibles a un deterioro cognitivo postratamiento (4).

Actualmente no se conoce bien el mecanismo de cómo el cáncer o

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LA MAYORÍA DE LOS ESTUDIOS CLÍNICOS DE CAMBIOS COGNITIVOS RELACIONADOS AL CÁNCER Y TRATAMIENTOS DEL CÁNCER HAN SIDO EN MUJERES CON CÁNCER DE SENO (4) QUE REPRESENTAN UN 22% DE LOS SOBREVIVIENTES DE CÁNCER EN ESTADOS UNIDOS

el tratamiento para el cáncer tienen un impacto en la función cognitiva. Por ende, se han propuesto diversas teorías, por ejemplo, que el tratamiento pudiera acelerar el envejecimiento de la cognición o que el tratamiento pudiera causar disrupción de las redes estructurales cerebrales que procesan e integran información a través del cerebro. Probablemente son muchos los mecanismos que contribuyen al deterioro cognitivo en los pacientes de cáncer, incluyendo inflamación, efectos neurotóxicos directos de los tratamientos, daño a las células progenitoras, o también estados psicológicos de base como la depresión o la ansiedad. Otro factor de riesgo conocido para el deterioro cognitivo es la edad; se ha visto que individuos de avanzada edad tienen niveles mas bajos de reservas cognitivas pre tratamiento y otros pudieran ser portadores de variantes del gen apolipoproteína E (APOE) que los pone en riesgo de desarrollar una demencia futura.

La mayoría de los estudios clínicos de cambios cognitivos relacionados con el cáncer y sus tratamientos han sido realizados en mujeres con cáncer de seno (4) que representan un 22% de los sobrevivientes de cáncer en Estados Unidos, pero también hay data en otros tipos de cáncer como cáncer testicular, linfoma, mieloma múltiple, cáncer colorectal, cáncer de ovarios y cáncer de próstata, entre otros. ¿DE QUÉ SE AQUEJAN LOS PACIENTES? Los pacientes se aquejan de problemas relacionados a la cognición de diferentes maneras, por ejemplo: “Me siento lento”, “No puedo llevar a cabo múltiples tareas a la vez”, “Se me hace difícil prestar atención o entender lo que leo”, “Siento que se me olvidan las cosas”. Las quejas pueden ser sutiles, pero deben de ser tomadas en serio por su equipo médico. Si las quejas persisten

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después de finalizar los tratamientos e interfieren con la calidad de vida del paciente (por ejemplo, pobre desempeño en el trabajo o en la casa) se debe referir al paciente para una evaluación neuropsicológica y -de esta manera- guiar el tratamiento.

Usualmente se afectan la memoria, la velocidad de procesamiento y la atención. Lamentablemente, no hay un consenso acerca de qué pruebas neuropsicológicas realizar.

Otro problema es que la evaluación de la función cognitiva no se hace de manera rutinaria y solo se hace cuando la disfunción cognitiva afecta la calidad de vida. El costo de estas pruebas neuropsicológicas es otro de los problemas en el diagnóstico de los pacientes porque, en adición a su alto costo, los planes médicos no cubren las mismas. ¿QUÉ OPCIONES DE TRATAMIENTO EXISTEN? No hay un tratamiento estándar para el manejo o prevención de los cambios cognitivos que experimentan los pacientes con cáncer debido a su condición o secundarios a sus tratamientos. Debido a que la disfunción cognitiva ha sido asociada a ansiedad, depresión y disturbios de sueño, sería importante primero tratar estos potenciales factores que nos podrían confundir en aquellos pacientes que tienen deterioro cognitivo luego del tratamiento para el cáncer.

También es importante identificar si el paciente está recibiendo medicamentos que puedan afectar la función cognitiva y, si es posible, eliminarlos (por ejemplo, los psicofármacos). Una combinación de terapias cognitivas conductuales y tratamientos farmacológicos pudiera resultar en una mejoría en la

LAS INTERVENCIONES DE TERAPIAS COGNITIVAS CONDUCTUALES ESTÁN ENFOCADAS EN DESARROLLAR ESTRATEGIAS COMPENSATORIAS PARA PROBLEMAS COGNITIVOS DURANTE O DESPUÉS DEL TRATAMIENTO.

función cognitiva y calidad de vida de los sobrevivientes de cáncer.

Las intervenciones de terapias cognitivas conductuales están enfocadas en desarrollar estrategias compensatorias para problemas cognitivos durante o después del tratamiento. Ejemplos de estas terapias son: técnicas de relajación, programas de ejercicio físico, terapia ocupacional, programas de entrenamiento cerebrales (programas basados en computadora dirigidos a hacer ejercicios mentales que aumentan el desempeño del cerebro) y rehabilitación cognitiva grupal, entre otros. En cuanto a las intervenciones farmacológicas, la data es limitada debido a que no hay ensayos clínicos aleatorios. Entre estos tratamientos se encuentran los estimulantes del sistema nervioso central como el modafinil o el metilfenidato. También se encuentran

los inhibidores reversibles de la acetilcolinesterasa utilizados para tratar la demencia de alzhéimer como el donepezil.

CONCLUSIÓN El deterioro cognitivo relacionado al cáncer y su tratamiento es una condición frecuente de gran preocupación para los pacientes de cáncer. Lamentablemente no se conoce su causa, probablemente multifactorial.

Las pruebas diagnósticas no han sido estandarizadas y los tratamientos existentes carecen de una data robusta que los respalde. Se requieren estudios que incluyan una muestra grande y significativa para identificar factores de riesgo y posibles tratamientos para esta condición.

REFERENCIAS: 1. American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2019-2021. Atlanta: American Cancer Society; 2019.

2. Ahles TA, Root JC, Ryan EL. Cancer and cancer

treatment associated cognitive change: an update on the state of the science. J Clin Oncol 2012; 30:3675 3. Schilder CM, Seynaeve C, Beex LV, et al. Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. J Clin Oncol.

2010;28:1294-1300 4. Wefel JS, Saleeba AK, Buzdar AU, et al. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer. 2010; 3348-3356

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Elsa Pedro Gutiérrez, Pharm D. BCPS Catedrática Asociada Departamento de Práctica en Farmacia, Escuela de Farmacia UPR Hospital del Centro Comprensivo de Cáncer, UPR

José R. Rivera Del Río, MD, FACC, FASE, FECOSIAC, RDCS Cardiology and Internal Medicine Section Director Cardiac Lab Section Director Hospital del Centro Comprensivo de Cáncer, UPR

EL USO DE AGENTES ANTINEOPLÁSICOS EN PACIENTES CON CÁNCER:

efectos secundarios al sistema cardiovascular PALABRAS CLAVES:

KEYWORDS:

Cardio-oncólogo, farmacología, quimioterapias, condiciones cardiovasculares

Cardio-oncologist, pharmacology, chemotherapies, cardiovascular conditions

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MSP ARTÍCULO / ORIGINAL RESUMEN

INTRODUCCIÓN

Los avances de las terapias para el manejo de los pacientes de cáncer han logrado una gran reducción en la mortalidad, pero el uso de los agentes antineoplásicos está asociados a efectos secundarios en el desarrollo de condiciones cardiovasculares. Los efectos de farmacocinética y farmacodinámica deben tomarse muy en cuenta al manejar estos pacientes. Es importante que el paciente sea evaluado por el equipo multidisciplinario antes, durante y después del tratamiento.

El manejo moderno de pacientes con cáncer ha logrado una reducción en la mortalidad y morbilidad de nuestros pacientes. El uso de las antraciclinas (1) (adriamicina, daunorubicina, etc.) y, de modo progresivo, los agentes alquilantes (ciclofosfamida, etc.), los anticuerpos monoclonales (trastuzumab, pertuzumab, etc.), los inhibidores de los factores de crecimiento endotelial vascular (VSP) y los inhibidores de las proteasas, entre otros, han contribuido al incremento en la posibilidad de cura de muchas malignidades. A pesar de estos avances, estos productos están asociado a un número significativo de efectos secundarios cardiovasculares. En adición al daño al sistema cardiovascular que pueden causar estos tratamientos, se ha observado que estos medicamentos pueden interferir con la farmacología de los agentes antineoplásicos alterando su efectividad o toxicidad. (1) La tabla 1 resume el perfil de efectos cardiovasculares asociados a la terapia antineoplásica.

ABSTRACT The advances in therapies for the management of cancer patients have achieved a great reduction in mortality; but the use of antineoplastic agents are associated with side effects in the development of cardiovascular conditions. The effects of pharmacokinetics and pharmacodynamics must be considered when handling these patients. It is important that the patient be evaluated by the multidisciplinary team before the start during and after the treatment.

Tabla 1

MECANISMOS DE TOXICIDAD CARDIOVASCULAR El número de medicamentos que causan disfunción del ventrículo izquierdo ha ido en incremento. Las antraciclinas representan el prototipo de drogas que causan disfunción cardíaca. Por su uso y frecuencia, se discuten aquí. Estas drogas (ej. adriamicina) inhiben la topoisimerasa 2B y activan el p53, lo que provoca la muer te del músculo cardíaco y hiperóxidos que, finalmente, causan mitocondriopatía. Previamente se ha considerado que la toxicidad ocurre al superar dosis de 500 mg/m2, pero en eventos subclínicos se ha visto hasta un 30%, incluso en dosis de 180-240 mg/m2, trece años luego de la terapia.

Cambios histopatológicos se han visto en biopsia del músculo cardíaco aun en dosis de 240 mg/m2.

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Tabla 2

MSP ARTÍCULO / ORIGINAL

ANTICUERPOS MONOCLONALES Los anticuerpos monoclonales son estructuras bien complejas de administración intravenosa que se enlazan a diferentes receptores y pueden actuar de una de las siguientes maneras: • Reconocen un marcador en las células cancerosas, se enlazan y forman un complejo que activa el sistema inmunológico para que ataque ese complejo.

• Activan las células T para que ataquen a las células cancerosas.

• Inhiben proteínas que son sobreexpresadas en células cancerosas.

Estas proteínas aumentan la replicación de la célula cancerosa.

EL MECANISMO DE ACCIÓN ESPECÍFICO DE ESTOS ANTICUERPOS MONOCLONALES SON LOS SIGUIENTES: Inhibidores de receptor de tirosina del factor de crecimiento epidermal (HER-2, por sus siglas en inglés): Este receptor se encuentra en diferentes tejidos del cuerpo y se sobre expresa en algunos tipos de cáncer de seno, endometrio, ovario y gástrico. La activación de este receptor en el corazón es crítica para el crecimiento del miocito, sobrevivencia y homeostasis. Estas terapias interrumpen la homeostasis del miocito y su reparación. Su efecto cardiovascular más significativo es la inducción de fallo cardíaco congestivo. (4) Se recomienda un ecocardiograma de base y repetirlo durante la terapia. Este efecto adverso es reversible.

“VEGFR inhibitors”: La activación de este receptor promueve el desarrollo de vasos sanguíneos nuevos. Las células cancerosas producen VEGF y este activa el receptor VEGFR localizado en los vasos sanguíneos. De esta manera, aumenta la cantidad de oxígeno y nutrientes que llega a las células cancerosas. La activación del receptor también está asociado a vasoconstricción y rarefacción microvascular. Estos, a su vez están asociados con el desarrollo de hipertensión y tromboembolismo. (3) El bevacizumab es el antineoplásico más asociado con hipertensión. La presión sanguínea debe monitorearse continuamente: ›› ››

Antes de comenzar el tratamiento: Los pacientes deben tener la presión controlada Antes de cada tratamiento: Pacientes con la presión sanguínea > 160/100 mm/Hg no deben recibir el mismo tratamiento. Este último se puede reiniciar en pacientes que no presenten complicaciones mayores una vez estén controlados.

Anti-CD52 (alemtuzumab): Observado más comúnmente en pacientes con Mycosis Fungoides o Sézary Syndrome. Un posible mecanismo es la activación o destrucción de células T y estas a su vez secretan tumor necrosis factor- α , interferon-γ e interleukin-6. Estas citoquinas pueden causar daño al miocardio aumentando el riesgo de fallo cardíaco. (5) Alemtuzumab tiene un “boxed warning” regulado por la FDA, sobre el riesgo de derrame el cual ocurre dentro de los primeros 3 días después de la administración.

EGFR inh: El cetuximab tiene un “boxed warning” sobre el riesgo de arresto cardiopulmonar en pacientes con cáncer escamoso de cabeza y cuello.

Este efecto adverso es raro, sin embargo, debido a su severidad es importante el monitoreo de electrolitos durante y después de la terapia. Se han reportado fatalidades en pacientes con historial cardiovascular.

INHIBIDORES DE TIROSINA CINASAS Las cinasas de tirosina se activan unas a otras por medio de la fosforilización de este aminoácido con el propósito promover la proliferación celular y disminuir la apoptosis. Estos inhibidores se enlazan a diferentes cinasas de tirosina en el receptor de ATP y evitan su fosforilización al impedir su activación. Dependiendo de las tirosinas cinasas que inhiben, son los efectos adversos presentados.

La mayoría de estas cinasas inhiben receptores a diferentes niveles de relevancia intracelular.

Entre los agentes relacionados a cardiotoxicidad se encuentran aquellos que inhiben el VEGFR. Al igual que los anticuerpos monoclonales que inhiben este receptor, se observa hipertensión y, en algunos de ellos, tromboembolismo. Los pacientes con hipertensión descontrolada no son candidatos para esta terapia y aquellos con la presión arterial controlada deben ser monitoreados frecuentemente. En los pacientes con lapatinib (anti-HER2), la fracción de eyección debe ser evaluada frecuentemente. El crizotinib se debe monitorear con electrocardiograma a los pacientes con fallo cardíaco, brady-arritmias, desbalance de electrolitos o que estén tomando medicamentos que prolonguen el intervalo QT. Además, el uso de crizotinib debe evitarse con β-blockers, clonidine, digoxin o nondihydropyridines, ya que se ha documentado un incremento en bradicadia con esta.

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MSP ARTÍCULO / ORIGINAL

LOS AGENTES ALQUILANTES QUE PUEDEN CAUSAR DAÑO A NIVEL CARDIOVASCULAR SE UTILIZAN PARA EL TRATAMIENTO DE MUCHOS TIPOS DE CÁNCER. Los mecanismos propuestos para la cardiotoxicidad de los inhibidores de BCR-Abl tienen mayor variabilidad y parecen ser más específicos por medicamento. Los cuatro agentes están relacionados a fallo cardíaco. El nilotinib y dasatinib están asociados con la prolongación del intervalo QT.

FLUOROPIRIMIDINAS

La ciclofosfamida y la ifosfamida afectan la síntesis de proteínas en las células cardíacas durante la transcripción del ADN. La primera puede causar arritmias, fallo cardíaco y efusión pericárdica principalmente en altas dosis (utilizadas antes de un trasplante de médula ósea).

El cisplatin no se elimina del cuerpo completamente después de finalizar el tratamiento. El platino se puede medir en el suero años después del tratamiento por lo cual puede estar asociado con tromboembolismo a largo plazo. (7)

El fluorouracil es una agente que se puede utilizar para el tratamiento de muchos tipos de cáncer como el de seno, colorrectal, gástrico, páncreas, anal, vejiga, uterino cervical, esófago, cabeza y cuello, hígado, pene, escamoso de origen desconocido y vulva. La angina de pecho es el efecto adverso más común del fluorouracil. Los pacientes con fluorouracil y capecitabine pueden desarrollar este efecto adverso en las primeras 72 o 96 horas. Con el fluorouracil es más probable este efecto con altas dosis o infusiones continuas. La angina parece estar mediada por una respuesta autoinmune, activación del sistema de coagulación, trombo de la arteria coronaria, vasoespasmo o toxicidad del músculo cardíaco. (6)

Estos agentes se utilizan principalmente para el tratamiento de melanoma. El aldesleukin puede causar síndrome de extravasación capilar inmediatamente después de comenzar el tratamiento. El monitoreo incluye presión arterial, niveles de orina o arritmias cardíacas. A los pacientes con enfermedad cardíaca preexistente que van a utilizar interferón alfa se les realiza un electrocardiograma de base y luego se repite periódicamente.

AGENTES ALQUILANTES

TRIÓXIDO DE ARSÉNICO

Los agentes alquilantes que pueden causar daño a nivel cardiovascular se utilizan para el tratamiento de muchos tipos de cáncer.

Estos añaden un grupo alquilo (estructura química que contiene átomos de carbono e hidrógeno organizados en forma de cadena), al ácido desoxirribonucleico de las células cancerosas durante la división celular e inhiben su replicación y proliferación.

El trióxido de arsénico se utiliza para pacientes de leucemia promielocítica aguda. Este medicamento se caracteriza por causar prolongación del intervalo QT en un 40%. El monitoreo con electrocardiograma es esencial como mínimo una vez por semana. El nivel de potasio debe ser > 4 mEq/L y magnesio > 1.8 mg/dL durante el tratamiento.

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MODULADORES DE LA RESPUESTA BIOLÓGICA

MSP ARTÍCULO / ORIGINAL

ZIV-AFLIBERCEPT Este medicamento puede causar hipertensión grado 3/4. Este efecto adverso se presenta usualmente después del primer o segundo ciclo de tratamiento. Una vez se controle la presión sanguínea, se puede recomenzar nuevamente el tratamiento con una dosis reducida. En el caso de que el paciente desarrolle una crisis hipertensiva o encefalopatía, no se debe reiniciar el medicamento. Los pacientes con NYHA clase III o IV de fallo cardíaco fueron excluidos de los estudios clínicos.

INHIBIDORES DE MEK E INHIBIDORES DE BRAF Estos medicamentos son utilizados para el tratamiento de melanoma que sobreexpresan la proteína BRAF, la cual es importante para la replicación celular. Recientemente, el trimetinib se añadió como alternativa para otros tipos de cáncer que también sobreexpresan esta proteína. Estos medicamentos (excepto el vemurafenib) pueden causar fallo cardíaco, por lo cual se monitorea el ejection fraction con ecocardiograma o MUGA antes y durante el tratamiento. Con el vemurafenib se debe realizar un electrocardiograma antes y durante el tratamiento debido al riesgo de prolongación del intervalo QT.

INHIBIDORES DE PROTEOSOMAS Los proteosomas son responsables de la homeostasis de proteínas que regulan la proliferación de las células. De este grupo, el carfilzomib es un inhibidor irreversible de estas proteínas, por lo cual tiene mayor tendencia a precipitar eventos cardiovasculares. Estos agentes son parte esencial del tratamiento de mieloma múltiple.

THALIDOMIDE/LENALIDOMIDE/POMALIDOMIDE La talidomida se usó por primera vez aproximadamente hace veinte años para el mieloma múltiple. Se observó una actividad antitumoral sustancial en estos pacientes. (8) Actualmente, estos medicamentos son parte de la terapia principal de esta condición y su uso se ha extendido a otras malignidades hematológicas.

El mieloma múltiple se ha asociado a la formación de anticuerpos procuagulantes, aumento en la expresión de von Willebrand y el factor VIII, aumento de la agregación de plaquetas por la proteína M, entre otras. Los pacientes que utilizan alguno de estos medicamentos tienen más riesgo de desarrollar eventos tromboembólicos. Por tal razón, estos tienen un Boxed Warning, el cual recomienda el uso de profilaxis dependiendo del nivel de riesgo de los pacientes (Ver tabla 3).

AGENTES DESESTABILIZADORES DE MICROTÚBULOS Los taxanos pueden causar daño cardiovascular principalmente cuando se utilizan en conjunto con las antraciclinas o de manera secuencial. (11) La cardiotoxicidad con los alcaloides de vinca es poco común.

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LA CLAVE PARA EL ÉXITO EN EL MANEJO DE ESTOS PACIENTES ESTRIBA EN LA COORDINACIÓN Y COMUNICACIÓN EFECTIVA ENTRE LAS DISTINTAS ESPECIALIDADES QUE TIENEN INHERENCIA.

EVALUACIÓN, MANEJO Y PREVENCIÓN: Recientemente, la farmacología ha definido otra situación muy importante: el efecto interactivo bidireccional entre las quimioterapias y los medicamentos rutinarios que se utilizan para condiciones cardiovasculares. (1) Muchos productos quimioterapéuticos pueden variar de manera positiva o negativa el efecto de los productos cardiovasculares tales como las estatinas, medicamentos para la diabetes y antiplaquetarios.

Igualmente, los productos de uso rutinario en condiciones cardiovasculares intervienen en el efecto de la quimioterapia sobre la malignidad. Los efectos de farmacocinética y farmacodinámica deben tomarse muy en cuenta al manejar estos pacientes.

CONCLUSIÓN Los pacientes de cáncer deben tener una evaluación muy exhaustiva antes del inicio de su terapia, en el transcurso de su tratamiento y años después. Además del oncólogo, cada subespecialista debe estar consciente de los múltiples efectos que estos medicamentos producen para investigarlos con todos los componentes necesarios tales como: (12,13,14) • Evaluación clínica • Estudios (electrocardiograma, ecocardiograma, estudios vasculares y otros estudios para identificación de arritmias) • Monitoreo de presión sanguínea • Cualquier otra prueba necesaria para identificar la patología que se desarrolle El manejo será proporcional a la patología desarrollada, interacción expresada o componente clínico reportado. De haber una reducción en la fracción de expulsión o el strain (15) (nueva modalidad ecocardiográfica que puede preceder a la fracción de expulsión) se utilizan las terapias recomendadas por el Colegio de Americano de Cardiología en sus guías de Fallo Cardíaco Congestivo. (16,17) A su vez, decisiones terapéuticas como, por ejemplo, cuando se debe detener la quimioterapia ante un evento cardiovascular, deben ser discutidas entre el cardio-oncólogo y el hematólogo-oncólogo.

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La clave para el éxito en el manejo de estos pacientes estriba en la coordinación y comunicación efectiva entre las distintas especialidades que tienen inherencia: hematólogo-oncólogo, cirujanos, internistas, infectólogos, especialista en el manejo del dolor, emergenciólogos, intensivistas, cardio-Oncólogo, enfermeros y el farmacéutico. Las intervenciones enfocadas en la revisión de órdenes médicas, prevención y manejo de efectos adversos, prevención y manejo de interacciones, desarrollo de órdenes estandarizadas y protocolos de manejo de condiciones, evaluar la farmacocinética y farmacodinámica de los medicamentos, adiestrar al personal sobre la prevención de errores de medicación, colaborar con los programadores de sistemas de información para ajustar el sistema electrónico de manera que hayan menos errores, el proceso de ordenes médicas con su verificación triple, preparación y dilución de acuerdo a directrices, infundir de acuerdo a las guías y el seguimiento de los pacientes son responsabilidades compartidas entre todos.

En el Hospital del Centro Comprensivo de Cáncer de la Universidad de Puerto Rico estamos preparados para poder prevenir, manejar y monitorear nuestros pacientes de la manera más segura y eficaz.

MSP ARTÍCULO / ORIGINAL

REFERENCIAS: 1. Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA. Daunorubicin, an antitumor antibiotic, in the treatment of neoplastic disease.

Clinical evaluation with special reference to childhood leukemia.

Cancer 1967; 20:333-53.

2. Juan Carlos Plana, MD FASE, et al. Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J AM Soc Echocardiogr 2014; 27: 911-30.

3. Armenian SH, Lacchetti, CX, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivor of adult cancer: American Society of Clinical Oncology clinical practice guideline.

J Clin Oncol 2017; 35:893-911.

4. Edward Chu, Vincent T. DeVita, Jr,.Physician Cancer Chemotherapy Drug Manual 2019 5. Zamorano JL, et al. 2016 ESC Position Paper on cancer on cancer treatments and cardiovascular toxicity develop under the auspice of the ESC Committee for Practice Guidelines. The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37: 2768-2801.

6. Zukkoor, S PHARMD, Trohan, V; MD, FACC. Drug-Drug Interactions of Common Cardiac Medications and Chemotherapeutic Agents. Expert Analysis; ACC. Dec, 21. 2018.

7. Jones, DN; et al. Frequency of Transition From Stage A to Stage B Heart Failure After initiating Potentially Cardiotoxic Chemotherapy. J Am Coll Cardiol HF 2018; 6:1023-32.

8. Thavendiranatham, P, et al. Risk Imaging Mismatch in Cardiac Imaging Practice for Women Receiving Systemic Therapy for Early-Stage Breast Cancer: A Population-Based Cohort Study.

December 13, 2018. J Clin Oncol 36:2980-2987.

9. Mitchell Joshua, Leniham DJ, MD, FACC. Management of Cancer Therapy-Induced Left-Ventricular Dysfunction: Can the Guidelines Help? A Cardio-Oncology Connection: Expert Analysis.

October 30, 2018. Pp 1-11.

10. Zukkoor, S PHARMD, Trohan, V; MD, FACC. Drug-Drug Interactions of Common Cardiac Medications and Chemotherapeutic Agents. Expert Analysis; ACC. Dec, 21. 2018.

11. Chang HM, Moudgil R, Scarabelli T, et al. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. J Am Coll Cardiol. 2017 Nov 14;70(20):2536-2551.

12. Moudgil R, Yeh ET. Mechanisms of cardiotoxicity of cancer chemotherapeutic agents: Cardiomyopathy and beyond. Can J Cardiol. 2016; 32(7): 863–870.

13. Lenneman CG, Abdallah WM, Smith HM, et al. Sympathetic nervous system alterations with HER2+ antagonism: an early marker of cardiac dysfunction with breast cancer treatment?. Ecancermedicalscience 2014; 8: 446.

14. Lenihan DJ, Alencar AJ, Yang D, et al. Cardiac toxicity of alemtuzumab in patients with mycosis fungoides/Sézary syndrome.

Blood. 2004;104(3):655-8.

15. Smith J. The Cardiotoxicity of Cancer-Related Drug Therapies. US Pharm. 2014;39(2):HS2-HS10.

16. Hjelle LV, Gundersen PO, Oldenburg J, et al. Long-term platinum retention after platinum-based chemotherapy in testicular cancer survivors: a 20-year follow-up study. Anticancer Res. 2015 Mar;35(3):1619-25.

17. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565-1571.

18. NCCN Clinical Practice Guideline in Oncology. Venous Thromboembolic Disease v.1.2019. NCCN,2019. Available at: http://www. nccn.org. Accedido 3/15/19.

19. Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol. 2015;33:654-656.

20. Suter TM, Ewer MS/ Cancer drugs and the heart: importance and management. Eur heart J. 2013;34:1002-1111.

21. Juan Carlos Plana, MD FASE, et al. Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J AM Soc Echocardiogr 2014; 27: 911-30.

22. Armenian SH, Lacchetti, CX, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivor of adult cancer: American Society of Clinical Oncology clinical practice guideline.

J Clin Oncol 2017; 35:893-911.

23. Zamorano JL, et al. 2016 ESC Position Paper on cancer on cancer treatments and cardiovascular toxicity develop under the auspice of the ESC Committee for Practice Guidelines. The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37: 2768-2801.

24. Thavendiranatham, P, et al. Risk Imaging Mismatch in Cardiac Imaging Practice for Women Receiving Systemic Therapy for Early-Stage Breast Cancer: A Population-Based Cohort Study.

December 13, 2018. J Clin Oncol 36:2980-2987.

25. Jones, DN; et al. Frequency of Transition From Stage A to Stage B Heart Failure After initiating Potentially Cardiotoxic Chemotherapy. J Am Coll Cardiol HF 2018; 6:1023-32.

26. Mitchell Joshua, Leniham DJ, MD, FACC. Management of Cancer Therapy-Induced Left-Ventricular Dysfunction: Can the Guidelines Help? A Cardio-Oncology Connection: Expert Analysis.

October 30, 2018. Pp 1-11.

27. Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA. Daunorubicin, an antitumor antibiotic, in the treatment of neoplastic disease.

Clinical evaluation with special reference to childhood leukemia.

Cancer 1967; 20:333-53.

28. Edward Chu, Vincent T. DeVita, Jr,.Physician Cancer Chemotherapy Drug Manual 2019 29. Hamo CE, Bloom MW. Cancer and Heart Failure: Understanding the Intersection. Card Fail Rev. 2017; 3(1): 66–70.

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In HR+, HER2– MBC

Would you consider Verzenio for patients with 1-15 concerning clinical characteristics? *

Rapid progression

Primary resistance recurred on adjuvant ET at 22 months 1,2,8†

Metastases beyond the bone

Visceral metastases liver metastases1,3,9‡

Discover an option for concerning patients at verzenio.com/hcp

*Disease characteristics that typically confer a less favorable prognosis. Below, find data for the ITT population and subgroups with concerning clinical characteristics. Verzenio + AI (ITT PFS analysis: HR=0.540 [95% CI: 0.418-0.698]; N=493): treatment-free interval <36 months (exploratory PFS analysis: HR=0.441 [95% CI: 0.241-0.805]; n=76) and liver metastases (exploratory PFS analysis: HR=0.477 [95% CI: 0.272-0.837]; n=78).

Verzenio + fulvestrant (ITT PFS analysis: HR=0.553 [95% CI: 0.449-0.681]; N=669): primary resistance (preplanned PFS analysis: HR=0.454 [95% CI: 0.306-0.674]; n=169) and visceral disease (preplanned PFS analysis: HR=0.481 [95% CI: 0.369-0.627]; n=373). The analyses were not adjusted for multiplicity and the study was not powered to test the effect of Verzenio + AI/fulvestrant among subgroups. Verzenio single-agent (ITT ORR analysis: 19.7% [95% CI: 13.3-27.5]): progression on or after ET and prior chemotherapy in the metastatic setting and visceral disease.

For additional information and full trial design, see verzenio.com/hcp/efficacy.

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 • In combination with an aromatase inhibitor (AI) for postmenopausal women as initial endocrine-based therapy • As a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

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.

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.

†Primary resistance is defined as relapse while on the first 2 years of adjuvant ET, or progressive disease within the first 6 months of first-line endocrine therapy for MBC.1 ‡Visceral disease was defined as lesions on an internal organ or in the third space and could have included lung, liver, pleural, or peritoneal metastatic involvement.16 CI=confidence interval; ET=endocrine therapy; HR=hazard ratio; ITT=intent-to-treat; ORR=objective response rate; PFS=progression-free survival.

Select Important Safety Information (cont’d) 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.

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.

Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. 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.

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. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential.

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

Discover an option for concerning patients at

verzenio.com/hcp

Select Important Safety Information (cont’d)

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

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

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs 1%), leukopenia (8% vs <1%), ALT increased (7% vs 2%), and anemia (6% vs 1%).

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

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%), leukopenia (6%), anemia (5%), and nausea (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were increased serum creatinine (98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs <1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs 26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs <1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST (37% vs 23%; 4% vs <1%).

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

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (98%; <1%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte count (42%; 14%), decreased platelet count (41%; 2%), increased ALT (31%; 3%), and increased AST (30%; 4%).

PP-AL-US-1507 04/2019 ©Lilly USA, LLC 2019. All rights reserved. Verzenio® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries or affiliates.

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. Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. 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 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products.

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

With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

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

AL HCP ISI 29AUG2018 References: 1. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.

2. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884.

3. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer.

2019;5:5. https://www.nature.com/articles/s41523-018-0097-z. Published January 17, 2019. Accessed March 14, 2019. 4. Dickler MN, Tolaney SM, Rugo HS, et al.

MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res. 2017;23:5218-5224. 5. Imkampe A, Bendall S, Bates T. The significance of the site of recurrence to subsequent breast cancer survival. Eur J Surg Oncol. 2007;33:420-423.

6. Largillier R, Ferrero JM, Doyen J, et al. Prognostic factors in 1038 women with metastatic breast cancer. Ann Oncol. 2008;19:2012-2019. 7. Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat. 2000;59:271-278.

8. Cardoso F, Costa A, Senkus E, et al. 3rd ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 3). Breast. 2017;31:244-259. 9. Gerratana L, Fanotto V, Bonotto M, et al. Pattern of metastasis and outcome in patients with breast cancer.

Clin Exp Metastasis. 2015;32:125-133. 10. Vogel CL, Azevedo S, Hilsenbeck S, East DR, Ayub J. Survival after first recurrence of breast cancer: the Miami experience. Cancer.

1992;70:129-135. 11. Chang J, Clark GM, Allred DC, Mohsin S, Chamness G, Elledge RM. Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer. 2003;97:545-553. 12. Yamamoto N, Watanabe T, Katsumata N, et al. Construction and validation of a practical prognostic index for patients with metastatic breast cancer. J Clin Oncol. 1998;16:2401-2408. 13. Data on file. Lilly USA, LLC. ONC20180103a. 14. Data on file. Lilly USA, LLC. ONC20180108a.

15. Data on file. Lilly USA, LLC. ONC20180328a.

16. Data on file. Lilly USA, LLC. ONC20171128a.

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.

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 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.

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.

ADVERSE REACTIONS

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.

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.

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.

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.

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.

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.

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

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%).

VERZENIO™ (abemaciclib) tablets, for oral use

VERZENIO™ (abemaciclib) tablets, for oral use

AL HCP BS 29AUG2018

AL HCP BS 29AUG2018

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 6). 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 6: 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 Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 0 Dyspnea 12 <1 <1 Nervous System Disorders Dizziness 11 <1 0 a

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

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.

VERZENIO™ (abemaciclib) tablets, for oral use

AL HCP BS 29AUG2018

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 7: 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

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 % % % % % % 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.

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.

VERZENIO™ (abemaciclib) tablets, for oral use

AL HCP BS 29AUG2018

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 8). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.

Table 9: 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 8: 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 Anemiad 29 7 <1 4 1 0 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

b

c d

e f g

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

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.

VERZENIO™ (abemaciclib) tablets, for oral use

AL HCP BS 29AUG2018

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

Placebo plus Fulvestrant

N=223 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % 98 1 0 74 0 0 90 23 <1 33 <1 0 87

29

4

30

4

<1

84 63

3 12

0 <1

33 32

<1 2

0 0

53 41

<1 4

1 <1

15 32

0 1

0 0

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 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.

The most common reported adverse reactions (≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia (Table 10). Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib.

Table 10: Adverse Reactions (≥10% of Patients) in MONARCH 1 VERZENIO N=132 All Grades %

Grade 3 %

Grade 4 %

Diarrhea

90

20

0

Nausea

64

5

0

Abdominal pain

39

2

0

Vomiting

35

2

0

Constipation

17

<1

0

Dry mouth

14

0

0

Stomatitis

14

0

0

Gastrointestinal Disorders

VERZENIO™ (abemaciclib) tablets, for oral use

AL HCP BS 29AUG2018

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

VERZENIO N=132

Effect of Other Drugs on VERZENIO

All Grades %

Grade 3 %

Grade 4 %

31

5

2

Infections and Infestations Infections

General Disorders and Administration Site Conditions Fatiguea

65

13

0

Pyrexia

11

0

0

Blood and Lymphatic System Disorders Neutropeniab

37

19

5

Anemiac

25

5

0

Thrombocytopeniad

20

4

0

Leukopeniae

17

5

<1

Decreased appetite

45

3

0

Dehydration

10

2

0

0

0

15

0

0

Headache

20

0

0

Dysgeusia

12

0

0

Dizziness

11

0

0

Metabolism and Nutrition Disorders

Respiratory, Thoracic and Mediastinal Disorders Cough

19

Musculoskeletal and Connective Tissue Disorders Arthralgia Nervous System Disorders

12

0

0

Creatinine increased

13

<1

0

Weight decreased

14

0

0

Investigations

a b c

d e

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.

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.

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

Skin and Subcutaneous Tissue Disorders Alopecia

DRUG INTERACTIONS

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.

Table 11: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1 VERZENIO N=132

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

Lymphocyte count decreased

42

13

<1

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.

Platelet count decreased

41

2

0

Lactation

ALT increased

31

3

0

AST increased

30

4

0

All Grades %

Grade 3 %

Grade 4 %

Creatinine increased

98

<1

0

White blood cell decreased

91

28

0

Neutrophil count decreased

88

22

5

Anemia

68

0

0

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 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™ (abemaciclib) tablets, for oral use

AL HCP BS 29AUG2018

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 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

AL HCP BS 29AUG2018

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 ©2018, Eli Lilly and Company. All rights reserved.

AL HCP BS 29AUG2018 VERZENIO™ (abemaciclib) tablets, for oral use

AL HCP BS 29AUG2018

MSP ARTÍCULO / ORIGINAL

Autor Dr. Yamil E. Castillo Beauchamp Cirujano de Cabeza y Cuello Hospital del Centro Comprensivo de Cáncer

EL CÁNCER DE OROFARINGE:

EL ROL DE LA CIRUGÍA

36

PALABRAS CLAVES

KEYWORDS

Cáncer de orofaringe, virus papiloma humano, VPH, técnicas quirúrgicas, terapias

Oropharyngeal cancer, human papilloma virus, HPV, surgical techniques, therapies

Revista Puertorriqueña de Medicina y Salud Pública

LOS FACTORES QUE SE HAN ASOCIADO A TENER UN RIESGO MAYOR DE DESARROLLAR ESTE TIPO DE MALIGNIDAD HAN SIDO LA EXPOSICIÓN AL CIGARRILLO Y OTROS PODUCTOS DEL TABACO, EL ALCOHOL, Y EL MASTICAR NUEZ DE BETEL.

INTRODUCCIÓN:

RESUMEN:

ABSTRACT:

El cáncer de orofaringe es uno de los cánceres con más impacto negativo en los pacientes que lo padecen y se ha convertido en una verdadera epidemia global especialmente en la población más joven. La implementación de terapias multidisciplinarias utilizando la quimioterapia, radiación y las técnicas modernas quirúrgicas han permitido obtener la cura en muchos pacientes. Es esencial trabajar con técnicas de prevención en esta población, particularmente con el uso y adaptación de la vacuna contra el virus de papiloma humano y el uso de tabaco. Ulteriormente las nuevas generaciones de pacientes estarán protegidos de las etiologías más relevantes e importantes de estos procesos malignos.

Oropharyngeal cancer is one of the cancers with the most negative impact on patients who suffer from it and it has become a true global epidemic especially for a younger population. The implementation of multidisciplinary therapies using chemotherapy, radiation and modern surgical techniques have allowed the cure in many patients. It is essential to work with prevention techniques in this population, particularly with the use and adaptation of the human papillomavirus vaccine and the use of tobacco. Subsequently the new generations of patients will be protected from the most relevant and important etiologies of these malignant processes.

La orofaringe es el área anatómica en nuestro tracto aerodigestivo superior compuesta de las amígdalas, el paladar blando y la parte posterior de la lengua.

(Figura 1) Además de tener una función en el proceso de tragado, también tiene una función en la producción de sonido y en la protección de la vía aérea.

Adicionalmente, es un área de concentración de tejido linfático que pudiese tener una función como parte de nuestro sistemia inmunológico. Como en muchas otras partes del cuerpo y del tracto aerodigestivo, existen riesgos de desarrollar distintos tipos de cáncer en la orofaringe, el más común es el carcinoma escamoso. Los factores que se han asociado a tener un riesgo mayor de desarrollar este tipo de malignidad han sido la exposición al cigarrillo y otros poductos del tabaco, el alcohol, y masticar nuez de betel.

Recientemente también se ha identificado el virus del papiloma humano como otro factor importante en el desarrollo del cáncer orofaríngeo.

Históricamente el cáncer de orofaringe ha sido uno de los cánceres con más impacto negativo en los pacientes que lo padecen.

Este impacto negativo no solo se ha visto en términos del pronóstico y expectativa de vida; también se aprecia en términos de la calidad de vida, ya que estos tumores malignos crecen en las áreas de nuestro cuerpo con funciones tan esenciales como la comunicación, la respiración y la alimentación. Las terapias que usualmente se utilizan para librar a los pacientes de esta enfermedad (la cirugía, la quimioterapia, y la radiación), también pueden tener efectos secundarios que muchas veces afectan la calidad de vida de manera prolongada.

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MSP ARTÍCULO / ORIGINAL

TENDENCIAS EN LOS FACTORES DE RIESGOS Afortunadamente, en las últimas décadas se ha visto un cambio positivo en relación a las tendencias del uso de cigarrillo y otros productos de tabaco. Gracias a la divulgación de la evidencia científica y a distintos esfuerzos de salud pública, los peligros y daños asociados al uso y abuso de estas sustancias son ya de conocimiento general. Estos daños y peligros incluyen riesgos aumentados de distintos cánceres, al igual que riesgos de enfermedades crónicas respiratorias y cardíacas.

Es por esta razón que se ha podido ver una tendencia clara en la disminución del uso del cigarrillo y el tabaco. Junto a esta tendencia también se ha visto una clara disminución en la incidencia de diversas malignidades en el tracto aerodigestivo asociadas con el cigarrillo y el tabaco como el cáncer de pulmón, de cavidad oral, el cáncer de laringe y el cáncer de hipofaringe y esófago cervical.

Sin embargo, la incidencia del cáncer de orofaringe no ha experimentado reducción junto a la disminución en

exposición al cigarrillo. Sorprendentemente, la incidencia de carcinoma de orofaringe ha ido en aumento de manera casi exponencial. También se han vistos diferencias marcadas en términos del perfil de los pacientes que ahora se están viendo afectados más comúnmente por el cáncer. En tiempos pasados, el paciente típico era uno ya en su sexta o séptima década con un historial extenso de tabaquismo y alcoholismo. Hoy en día estamos viendo pacientes más jóvenes (en su tercera a quinta década de vida) sin los factores de riesgo típicos del cigarrillo o tabaco. Sabemos ya que esta diferencia en incidencia se explica por la asociación de cáncer orofaringeo al virus del papiloma humano (VPH). El contacto con el virus sucede como producto de la actividad sexual y se puede almacenar en el tejido linfático de la orofaringe.

El VPH se ha visto asociado tanto a enfermedades benignas (verrugas orales y anogenitales) como a enfermedades malignas (cáncer cervical, anogenital, y de orofaringe). Si la exposición fue a alguna de los subtipos oncogénicos del virus (16, 18, 31, 33), con el tiempo

pueden surgir lesiones cancerosas con la capacidad del salir de su lugar de origen y ocasionar metástasis regional y distante y, eventualmente, amenazar la vida.

Tabla: citas del Registro de Cáncer de Puerto Rico.

TERAPIAS Y RESULTADOS Otro de las diferencias importantes observadas con el cáncer de orofaringe es que los pacientes con tumores asociados al VPH tienden a responder mejor a la terapia oncológica que los pacientes con el cáncer causado por el cigarrillo. Esto podría deberse a que con el cigarrillo hay una acumulación de más mutaciones genéticas y más disrupciones a los controles celulares que

Figura 1 38

Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / ORIGINAL

protegen contra el desarrollo del cáncer. También se puede deber a que los pacientes con cánceres relacionados al VPH tienden a ser más jóvenes, con menos enfermedades comórbidas y con un sistema inmunológico más robusto. En todo caso, la terapia disponible actualmente es capaz de curar a la mayoría de los pacientes con cáncer de orofaringe asociado al VPH, incluso aquellos con enfermedad avanzada. La terapia estandar mutimodal de quimioterapia y radiación ofrece una posibilidad de cura en más del 90% de los pacientes. El desarrollo de técnicas quirúrgicas nuevas como la cirugía robótica ha permitido obtener resultados curativos en pacientes limitando los efectos secundarios de la terapia y, en ocasiones, evitando la necesidad de terapias adicionales. El éxito de la terapia ha sido tan marcado que existen estudios nuevos en donde se esta considerando disminuir la dosis y la intensidad de las terapias para saber si se logra obtener los mismos resultados curativos sin los efectos secundarios sufridos en el pasado.

Esto último resulta alentador, pero es importante entender que, apesar de los resultados exitosos en el tratamiento de carcinoma de orofaringe asociado el VPH, todavía sigue siendo una enfermedad que deja una triste huella en los pacientes. Someterse al tratamiento para esta condición significa exponerse a los efectos secundarios de quimioterapia y radiación dado durante 6 a 8 semanas o someterse a intervenciones quirúrgicas que pudiesen afectar negativemente la calidad de vida a corto y a largo plazo. Frecuentemente se ve afectada la capacidad del paciente de seguir haciendo sus tareas del diario vivir y casi siempre se ocasiona la necesidad de dejar de trabajar. Esto tiene implicaciones también a nivel social, ya que se pierde la aportación de estos individuos a la sociedad durante la época en su vida profesional más productiva. En adición, el costo de los tratamientos necesarios para llegar a la cura son muy altos y afectan de sobremanera los sistemas de salud encargados de cuidar de nuestros ciudadanos. No podemos olvidar tampoco que ser curado de esta enfermedad no es una certeza; todavía hay pacientes que no responden a la terapia y eventualmente fallecen a causa del cáncer.

CONCLUSIÓN Por estas razones no nos debemos conformar con poder tratar exitosamente el cáncer. La solución real está en la prevención. Desde hace casi 20 años se ha probado la eficacia de la vacuna en contra del VPH para prevenir el cáncer. Los estudios iniciales se concentraron en el cáncer cervical dando lugar a la recomendación inicial de ofrecer la vacuna a las niñas antes de que comenzaran su actividad sexual. En tiempos más recientes se ha confirmado una eficacia tal vez mayor en términos de la prevención de cáncer de orofaringe asociado al VPH. En los lugares en donde se ha utilizado efectivamente la vacuna, las incidencias del cáncer asociado al VPH ha disminuido significativamente al igual que la incidencia de condiciones benignas asociadas al VPH. Los estudios también han apoyado el perfil

de seguridad de la vacuna, siendo los efectos secundarios más comunes las reacciones febriles, dolor de cabeza, náuseas, y dolores musculares. Recientemente se extendió la recomendación para la vacuna a todas las personas hasta la edad de los 45 años con el uso más efectivo cuando se recibe antes de comenzar la actividad sexual.

El cáncer de orofaringe se ha convertido en una verdadera epidemia a nivel global. Adicionalmente, las respuestas a las terapias conocidas han sido generalmente exitosas aunque con un costo significativo en términos de efectos secundarios y del impacto a nuestra sociedad. El desarrollo de una vacuna efectiva en contra del VPH nos da la expectativa de que, con el uso rutinario, se elimine el VPH de la misma manera que se eliminó la viruela y el polio, y podamos prevenir que las malignidades asociadas al VPH, inluyendo el cáncer de orofaringe, afecten a nuestras futuras generaciones.

REFERENCIAS: 1. Deschler, D, et al. The “New” Head and Neck Cancer Patient – Young Nonsmoker, Nondrinker, and HPV positive: Evaluation.

Otolaryngol Head Neck Surg. 2014 Sep; 151(3): 375–380 2. Ang, K. et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. New England Journal of Medicine.

2010 Jul 1; 363(1): 24-35 3. Surgis, EM, et al. The epidemic of HPV associate oropharyngeal cancer is here: Is it time to change our treatment paradigms? Journal of National Comprehensive Cancer Network.

2011 Jun 1; 9(6): 665-673 4. Mehanna, H, et al. Radiotherapy plus cisplatin or cetuximab in low risk papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open label randomised controlled phase 3 trial. Lancet. 2019. Jan 5 393(10166): 51-60 5. Gillison, M, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus positive oropharyngeal cancer(NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019 Jan 5; 393 (10166): 40-50 6. Forman, D, et al. Global Burden of Human Papillomavirus and Related Diseases. Vaccine 305 (2012) F12-F23.

7. Garcia, F. et al. Prophylactic Human Papillomavirus Vaccination: A Breakthrough in Primary Cervical Cancer Prevention.

Obstetrics Gynecol Clin N Am 34 (2007) 761-781 8. Stillo, M, et al. Safety of human papillomavirus vaccines: a review. Expert Opinion. Drug Safety (2015) 14(5): 697-712 9. Castle, PE, et al. Prophylactic HPV vaccination: past , present, and future. Epidemiol Infect (2016)144, 449-468.

10. Osazuwa-Peters, N, et al. Human papillomavirus (HPV), HPV associated oropharyngeal cancer, and HPV vaccine in the United States – Do we need a broader vaccine policy? Vaccine 31 (2013) 550-5505

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T:7.875" S:7.125"

Important Safety Information Neutropenia and Thrombocytopenia – DARZALEX® may increase neutropenia and/or thrombocytopenia DARZALEX® (daratumumab) is contraindicated in induced by background therapy. Monitor complete patients with a history of severe hypersensitivity (eg, blood cell counts periodically during treatment anaphylactic reactions) to daratumumab or any of according to the manufacturer’s prescribing the components of the formulation. information for background therapies. Monitor WARNINGS AND PRECAUTIONS patients with neutropenia for signs of infection.

Infusion Reactions – DARZALEX® can cause DARZALEX® dose delay may be required to allow severe and/or serious infusion reactions, including recovery of neutrophils and/or platelets. No dose anaphylactic reactions. In clinical trials, approximately reduction of DARZALEX® is recommended. Consider half of all patients experienced an infusion reaction. supportive care with growth factors for neutropenia Most infusion reactions occurred during the first or transfusions for thrombocytopenia. infusion and were Grade 1-2. Infusion reactions Interference With Determination of Complete can also occur with subsequent infusions. Nearly Response – Daratumumab is a human IgG kappa all reactions occurred during infusion or within monoclonal antibody that can be detected on 4 hours of completing DARZALEX®. Prior to the both the serum protein electrophoresis (SPE) and introduction of post-infusion medication in clinical immunofixation (IFE) assays used for the clinical trials, infusion reactions occurred up to 48 hours after monitoring of endogenous M-protein. This interference infusion. Severe reactions have occurred, including can impact the determination of complete response bronchospasm, hypoxia, dyspnea, hypertension, and of disease progression in some patients with IgG laryngeal edema, and pulmonary edema. Signs and kappa myeloma protein. symptoms may include respiratory symptoms, such as Adverse Reactions – The most frequently reported nasal congestion, cough, throat irritation, as well as adverse reactions (incidence ≥20%) were: infusion chills, vomiting, and nausea. Less common symptoms reactions, neutropenia, thrombocytopenia, fatigue, were wheezing, allergic rhinitis, pyrexia, chest asthenia, nausea, diarrhea, constipation, decreased discomfort, pruritus, and hypotension. appetite, vomiting, muscle spasms, arthralgia, back Pre-medicate patients with antihistamines, pain, pyrexia, chills, dizziness, insomnia, cough, antipyretics, and corticosteroids. Frequently monitor dyspnea, peripheral edema, peripheral sensory patients during the entire infusion. Interrupt infusion neuropathy, bronchitis, pneumonia and upper for reactions of any severity and institute medical respiratory tract infection. management as needed. Permanently discontinue ® therapy if an anaphylactic reaction or life-threatening DARZALEX in combination with lenalidomide and dexamethasone (DRd): The most frequent (≥20%) (Grade 4) reaction occurs and institute appropriate adverse reactions for newly diagnosed or relapsed emergency care. For patients with Grade 1, 2, or 3 refractory patients were, respectively, infusion reactions, reduce the infusion rate when re-starting reactions (41%, 48%), diarrhea (57%, 43%), nausea the infusion.

(32%, 24%), fatigue (40%, 35%), pyrexia (23%, 20%), To reduce the risk of delayed infusion reactions, upper respiratory tract infection (52%, 65%), muscle administer oral corticosteroids to all patients following spasms (29%, 26%), dyspnea (32%, 21%), and cough DARZALEX® infusions. Patients with a history of chronic (30%, 30%). In newly diagnosed patients, constipation obstructive pulmonary disease may require additional (41%), peripheral edema (41%), back pain (34%), post-infusion medications to manage respiratory asthenia (32%), bronchitis (29%), pneumonia (26%), complications. Consider prescribing short- and longdecreased appetite (22%), and peripheral sensory acting bronchodilators and inhaled corticosteroids for neuropathy (24%) were also reported. In newly patients with chronic obstructive pulmonary disease. diagnosed patients, serious adverse reactions (≥2% Interference With Serological Testing – Daratumumab compared to Rd) were dehydration (2%), bronchitis binds to CD38 on red blood cells (RBCs) and results in (4%), and pneumonia (15%), and treatment-emergent a positive Indirect Antiglobulin Test (Indirect Coombs Grade 3-4 hematology laboratory abnormalities test). Daratumumab-mediated positive indirect (≥20%) were leukopenia (35%), neutropenia (56%), antiglobulin test may persist for up to 6 months after and lymphopenia (52%). In relapsed/refractory the last daratumumab infusion. Daratumumab bound patients, serious adverse reactions (≥2% compared to RBCs masks detection of antibodies to minor to Rd) were pneumonia (12%), upper respiratory antigens in the patient’s serum. The determination of tract infection (7%), influenza (3%), and pyrexia (3%), a patient’s ABO and Rh blood type are not impacted. and treatment-emergent Grade 3-4 hematology Notify blood transfusion centers of this interference laboratory abnormalities (≥20%) were neutropenia with serological testing and inform blood banks that (53%) and lymphopenia (52%). a patient has received DARZALEX®. Type and screen cp-76663v2 patients prior to starting DARZALEX®.

CONTRAINDICATIONS

S:10"

T:10.75"

T:7.875" S:7.125"

Now Approved:

For your adult patients with newly diagnosed, transplant-ineligible multiple myeloma

DARZALEX® (daratumumab) + Rd* REDEFINING APPROACHES IN EARLY LINES OF MULTIPLE MYELOMA For a strong start to their treatment journey *Rd=lenalidomide (R) + dexamethasone (d).

Deep and durable responses1 • Median PFS not reached with DARZALEX® + Rd after median follow-up of 28 months† vs 31.9 months for Rd alone1,2 • 44% reduction in the risk of disease progression or death vs Rd alone (HR=0.56; 95% CI, 0.43-0.73; P<0.0001)

• 93% ORR with 48% CR or better (≥CR) vs 81% ORR and 25% ≥CR with Rd alone

• Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%), and dehydration (DRd 2% vs Rd <1%) Study Design: MAIA, an open-label, randomized, phase 3 study, compared treatment with DARZALEX® + lenalidomide + dexamethasone (DRd) (n=368) to Rd (n=369) in adult patients with newly diagnosed, transplant-ineligible MM. Treatment was continued until disease progression or unacceptable toxicity.

The primary efficacy endpoint was PFS. CI= confidence interval; CR=complete response; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; ORR=overall response rate; PFS=progression-free survival.

Range: 0.0–41.4.

†

DARZALEX® is a CD38-directed cytolytic antibody indicated for the treatment of adult patients with multiple myeloma: • in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy References: 1. DARZALEX® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. 2. Facon T, Kumar S, Plesner T, et al; the MAIA Trial Investigators.

Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104–2115.

Please see Important Safety Information and Brief Summary of full Prescribing Information on adjacent pages. © Janssen Biotech, Inc. 2019

08/19

cp-79227v3

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• The most frequent (≥20%) adverse reactions were infusion reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea, and cough

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Demonstrated safety profile when combined with Rd in the MAIA study2

DARZALEX® (daratumumab) injection, for intravenous use Brief Summary of Full Prescribing Information INDICATIONS AND USAGE DARZALEX is indicated for the treatment of adult patients with multiple myeloma: • in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.

• in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.

• in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.

• in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

• as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.

CONTRAINDICATIONS DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation [see Warnings and Precautions and Adverse Reactions].

WARNINGS AND PRECAUTIONS Infusion Reactions: DARZALEX can cause severe and/or serious infusion reactions including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were Grade 1-2 [see Adverse Reactions].

Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion.

Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension [see Adverse Reactions].

Pre-medicate patients with antihistamines, antipyretics and corticosteroids.

Frequently monitor patients during the entire infusion. Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion [see Dosage and Administration (2.1) in Full Prescribing Information].

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions [see Dosage and Administration (2.2) in Full Prescribing Information]. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and longacting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing: Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum [see References]. The determination of a patient’s ABO and Rh blood type are not impacted [see Drug Interactions].

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX. Neutropenia: DARZALEX may increase neutropenia induced by background therapy [see Adverse Reactions].

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.

Thrombocytopenia: DARZALEX may increase thrombocytopenia induced by background therapy [see Adverse Reactions].

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response: Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions].

This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

ADVERSE REACTIONS The following clinically significant adverse reactions are also described elsewhere in the labeling: • Infusion reactions [see Warning and Precautions].

• Neutropenia [see Warning and Precautions].

• Thrombocytopenia [see Warning and Precautions].

DARZALEX® (daratumumab) injection 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 practice.

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 1530 patients with multiple myeloma including 1374 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy.

Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant Combination Treatment with Lenalidomide and Dexamethasone (DRd) Adverse reactions described in the table below reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for the daratumumab-lenalidomide-dexamethasone (DRd) group and median treatment duration of 21.3 months (range: 0.03 to 40.64 months) for the lenalidomidedexamethasone group (Rd) in a Phase 3 active-controlled study MAIA. The most frequent (≥20%) adverse reactions were infusion reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea and cough. Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%).

Table 1: Adverse reactions reported in ≥10% of patients and with at least a 5% greater frequency in the DRd arm in MAIA Body System DRd (N=364) Rd (N=365) Adverse Reaction Any Grade 3 Grade 4 Any Grade 3 Grade 4 Grade (%) (%) Grade (%) (%) (%) (%) 41 2 <1 0 0 0 Infusion reactionsa Gastrointestinal disorders Diarrhea 57 7 0 46 4 0 Constipation 41 1 <1 36 <1 0 Nausea 32 1 0 23 1 0 Vomiting 17 1 0 12 <1 0 General disorders and administration site conditions 41 2 0 33 1 0 Peripheral edemab Fatigue 40 8 0 28 4 0 Asthenia 32 4 0 25 3 <1 Pyrexia 23 2 0 18 2 0 Chills 13 0 0 2 0 0 Infections and infestations Upper respiratory 52 2 <1 36 2 <1 tract infectionc 29 3 0 21 1 0 Bronchitisd Pneumoniae 26 14 1 14 7 1 Urinary tract 18 2 0 10 2 0 infection Metabolism and nutrition disorders Decreased appetite 22 1 0 15 <1 <1 Hyperglycemia 14 6 1 8 3 1 Hypocalcemia 14 1 <1 9 1 1 Musculoskeletal and connective tissue disorders Back pain 34 3 <1 26 3 <1 Muscle spasms 29 1 0 22 1 0 Nervous system disorders Peripheral sensory 24 1 0 15 0 0 neuropathy Headache 19 1 0 11 0 0 Paresthesia 16 0 0 8 0 0 Respiratory, thoracic and mediastinal disorders 32 3 <1 20 1 0 Dyspneaf Coughg 30 <1 0 18 0 0 Vascular disorders 13 6 <1 7 4 0 Hypertensionh Key: D=daratumumab, Rd=lenalidomide-dexamethasone. a Infusion reaction includes terms determined by investigators to be related to infusion, see section on Infusion Reactions below b Generalized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling c Acute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection

DARZALEX® (daratumumab) injection

DARZALEX® (daratumumab) injection

Bronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis e Atypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis f Dyspnea, Dyspnea exertional g Cough, Productive cough h Blood pressure increased, Hypertension Laboratory abnormalities worsening during treatment from baseline listed in Table 2.

Table 2: Treatment-emergent hematology laboratory abnormalities in MAIA DRd (N=364) % Rd (N=365) % Any Grade 3 Grade 4 Any Grade 3 Grade 4 Grade Grade Anemia 47 13 0 57 24 0 Thrombocytopenia 67 6 3 58 7 4 Leukopenia 90 30 5 82 20 4 Neutropenia 91 39 17 77 28 11 Lymphopenia 84 41 11 75 36 6 Key: D=daratumumab, Rd=lenalidomide-dexamethasone.

Laboratory abnormalities worsening during treatment from baseline listed in Table 4.

Table 4: Treatment-emergent hematology laboratory abnormalities in ALCYONE

d

Combination Treatment with Bortezomib, Melphalan and Prednisone Adverse reactions described in Table 3 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for the daratumumab, bortezomib, melphalan and prednisone (D-VMP) group, and median treatment duration of 12 months (range: 0.1 to 14.9 months) for the VMP group in a Phase 3 active-controlled study ALCYONE. The most frequent adverse reactions (≥20% with at least 5% greater frequency in the D-VMP arm) were infusion reactions, upper respiratory tract infection and edema peripheral. Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).

Table 3: Adverse reactions reported in ≥10% of patients and with at least a 5% greater frequency in the D-VMP arm in ALCYONE Body System D-VMP (N=346) Adverse Reaction Any Grade 3 Grade 4 Grade (%) (%) (%)

VMP (N=354) Any Grade 3 Grade 4 Grade (%) (%) (%)

28 4 1 0 0 0 Infusion reactionsa General disorders and administration site conditions Edema 21 1 <1 14 1 0 peripheralb Infections and infestations Upper respiratory tract infectionc 48 5 0 28 3 0 Pneumoniad 16 12 <1 6 5 <1 Respiratory, thoracic and mediastinal disorders Coughe 16 <1 0 8 <1 0 Dyspneaf 13 2 1 5 1 0 Vascular disorders 4 <1 3 2 0 Hypertensiong 10 Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone a Infusion reaction includes terms determined by investigators to be related to infusion, see section on Infusion Reactions below. b edema peripheral, generalized edema, peripheral swelling c upper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection. d pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis e cough, productive cough f dyspnea, dyspnea exertional g hypertension, blood pressure increased

Anemia Thrombocytopenia Neutropenia Lymphopenia

D-VMP (N=346) % Any Grade 3 Grade 47 18 88 27 86 34 85 46

VMP (N=354) % Grade 4 Any Grade 3 Grade 0 50 21 11 88 26 10 87 32 12 83 44

Grade 4 0 16 11 9

Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone Relapsed/Refractory Multiple Myeloma Combination Treatment with Lenalidomide and Dexamethasone Adverse reactions described in Table 5 reflect exposure to DARZALEX for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for the daratumumab-lenalidomide-dexamethasone (DRd) group and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomidedexamethasone group (Rd) in a Phase 3 active-controlled study POLLUX. The most frequent adverse reactions (≥20%) were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough and dyspnea. The overall incidence of serious adverse reactions was 49% for the DRd group compared with 42% for the Rd group. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 12% vs Rd 10%), upper respiratory tract infection (DRd 7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each).

Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm.

Table 5: Adverse reactions reported in ≥ 10% of patients and with at least a 5% greater frequency in the DRd arm in POLLUX Adverse Reaction

DRd (N=283) % Rd (N=281) % Any Grade 3 Grade 4 Any Grade 3 Grade 4 Grade Grade 5 0 0 0 0 Infusion reactionsa 48 Gastrointestinal disorders Diarrhea 43 5 0 25 3 0 Nausea 24 1 0 14 0 0 Vomiting 17 1 0 5 1 0 General disorders and administration site conditions Fatigue 35 6 < 1 28 2 0 Pyrexia 20 2 0 11 1 0 Infections and infestations Upper respiratory 65 6 < 1 51 4 0 tract infectionb Musculoskeletal and connective tissue disorders Muscle spasms 26 1 0 19 2 0 Nervous system disorders Headache 13 0 0 7 0 0 Respiratory, thoracic and mediastinal disorders Coughc 30 0 0 15 0 0 Dyspnead 21 3 < 1 12 1 0 Key: D=daratumumab, Rd=lenalidomide-dexamethasone. a Infusion reaction includes terms determined by investigators to be related to infusion, see section on Infusion Reactions below. b upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection c cough, productive cough, allergic cough d dyspnea, dyspnea exertional

DARZALEX® (daratumumab) injection

DARZALEX® (daratumumab) injection

Laboratory abnormalities worsening during treatment from baseline listed in Table 6.

Table 6: Treatment-emergent hematology laboratory abnormalities in POLLUX

Laboratory abnormalities worsening during treatment are listed in Table 8.

Table 8: Treatment-emergent hematology laboratory abnormalities in CASTOR DVd (N=243) % Vd (N=237) % Any Grade 3 Grade 4 Any Grade 3 Grade 4 Grade Grade Anemia 48 13 0 56 14 0 Thrombocytopenia 90 28 19 85 22 13 Neutropenia 58 12 3 40 5 < 1 Lymphopenia 89 41 7 81 24 3 Key: D=Daratumumab, Vd=bortezomib-dexamethasone.

DRd (N=283) % Rd (N=281) % Any Grade 3 Grade 4 Any Grade 3 Grade Grades Anemia 52 13 0 57 19 Thrombocytopenia 73 7 6 67 10 Neutropenia 92 36 17 87 32 Lymphopenia 95 42 10 87 32 Key: D=Daratumumab, Rd=lenalidomide-dexamethasone.

Grade 4 0 5 8 6

Combination Treatment with Bortezomib and Dexamethasone Adverse reactions described in Table 7 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) in the daratumumab-bortezomib-dexamethasone (DVd) group and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomibdexamethasone group (Vd) in a Phase 3 active-controlled study CASTOR. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough and dyspnea. The overall incidence of serious adverse reactions was 42% for the DVd group compared with 34% for the Vd group.

Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each).

Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm.

Table 7: Adverse reactions reported in ≥10% of patients and with at least a 5% greater frequency in the DVd arm CASTOR Adverse Reaction

DVd (N=243) % Any Grade 3 Grade 4 Grade 45 9 0

Vd (N=237) % Any Grade 3 Grade 4 Grade 0 0 0

Infusion reactionsa Gastrointestinal disorders Diarrhea 32 3 < 1 22 1 0 Vomiting 11 0 0 4 0 0 General disorders and administration site conditions Edema 22 1 0 13 0 0 peripheralb Pyrexia 16 1 0 11 1 0 Infections and infestations Upper respiratory tract infectionc 44 6 0 30 3 < 1 Nervous system disorders Peripheral sensory neuropathy 47 5 0 38 6 < 1 Respiratory, thoracic and mediastinal disorders Coughd 27 0 0 14 0 0 Dyspneae 21 4 0 11 1 0 Key: D=daratumumab, Vd=bortezomib-dexamethasone. a Infusion reaction includes terms determined by investigators to be related to infusion, see section on Infusion Reactions below. b edema peripheral, edema, generalized edema, peripheral swelling c upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection d cough, productive cough, allergic cough e dyspnea, dyspnea exertional

Combination Treatment with Pomalidomide and Dexamethasone Adverse reactions described in Table 9 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in EQUULEUS. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, constipation, nausea, vomiting, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, back pain, arthralgia, dizziness, insomnia, cough and dyspnea. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients.

Table 9: Adverse reactions with incidence ≥10% reported in EQUULEUS Body System DPd (N=103) Any Grade (%) Grade 3 (%) Grade 4 (%) Adverse Reaction 50 4 0 Infusion reactionsa Gastrointestinal disorders Diarrhea 38 3 0 Constipation 33 0 0 Nausea 30 0 0 Vomiting 21 2 0 General disorders and administration site conditions Fatigue 50 10 0 Pyrexia 25 1 0 Chills 20 0 0 17 4 0 Edema peripheralb Asthenia 15 0 0 Non-cardiac chest pain 15 0 0 Pain 11 0 0 Infections and infestations Upper respiratory tract infectionc 50 4 1 Pneumoniad 15 8 2 Metabolism and nutrition disorders Hypokalemia 16 3 0 Hyperglycemia 13 5 1 Decreased appetite 11 0 0 Musculoskeletal and connective tissue disorders Muscle spasms 26 1 0 Back pain 25 6 0 Arthralgia 22 2 0 Pain in extremity 15 0 0 Bone pain 13 4 0 Musculoskeletal chest pain 13 2 0 Nervous system disorders Dizziness 21 2 0 Tremor 19 3 0 Headache 17 0 0 Psychiatric disorders Insomnia 23 2 0 Anxiety 13 0 0 Respiratory, thoracic and mediastinal disorders 43 1 0 Coughe Dyspneaf 33 6 1 Nasal congestion 16 0 0 Key: D=Daratumumab, Pd=pomalidomide-dexamethasone. a Infusion reaction includes terms determined by investigators to be related to infusion, see section on Infusion Reactions below. b edema, edema peripheral, peripheral swelling. c acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection d lung infection, pneumonia, pneumonia aspiration e cough, productive cough, allergic cough f dyspnea, dyspnea exertional

DARZALEX® (daratumumab) injection

DARZALEX® (daratumumab) injection

Laboratory abnormalities worsening during treatment are listed in Table 10.

Table 10: Treatment-emergent hematology laboratory abnormalities in EQUULEUS DPd (N=103) % Any Grade Grade 3 Grade 4 Anemia 57 30 0 Thrombocytopenia 75 10 10 Neutropenia 95 36 46 Lymphopenia 94 45 26 Key: D=Daratumumab, Pd=pomalidomide-dexamethasone.

Monotherapy The safety data reflect exposure to DARZALEX in 156 adult patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg in three open-label, clinical trials. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients.

Adverse reactions occurring in at least 10% of patients are presented in Table 11. Table 12 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.

Infusion Reactions: In clinical trials (monotherapy and combination treatments; N=1530) the incidence of any grade infusion reactions was 40% with the first (16 mg/kg, Week 1) infusion of DARZALEX, 2% with the Week 2 infusion, and cumulatively 4% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion reaction at Week 2 or subsequent infusions.

The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modification due to reactions was 37%. Median durations of 16 mg/kg infusions for the 1st week, 2nd week and subsequent infusions were approximately 7, 4, and 3 hours respectively.

Severe infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions included nasal congestion, cough, chills, throat irritation, vomiting and nausea.

In EQUULEUS, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2 respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 h for Week 1-Day 1, 4.2 h for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

Herpes Zoster Virus Reactivation: Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2-5% of patients receiving DARZALEX. Infections: In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported as follows: Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28% Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (1-4%) and fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms.

Fatal infections were primarily due to pneumonia and sepsis.

Hepatitis B Virus (HBV) Reactivation: Hepatitis B virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.

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 the incidence of antibodies to daratumumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 of the 749 combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of DARZALEX. 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.

Immune System disorders: Anaphylactic reaction DRUG INTERACTIONS Effects of Daratumumab on Laboratory Tests: Interference with Indirect Antiglobulin Tests (Indirect Coombs Test): Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, K-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, non-cross-matched ABO/RhDcompatible RBCs can be given per local blood bank practices.

Interference with Serum Protein Electrophoresis and Immunofixation Tests: Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDAapproved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.

Table 11: Adverse reactions with incidence ≥10% in patients with multiple myeloma treated with DARZALEX 16 mg/kg DARZALEX 16 mg/kg N=156 Incidence (%) Adverse Reaction Any Grade Grade 3 Grade 4 48 3 0 Infusion reactiona General disorders and administration site conditions Fatigue 39 2 0 Pyrexia 21 1 0 Chills 10 0 0 Respiratory, thoracic and mediastinal disorders Cough 21 0 0 Nasal congestion 17 0 0 Dyspnea 15 1 0 Musculoskeletal and connective tissue disorders Back pain 23 2 0 Arthralgia 17 0 0 Pain in extremity 15 1 0 Musculoskeletal chest pain 12 1 0 Infections and infestations Upper respiratory tract infection 20 1 0 Nasopharyngitis 15 0 0 11 6 0 Pneumoniab Gastrointestinal disorders Nausea 27 0 0 Diarrhea 16 1 0 Constipation 15 0 0 Vomiting 14 0 0 Metabolism and nutrition disorders Decreased appetite 15 1 0 Nervous system disorders Headache 12 1 0 Vascular disorders Hypertension 10 5 0 a Infusion reaction includes terms determined by investigators to be related to infusion, see section on Infusion Reactions below. b Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia.

Table 12: Treatment emergent Grade 3-4 laboratory abnormalities (≥10%) Daratumumab 16 mg/kg (N=156) Anemia Thrombocytopenia Neutropenia Lymphopenia

Any Grade (%) 45 48 60 72

Grade 3 (%) 19 10 17 30

Grade 4 (%) 0 8 3 10

DARZALEX® (daratumumab) injection USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no human data to inform a risk with use of DARZALEX during pregnancy. Animal studies have not been conducted. However, there are clinical considerations (see Clinical Considerations). 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. 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 Fetal/Neonatal Adverse Reactions Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. Defer administering live vaccines to neonates and infants exposed to DARZALEX in utero until a hematology evaluation is completed.

Data Animal Data Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. In cynomolgus monkeys exposed during pregnancy to other monoclonal antibodies that affect leukocyte populations, infant monkeys had a reversible reduction in leukocytes.

Lactation: Risk Summary: There is no information regarding the presence of daratumumab in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts.

The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for DARZALEX and any potential adverse effects on the breast-fed child from DARZALEX or from the underlying maternal condition.

Females and Males of Reproductive Potential: Contraception: To avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after cessation of DARZALEX treatment.

Pediatric Use: Safety and effectiveness of DARZALEX in pediatric patients have not been established.

Geriatric Use: Of the 1530 patients that received DARZALEX at the recommended dose, 48% were 65 to 75 years of age, and 22% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Studies (14) in Full Prescribing Information].

REFERENCES 1. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf).

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion Reactions Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion reactions: • itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing [see Warnings and Precautions and Adverse Reactions].

Neutropenia • Advise patients that if they have a fever, they should contact their healthcare professional [see Warnings and Precautions and Adverse Reactions].

Thrombocytopenia • Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding [see Warnings and Precautions and Adverse Reactions].

Interference with Laboratory Tests Advise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking DARZALEX, in the event of a planned transfusion [see Warnings and Precautions and Drug Interactions].

Advise patients that DARZALEX can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response [see Warnings and Precautions and Drug Interactions].

Hepatitis B Virus (HBV) Reactivation: Advise patients to inform healthcare providers if they have ever had or might have a hepatitis B infection and that DARZALEX could cause hepatitis B virus to become active again [see Adverse Reactions].

Manufactured by: Janssen Biotech, Inc. Horsham, PA 19044 U.S. License Number 1864 © 2015 Janssen Pharmaceutical Companies cp-60865v3

Autor Saisha M. Muñiz Alers, MD Hematóloga-Oncóloga/Transplante de Médula Osea Pediátrica Hospital del Centro Comprensivo de Cáncer de la Universidad de Puerto Rico

MSP ARTÍCULO / ORIGINAL Credenciales MD: Universidad de Puerto Rico Recinto de Ciencias Médicas Pediatría: Universidad de Miami/Jackson Memorial Hospital Hematología-Oncología Pediátrica: Duke University Medical Center Transplante de Médula Ósea/Terapia Celular: Duke University Medical Center

Los adolescentes, jóvenes adultos y sobrevivientes de cánceres pediátricos componen una población particular RESUMEN Los adolescentes y jóvenes adultos componen una población particular que padecen de un grupo de tumores malignos de los cuales no se ha logrado incrementar la supervivencia en las últimas décadas. En contraposición, los avances en terapia han logrado incrementar la cura y supervivencia de personas con cánceres pediátricos y de edad avanzada. Para los científicos, este grupo se ha tornado de interés; los esfuerzos han sido enfocados para identificar el porqué de estos hallazgos. Otro reglón de significancia en este grupo de edad son los sobrevivientes de cánceres pediátricos. Estos padecen un espectro de condiciones que incluyen un riesgo aumentado de segundas neoplasias o relapsos tardíos del tumor primario, enfermedades cardíacas, enfermedades pulmonares y endocrinas, problemas de fertilidad y problemas psico-sociales. Todos estos fomentan la importancia de crear clínicas especializadas en adolescentes y jóvenes adultos en donde se puedan atender las necesidades de esta población y la relevancia del desarrollo de investigaciones clínicas.

PALABRAS CLAVE Cáncer, pediátrico, jóvenes, adultos, sobreviviente

KEYWORDS Cancer, pediatric, young, adults, survivors

ABSTRACT Teenagers and young adults make up a particular population that suffers from a group of malignant tumors in which it has not been possible to increase survival in recent decades. In contrast, advances in therapy have managed to increase the cure and survival of people with pediatric and elderly cancers.

For scientists, this group has become one of interest and efforts have been focused to identify the reason for these findings. Another region of significance in this age group is pediatric cancer survivors. These suffer from a spectrum of conditions that include an increased risk of second malignancies or late relapses of the primary tumor, heart disease, lung and endocrine diseases, fertility problems, and psychosocial problems. All of this encourages the importance of creating specialized clinics in adolescents and young adults where the needs of this population and the relevance of the development of clinical research in this population.

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MSP ARTÍCULO / ORIGINAL

INTRODUCCIÓN

COMPLICACIONES CARDÍACAS

La población de adolescentes y jóvenes adultos está compuesta por aquellos individuos que se encuentran entre las edades entre 15 y 39 años de edad. La literatura oncológica en las últimas décadas ha destacado a esta población como de interés y con ciertas particularidades. Entre los diagnósticos de cáncer más comunes que aquejan a este conjunto son las leucemias, linfomas, sarcomas de huesos y tejido blando, tumores de células germinales, testicular, tracto genital femenino, seno y melanoma. Una de las características de este grupo es el hecho de que no se han logrado avances en la supervivencia de estos pacientes en comparación a los pacientes pediátricos y aquellos de edad avanzada (Coccia et al., 2018). Esto ha motivado a desarrollar esfuerzos mediante investigaciones clínicas para poder identificar rasgos específicos de los tumores que aquejan a esta población y así desarrollar tratamientos especializados e identificar barreras psicosociales que interfieran con que estos pacientes reciban tratamientos.

Un segundo componente dentro de la problación de adolescentes y jóvenes adultos son los sobrevivientes de cánceres pediátricos. En las últimas décadas, un diagnóstico de cáncer pediátrico ha pasado de ser una sentencia de muerte a una probabilidad de cura y supervivencia de alrededor de un 80% (Landier & Bhatia, 2008). Esto permite que muchos de estos pacientes logren llegar a la adultez. Los efectos tardíos de los tratamientos antineoplásicos que recibieron son causa para un incremento significativo de enfermedades cardíacas y pulmonares, problemas de infertilidad, endocrinos, del sistema óseo, riesgos a segundos cánceres, dificultades con el aprendizaje y problemas psicosociales (Green, Reese, Michalek, Zevon, & Lowrie, 1996; Kieran et al., 2015).

Las complicaciones cardíacas son una de las causas más frecuentes de mortalidad y morbilidad en los sobrevivientes de cánceres pediátricos. Los pacientes que presentan mayor riesgo son aquellos sobrevivientes de leucemias y linfomas. Esto debido –principalmente- al uso de antraciclinas y radioterapia a la caja toráxica. De igual forma sabemos que los sobrevivientes de cánceres pediátricos, en especial aquellos de leucemias, tienen un mayor riesgo de desarrollar diabetes, hipertensión y dislipidemia (Chao et al., 2016). Estos, a su vez, aumentan los riesgos de desarrollar condiciones cardíacas.

Las condiciones cardíacas más comunes son el fallo congestivo cardíaco e infartos cardíacos debido a enfermedad coronaria. (Mulrooney et al., 2009). Es vital un seguimiento interdisciplinario para detectar y manejar estas complicaciones en una fase temprana.

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COMPLICACIONESPULMONARES Las complicaciones pulmonares tardías son frecuentes en esta población. Las etiologías más comunes son el uso de ciertos agentes quimioterapéuticos (i.e. bleomycin, busulfan, carmustine) y el uso de radioterapia al tórax con sus efectos nocivos al pulmón. Estos tratamientos incrementan el riesgo de fibrosis pulmonar, neumonitis intersticial y enfermedad pulmonar restrictiva/obstructiva (Landier & Bhatia, 2008). El cernimiento por médicos es de suma importancia para la detección y prevención.

COMPLICACIONES ENDOCRINÓLOGAS Y DE FERTILIDAD La fertilidad y sexualidad son temas que aquejan a adolescentes y jóvenes adultos, no tan solo mientras reciben tratamientos, sino de forma continua cuando hayan completado tratamiento y hayan sobrevivido su cáncer. Está muy bien establecido el riesgo sustancial de infertilidad a largo plazo de esta población (Frederick, Revette, Michaud, & Bober, 2019). En especial aquellos individuos que hayan recibidos agentes alquilantes (i.e. ciclofosfamida, ifofosfamida, melfalán, tiotepa, busulfán, entre otros) y/o radiación. Estos tratamientos pueden llegar a causar disfunción gonadal en la mayoría de

LAS COMPLICACIONES CARDÍACAS ES UNA DE LAS CAUSANTES MÁS FRECUENTE DE MORTALIDAD Y MORBILIDAD EN LOS SOBREVIVIENTES DE CÁNCERES PEDIÁTRICOS.

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los pacientes. Es importante que estos pacientes estén informados no solo del riesgo de esterilidad sino también sobre cuáles son los pasos necesarios para preservar el potencial de procrear en un futuro, por ejemplo, acudir a un banco de esperma, preservación de óvulo y/o preservación de tejido gonadal.

A pesar de que existe un alto riesgo de infertilidad, no todos los adolescentes, jóvenes adultos y sobrevivientes de cánceres pediátricos resultan estériles luego de tratamiento. Es importante discutir con estos pacientes cuáles son los métodos anticonceptivos y las prácticas sexuales seguras.

Estudios han reportado que esta población tiende a practicar conductas sexuales de alto riesgo.

Esto conlleva a que estos pacientes padezcan de enfermedades venéreas y embarazos no deseados y, si los pacientes se encuentran en tratamiento, existe un mayor grado de morbilidad (Rosenberg et al., 2017).

RIESGO DE SEGUNDOS CÁNCERES Y RELAPSO El riesgo de desarrollar nuevas condiciones malignas o un relapso del tumor original en esta población es más alto que en la población en general. La etiología de estos eventos frecuentemente se asocian a los tratamienros antineoplásicos previos y causan daño al sistema genético del individuo o una predisposición genética para el desarrollo de cáncer (Cardous-Ubbink et al., 2004; Lee et al., 2016; Mertens, 2007). Aquellos pacientes que hayan recibido radiación, agentes alquilantes, antriciclinas y/o inhibidores de topoisomerasa como parte de su tratamiento presentan un mayor riesgo. Entre los cánceres más frecuentemente se encuentran leucemias, linfomas y melanomas (Lee et al., 2016).

Estos segundos cánceres y relapsos tardíos son la razón primordial de mortalidad en esta población y la importancia de que esta población tenga acceso médico para visitas anuales de

MSP ARTÍCULO / ORIGINAL

A PESAR DE UN RIESGO ALTO DE INFERTILIDAD, NO TODOS LOS ADOLESCENTES, JÓVENES ADULTOS Y SOBREVIVIENTES DE CÁNCERES PEDIÁTRICOS RESULTAN ESTÉRILES LUEGO DE TRATAMIENTO. cernimiento (Cardous-Ubbink et al., 2004; Lee et al., 2016; Mertens, 2007). Sabemos que en esta población el acceso médico es variable debido a no poseer seguro médico, dificultades con la transportación, problemas financieros y sociales (Isenalumhe, Fridgen, Beaupin, Quinn, & Reed, 2016). El acceso médico juega un rol importante en la detección y tratamiento temprano en estos pacientes.

CONCLUSIÓN Los adolescentes, jóvenes adultos y sobrevivientes de cánceres pediátricos constituyen una población que aglomera características específicas. Este grupo posee mayor riesgo de ciertos diagnósticos oncológicos, entre ellos, leucemias, linfomas, sarcomas de huesos y tejido blando, tumores de células germinales, testicular, tracto genital femenino, seno y melanoma. No se ha logrado incrementar la supervivencia en este conjunto a pesar de los avances que se han logrado en otras poblaciones con diagnósticos similares. Los sobrevivientes de cánceres pediátricos tienen un alto riesgo de enfermedades crónicas en especial cardíacas, pulmonares, endocrinólogas y de fertilidad. La primordial causa de muerte en este grupo es debido a un relapso tardío y/o el desarrollo de un segundo cáncer. Las particularidades psicosociales de este conjunto pueden crear barreras que limiten el acceso al cuidado que necesitan.

Esta población vulnerable amerita cuidado especializado por profesionales que estén al tanto de los detalles de su historial médico pasado y de los riesgos que estos poseen.

El Children’s Oncology Group y el National Comprehensive Cancer Network han desarrollado guías comprensivas de cuidado para esta población. De ser posible, este cuidado debe ser provisto en una clínica multidisciplinaria compuesta de oncólogos de adultos y pediátricos con acceso a personal de salud mental que pueda ayudar con el estado psicosocial (Cancers, 2018; Coccia et al., 2018). El Hospital del Centro Comprensivo de Cáncer ha desarrollado este equipo multidisciplinario para mejorar la calidad de vida de esta población de pacientes jóvenes adultos.

REFERENCIAS 1. Cancers, Y. A. (2018). Long-Term Guidelines. (October).

2. Cardous-Ubbink, M. C., Heinen, R. C., Langeveld, N. E., Bakker, P. J. M., Voûte, P. A., Caron, H. N., & Van Leeuwen, F. E. (2004). Long-term cause-specific mortality among five-year survivors of childhood cancer. Pediatric Blood and Cancer, 42(7), 563–573. https://doi.org/10.1002/pbc.20028 3. Chao, C., Xu, L., Bhatia, S., Cooper, R., Brar, S., Wong, F. L., & Armenian, S. H. (2016). Cardiovascular disease risk profiles in survivors of adolescent and young adult (AYA) cancer: The kaiser permanente AYA cancer survivors study. Journal of Clinical Oncology, 34(14), 1626–1633. https://doi. org/10.1200/JCO.2015.65.5845 4. Coccia, P. F., Pappo, A. S., Beaupin, L., Borges, V. F., Borinstein, S. C., Chugh, R., … Shead, D. A. (2018). Adolescent and young adult oncology, version 2.2018: Clinical practice guidelines in oncology. JNCCN Journal of the National Comprehensive Cancer Network, 16(1), 66–97. https://doi. org/10.6004/jnccn.2018.0001 5. Frederick, N. N., Revette, A., Michaud, A., & Bober, S. L. (2019). A qualitative study of sexual and reproductive health communication with adolescent and young adult oncology patients. Pediatric Blood and Cancer, 66(6), 1–9. https://doi.org/10.1002/pbc.27673 6. Green, D. M., Reese, P. A., Michalek, A. M., Zevon, M. A., & Lowrie, G. S. (1996). Factors that influence the further survival of patients who survive five years after the diagnosis of cancer in childhood or adolescence. Medical and Pediatric Oncology, 26(1), 72–72. https://doi.org/10.1002/(SICI)1096 -911X(199601)26:1<72::AID-MPO13>3.0.CO;2-D 7. Isenalumhe, L. L., Fridgen, O., Beaupin, L. K., Quinn, G. P., & Reed, D. R. (2016). Disparities in adolescents and young adults with cancer. Cancer Control, 23(4), 424–433. https://doi.org/10.1177/107327481602300414 8. Kieran, M. W., Chi, S. N., Manley, P. E., Green, A. L., Bandopadhayay, P., Bergthold, G., … Segal, R. A. (2015). Chapter 57 – Tumors of the Brain and Spinal Cord. In Nathan and Oski’s Hematology and Oncology of Infancy and Childhood (Eighth Edi). https://doi.org/10.1016/B978-1-4557-54144.00057-7 9. Landier, W., & Bhatia, S. (2008). Cancer Survivorship: A Pediatric Perspective. The Oncologist, 13(11), 1181–1192. https://doi.org/10.1634/theoncologist.2008-0104 10. Lee, J. S., Dubois, S. G., Coccia, P. F., Bleyer, A., Olin, R. L., & Goldsby, R. E. (2016). Increased risk of second malignant neoplasms in adolescents and young adults with cancer. Cancer, 122(1), 116–123. https://doi. org/10.1002/cncr.29685 11. Mertens, A. C. (2007). Cause of Mortality in 5-year survivors of childhood cancer. Pediatric Blood & Cancer, 49(4), 505–505. https://doi.org/10.1002/ pbc 12. Mulrooney, D. A., Yeazel, M. W., Kawashima, T., Mertens, A. C., Mitby, P., Stovall, M., … Leisenring, W. M. (2009). Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: Retrospective analysis of the childhood cancer survivor study cohort. BMJ (Online), 339(7736), 34. https://doi.org/10.1136/bmj.b4606 13. Rosenberg, A. R., Bona, K., Ketterl, T., Wharton, C. M., Wolfe, J., & Baker, K. S. (2017). Intimacy, Substance Use, and Communication Needs During Cancer Therapy: A Report From the “Resilience in Adolescents and Young Adults” Study. Journal of Adolescent Health, 60(1), 93–99. https://doi. org/10.1016/j.jadohealth.2016.08.017

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NEW INDICATION Now approved for the treatment of patients with metastatic castrationsensitive prostate cancer (mCSPC).

Start early with ERLEADA® For your patients with metastatic prostate cancer who will be starting ADT or have recently initiated ADT*

In the TITAN study†:

ERLEADA® + ADT reduced the risk of death by 33% vs placebo + ADT1 (Median overall survival was not estimable in either arm; HR=0.67; 95% CI: 0.51, 0.89; P=0.0053)

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.

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 References: 1. ERLEADA® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. 2. Chi KN, Agarwal N, Bjartell A, et al; on behalf of TITAN investigators. Apalutamide for metastatic castration-sensitive prostate cancer. N Engl J Med. In press.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2019 9/19 cp-91757v1

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 placebocontrolled 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%) Rash—In 2 randomized studies, rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA® vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA® treatment (6%) vs placebo (0.5%).

The onset of rash occurred at a median of 83 days. 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®.

ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; TITAN = Targeted Investigational Treatment Analysis of Novel Antiandrogen.

Hypothyroidism—In 2 randomized studies, hypothyroidism was reported for 8% of patients treated with ERLEADA® and 2% of patients treated with placebo based on assessments of thyroid-stimulating 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, when clinically indicated, should be initiated or dose-adjusted.

DRUG INTERACTIONS Effect of Other Drugs on ERLEADA®—Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA® dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA® on Other Drugs—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.

P-gp, BCRP, or OATP1B1 Substrates—Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. 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 coadministered with ERLEADA® and evaluate for loss of activity if medication is continued.

Please see Brief Summary of full Prescribing Information for ERLEADA® on subsequent pages.

cp-50507v2

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)

*All patients who enrolled in the TITAN study started ADT for mCSPC ≤6 months prior to randomization. † Study Design: TITAN was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of patients with mCSPC (N=1052).

Patients had de novo mCSPC or relapsed metastatic disease after initial diagnosis of localized disease. All patients in the TITAN trial received a concomitant GnRH analog or had a bilateral orchiectomy. Patients with visceral (ie, liver or lung) metastases as the only sites of metastases were excluded. Patients were randomized 1:1 to receive ERLEADA® 240 mg orally once daily + ADT or placebo orally once daily + ADT. The dual primary endpoints were overall survival and radiographic progression-free survival.1,2

Visit erleadahcp.com

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 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.

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

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

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.

ERLEADA® (apalutamide) tablets

ERLEADA® (apalutamide) tablets

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) (continued)

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 2

3

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).

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) ERLEADA N=803 Laboratory Abnormality Hematology Anemia Leukopenia Lymphopenia

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

ERLEADA N=803 Laboratory Abnormality Chemistry Hypercholesterolemia1 Hyperglycemia1 Hypertriglyceridemia1 Hyperkalemia

Placebo N=398

All Grades %

Grade 3-4 %

All Grades %

Grade 3-4 %

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].

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].

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.

1

ERLEADA® (apalutamide) tablets 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].

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-50509v2

T:7.875” S:7”

XARELTO® is the DOAC with the most FDA-approved indications for the most thrombotic conditions CHRONIC CAD/PAD

NVAF

DVT/PE

Significantly reduced a composite of CV death, MI, and stroke in combination with aspirin1

Proven once-daily,† 24-hour stroke risk reduction in patients with elevated risk‡2,3

Treat and help prevent recurrent DVT/PE, whether initiated inpatient or outpatient§4-8

*XARELTO® 2.5 mg twice daily with aspirin (75 mg to 100 mg) once daily. †Taken with evening meal. ‡Patients were considered at an increased risk for stroke if they had a higher CHADS

2

score (range 1-6). Patients in ROCKET AF had a mean CHADS2 score of 3.5.

The decision regarding initiation setting should be based on the prescriber’s clinical judgement.

§

INDICATIONS

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.

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

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.

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, 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 Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

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, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).

CHADS2 = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or TIA; DOAC = direct oral anticoagulant; NVAF = nonvalvular atrial fibrillation; TIA = transient ischemic attack.

Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS, or visit www.XareltoHCP.com/PI.

S:10”

IMPORTANT SAFETY INFORMATION

T:10.75”

XARELTO® 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 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).

S:7”

WARNINGS AND PRECAUTIONS (cont’d)

Janssen Pharmaceuticals, Inc.

Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase risk of bleeding.

Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase risk of thromboembolic events.

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 (eg, erythromycin) unless the potential benefit justifies the potential risk.

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase risk of bleeding.

Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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 to a pregnant woman.

• 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: The risk of bleeding should be balanced with the risk of thrombotic events when considering use in this setting.

• There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Postmarketing experience is currently insufficient to determine a rivaroxabanassociated risk for major birth defects or miscarriage.

Lactation: 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. Consider the developmental and health benefits of breastfeeding 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.

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.

OVERDOSAGE

Overdose of XARELTO® may lead to hemorrhage. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

ADVERSE REACTIONS IN CLINICAL STUDIES

Most common adverse reactions with XARELTO® were bleeding complications.

Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS, or visit www.XareltoHCP.com/PI. References: 1. Eikelboom JW, Connolly SJ, Bosch J, et al; for the COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. 2. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

N Engl J Med. 2011;365(10):883-891. 3. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4): 412-421. 4. Bookhart BK, Haskell L, Bamber L, Wang M, Schein J, Mody SH. Length of stay and economic consequences with rivaroxaban vs enoxaparin/vitamin K antagonist in patients with DVT and PE: findings from the North American EINSTEIN clinical trial program. J Med Econ. 2014;17(10):691-695. 5. Peacock WF, Coleman CI, Diercks DB, et al. Emergency department discharge of pulmonary embolus patients. Acad Emerg Med. 2018;25(9):995-1003. 6. Weitz JI, Lensing AWA, Prins MH, et al; for the EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376(13):12111222. 7. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. 8. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297.

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XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2019 August 2019 cp-66067v4

DRUG INTERACTIONS

S:10”

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 removed before at least 2 half-lives have elapsed (ie, 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®.

The next 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. Monitor frequently to detect signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction.

Instruct patients to immediately report 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.

Use in Patients with Renal Impairment: • Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation in patients who develop acute 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.

• Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamics effects in this patient population.

• Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamics effects in this patient population. Observe closely and promptly evaluate signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO® should discontinue treatment.

• Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD: For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15-30 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, whose efficacy and safety outcomes were similar to those with preserved renal function. Clinical efficacy and safety studies with XARELTO® did not enroll patients with end-stage renal disease (ESRD) on dialysis.

Use in Patients with Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use 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.

Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of XARELTO® with known combined P-gp and strong CYP3A inhibitors or inducers.

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 signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

Patients with Prosthetic Heart Valves: Safety and efficacy of XARELTO® have not been studied in patients with prosthetic heart valves. Use of XARELTO® is not recommended in these patients.

Acute PE in Hemodynamically Unstable Patients/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.

cp-62551v2

IMPORTANT SAFETY INFORMATION (cont’d)

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.

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] 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

XARELTO® (rivaroxaban) tablets 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].

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.

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 Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in Specific Populations].

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations].

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].

Patients with Prosthetic Heart Valves The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.

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.

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]

Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days

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, 27,694 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); 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.

Parameter

XARELTO Warfarin N=7111 N=7125 n (%/year) n (%/year)

Major Bleeding†

XARELTO vs. Warfarin HR (95% CI)

395 (3.6)

386 (3.5)

1.04 (0.90, 1.20)

55 (0.5)

84 (0.7)

0.67 (0.47, 0.93)

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)

221 (2.0)

140 (1.2)

1.61 (1.30, 1.99)

27 (0.2)

55 (0.5)

0.50 (0.31, 0.79)

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)

Intracranial Hemorrhage (ICH)‡

Gastrointestinal

(GI)¶

Fatal Bleeding#

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.

Figure 1 shows the risk of major bleeding events across major subgroups.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

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.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

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 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) 1 (<0.1) 8 (0.2) Retroperitoneal‡ Intraocular‡ 3 (<0.1) 2 (<0.1) 0 4 (<0.1) Intra-articular‡ 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 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.

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)

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.

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

Total treated patients Major bleeding event

XARELTO 10 mg

Enoxaparin†

N=4487 n (%)

N=4524 n (%)

14 (0.3)

9 (0.2)

Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

2 (<0.1)

3 (0.1)

Bleeding that required re-operation

7 (0.2)

5 (0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

4 (0.1)

1 (<0.1)

261 (5.8)

251 (5.6)

N=3281 n (%)

N=3298 n (%)

7 (0.2)

3 (0.1)

Any bleeding event‡ Hip Surgery Studies Major bleeding event Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

1 (<0.1)

1 (<0.1)

Bleeding that required re-operation

2 (0.1)

1 (<0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

3 (0.1)

1 (<0.1)

201 (6.1)

191 (5.8)

N=1206 n (%)

N=1226 n (%)

7 (0.6)

6 (0.5)

0

0

Bleeding into a critical organ

1 (0.1)

2 (0.2)

Bleeding that required re-operation

5 (0.4)

4 (0.3)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

1 (0.1)

0

60 (5.0)

60 (4.9)

Any bleeding event‡ Knee Surgery Study Major bleeding event Fatal bleeding

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.

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 5 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Table 5: Major Bleeding Events* in COMPASS - On Treatment Plus 2 days XARELTO plus Aspirin aspirin† N=9107 N=9134 n (%/year) n (%/year)

alone†

Parameter Modified ISTH Major Bleeding‡

XARELTO plus aspirin vs.

Aspirin alone 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 6.

Table 6: 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 Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 7.

Table 7: 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) Other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

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

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.

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 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, but the risk-benefit profile was favorable in all age groups [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

XARELTO® (rivaroxaban) tablets 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. Avoid the use of XARELTO in patients with CrCl <30 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. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 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 15-30 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 [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 Gurabo, PR 00778 or Bayer AG 51368 Leverkusen, Germany Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

© 2011 Janssen Pharmaceutical Companies cp-62544v3

Autor Marielba Agosto Mújica, M.D. Endocrinología Diabetes y Metabolismo

PALABRAS CLAVES Diabetes, nefropatía diabética, control glucémico, hemoglobina glucosilada

KEYWORDS Diabetes, diabetic nephropathy, glycemic control, glycosylated hemoglobin

MANEJO DEL PACIENTE con nefropatía diabética

62

RESUMEN:

ABSTRACT:

El control en los niveles de azúcar es lo más importante para prevenir la enfermedad renal debido a la diabetes, llamada nefropatía diabética. Existe un sinnúmero de medicamentos disponibles para manejar la diabetes, pero solo algunos de ellos pueden ser utilizados de manera segura en pacientes que ya tienen afectación renal y la mayoría necesita ajuste en sus dosis. De igual manera, la meta en el control glucémico debe ser ajustada basada en las necesidades del paciente ya complicado y para prevenir el daño, la hemoglobina glucosilada debe mantenerse bajo el 7% desde temprano en la condición. Es un manejo multidisciplinario de control glucémico, y de factores de riesgo cardiovasculares.

Controlling blood sugar levels is the most important thing to prevent kidney disease due to diabetes, called diabetic nephropathy. There are a number of medications available to manage diabetes, but only a few of them can be used safely in patients who already have kidney disease and most need dosage adjustments. Similarly, the goal in glycemic control should be adjusted based on the needs of the already complicated patient and to prevent damage, glycosylated hemoglobin should be kept below 7% early in the condition. It is a multidisciplinary management of glycemic control and cardiovascular risk factors.

Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / ORIGINAL

INTRODUCCIÓN La diabetes es una epidemia en crecimiento y es la causa más común de enfermedad y fallo renal. La llamada nefropatía diabética es la afectación renal que ocurre por el daño provocado directamente por niveles altos de glucosa en sangre durante mucho tiempo. Lamentablemente, esta condición afecta actualmente hasta 50% de los pacientes con diabetes, debido a un pobre control. Es la complicación más común en el paciente diabético.

DESARROLLO Para evitar la condición y retrasar su progresión es importante una intervención temprana en el manejo de la diabetes mediante un control glucémico adecuado. Padecer diabetes no significa que deba ocurrir daño en el riñón. Sin embargo, este podría ocurrir si los niveles de azúcar se encuentran elevados. La recomendación actual para prevenir las complicaciones por la hiperglucemia es mantener una hemoglobina glucosilada menor a 7% en el paciente no complicado o durante el inicio de la condición, lo cual se traduce en niveles de azúcar en ayuna promedio 70-130mg/dl y después de comer menores a 160mg/dl.

El cernimiento para la nefropatía diabética debe comenzar en el paciente diabético tipo 1 luego de cinco años de ser diagnosticado; en el diabético tipo 2, al momento del diagnóstico. El mismo se realiza mediante la medición de albúmina en orina, ya que usualmente esta es la primera señal o primera etapa de nefropatía. Además, predecirá el desarrollo de enfermedad crónica renal y la disminución gradual en la filtración glomerular. De igual manera se deben medir los niveles de creatinina en sangre. Se recomienda que ambas pruebas sean realizadas al menos anualmente y, en caso de resultar alteradas, sean confirmadas en un período de 6 meses, siempre considerando que otras causas de elevación de proteínas en orina pueden estar presentes como infección, ejercicio extremo, alta presión, fallo cardíaco, entre otras.

El control glucémico es esencial para prevenir el inicio de las complicaciones de la diabetes y puede ser sumamente retante incluso para el médico más experimentado. En el paciente que ya tiene enfermedad renal, hay una limitación en los medicamentos que pueden ser utilizados de manera segura para el tratamiento. Adicionalmente, la medición de los niveles de azúcar en sangre puede ser más difícil, lo cual añade, entre otras cosas, complejidad al manejo.

El medicamento metformina es uno de los más comunes en el manejo de la diabetes tipo 2; de hecho es el medicamento que debe ser recomendado y recetado como primera línea, incluso de manera preventiva, desde que el paciente es diagnosticado con prediabetes, ya que es amplia la data de disminución en la resistencia a insulina y la prevención de progresión de la condición. Muchos rumores y mitos erróneos afirman que la metformina daña el riñón, lo cual es totalmente falso. Todo lo contrario, al mejorar el control glucémico, previene el desarrollo y la progresión de la nefropatía diabética.

Al igual que muchos otros medicamentos como antiinflamatorios y antibióticos, si ya el paciente tiene o desarrolla una afección renal, el medicamento debe ser ajustado, disminuir su dosis e incluso descontinuado en ocasiones para que el mismo no se acumule en el sistema debido a que se metaboliza por vía renal. Esto no debe ser confundido y jamás debe ser traducido a que la metformina daña el riñón. No tendría ningún sentido que utilizáramos como primera línea un medicamento que causara precisamente lo que queremos prevenir y este mensaje debe ser llevado a toda la población, ya que es común escuchar en nuestras prácticas: “Me quitaron la metformina porque me dañó el riñón”.

CONCLUSIONES Entre los medicamentos seguros para tratar al paciente diabético con nefropatía diabética se encuentran los inhibidores de DDP-4, aunque algunos requieren ajustes de dosis. Las insulinas análogas son preferidas por su función fisiológica. La mayoría de las sulfonilureas no se recomiendan debido a un riesgo aumentado de hipoglucemias bajo una filtración glomerular debajo de 30ml/min. Tenemos disponibilidad con data de seguridad en valores bajos de filtración glomerular de los análogos de GLP-1, con precaución menos de 30ml/min. Data muy interesante y prometedora está surgiendo de los inhibidores del receptor SGLT-2, con respecto a la prevención de la progresión de enfermedad renal, pero actualmente la recomendación de su uso es sobre 45ml/min y 60ml/min de filtración glomerular.

Consulte con su proveedor de salud para evaluación, control temprano y tratamiento de condición renal, ya sea para usted o para llevar el mensaje a algún familiar o amigo. Juntos podemos disminuir las complicaciones.

REFERENCIAS 1. Lalau JD, Lacroix C, Compagnon P, de Cagny B, Rigaud JP, Bleichner G, et al. Role of metformin accumulation in metformin-associated lactic acidosis.

Diabetes Care. 1995;18:779–84.

2. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(15):1845–55.

3. Chan JCN, Scott R, Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab. 2008 Jul;10(7):545-55.

4. Kastarinen M, Juutilainen A, Kastarinen H, Salomaa V, Karhapää P, Tuomile- hto J, et al. Risk factors for end-stage renal disease in a community-based population: 26-year follow-up of 25,821 men and women in eastern Finland. J Intern Med. 2010;267(6):612–20.

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NOW APPROVED The first and only glucagon with nasal administration Learn more at BAQSIMI.com A new way to deliver glucagon to treat severe hypoglycemia

Keep tube sealed until ready to use.

Indication BAQSIMI is indicated for the treatment of severe hypoglycemia in patients with diabetes ages 4 years and above.

IMPORTANT SAFETY INFORMATION Contraindications BAQSIMI is contraindicated in patients with pheochromocytoma, insulinoma, and known hypersensitivity to glucagon or to any of the excipients in BAQSIMI. Allergic reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension.

Warnings and Precautions BAQSIMI is contraindicated in patients with pheochromocytoma because glucagon may stimulate release of catecholamines from the tumor. If the patient develops a dramatic increase in blood pressure and a previously undiagnosed pheochromocytoma is suspected, 5 to 10 mg of phentolamine mesylate, administered intravenously, has been shown to be effective in lowering blood pressure.

In patients with insulinoma, administration of glucagon may produce an initial increase in blood glucose; however, BAQSIMI administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. BAQSIMI is contraindicated in patients with insulinoma. If a patient develops symptoms of hypoglycemia after a dose of BAQSIMI, give glucose orally or intravenously.

PP-GN-US-0008

07/2019

Š Lilly USA, LLC 2019.

Printed in USA.

Allergic reactions have been reported with glucagon, these include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. BAQSIMI is contraindicated in patients with a prior hypersensitivity reaction.

BAQSIMI is effective in treating hypoglycemia only if sufficient hepatic glycogen is present. Patients in states of starvation, with adrenal insufficiency or chronic hypoglycemia may not have adequate levels of hepatic glycogen for BAQSIMI administration to be effective. Patients with these conditions should be treated with glucose.

Adverse Reactions Most common (â&#x2030;Ľ10%) adverse reactions associated with BAQSIMI are nausea, vomiting, headache, upper respiratory tract irritation (i.e., rhinorrhea, nasal discomfort, nasal congestion, cough, and epistaxis), watery eyes, redness of eyes, and itchy nose, throat and eyes.

Drug Interactions Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given BAQSIMI. In patients taking indomethacin, BAQSIMI may lose its ability to raise blood glucose or may even produce hypoglycemia. BAQSIMI may increase the anticoagulant effect of warfarin.

GN HCP ISI 24JUL2019 BAQSIMITM is a trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Please see Brief Summary of Prescribing Information on following pages. See Instructions for Use included with the device.

All rights reserved.

BAQSIMI™ (glucagon) nasal powder

Table 4: Solicited Nasal and Non-Nasal Adverse Reactions in Pediatric Patients with Type 1 Diabetes (Cont.)

Brief Summary: Consult the package insert for complete prescribing information.

Adverse Reactiona

BAQSIMI 3 mg (n=36) % Any increase in symptom severitya

INDICATIONS AND USAGE BAQSIMI™ is indicated for the treatment of severe hypoglycemia in patients with diabetes ages 4 years and above.

CONTRAINDICATIONS BAQSIMI is contraindicated in patients with: pheochromocytoma, insulinoma, known hypersensitivity to glucagon or to any of the excipients in BAQSIMI. Allergic reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension. [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Catecholamine Release in Patients with Pheochromocytoma: BAQSIMI is contraindicated in patients with pheochromocytoma because glucagon may stimulate release of catecholamines from the tumor [see Contraindications]. If the patient develops a dramatic increase in blood pressure and a previously undiagnosed pheochromocytoma is suspected, 5 to 10 mg of phentolamine mesylate, administered intravenously, has been shown to be effective in lowering blood pressure.

Lack of Efficacy in Patients with Insulinoma: In patients with insulinoma, administration of glucagon may produce an initial increase in blood glucose; however, BAQSIMI administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. BAQSIMI is contraindicated in people with insulinoma [see Contraindications]. If a patient develops symptoms of hypoglycemia after a dose of BAQSIMI, give glucose orally or intravenously.

Hypersensitivity and Allergic Reactions: Allergic reactions have been reported with glucagon, these include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. BAQSIMI is contraindicated in patients with a prior hypersensitivity reaction [see Contraindications].

Runny nose 25.0 Sneezing 19.4 Itchy eyes 16.7 Redness of eyes 13.9 Itching of throat 2.8 Itching of ears 2.8 a Subjects were asked to report whether they have the symptom, as well as severity (mild, moderate, severe) at baseline, and after glucagon administration.

Other Adverse Reactions in Adult and Pediatric Patients Other observed adverse reactions with BAQSIMI-treated patients across clinical trials were, dysgeusia, pruritus, and additional upper respiratory tract irritation events (nasal pruritus, throat irritation, and parosmia). Glucagon exerts positive inotropic and chronotropic effects and as a result tachycardia and hypertension have been reported.

DRUG INTERACTIONS

Lack of Efficacy in Patients with Decreased Hepatic Glycogen: BAQSIMI is effective in treating hypoglycemia only if sufficient hepatic glycogen is present. Patients in states of starvation, with adrenal insufficiency or chronic hypoglycemia may not have adequate levels of hepatic glycogen for BAQSIMI administration to be effective. Patients with these conditions should be treated with glucose.

Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given BAQSIMI. In patients taking indomethacin, BAQSIMI may lose its ability to raise blood glucose or may even produce hypoglycemia. BAQSIMI may increase the anticoagulant effect of warfarin.

ADVERSE REACTIONS

USE IN SPECIFIC POPULATIONS

The following serious adverse reactions are described below and elsewhere in labeling:

Pregnancy

• Hypersensitivity and Allergic Reactions [see Warnings and Precautions].

Risk Summary

Adverse Reactions in Adult Patients

Available data from case reports and a small number of observational studies with glucagon use in pregnant women over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated a lack of transfer of pancreatic glucagon across the human placental barrier during early gestation. In a rat reproduction study, no embryofetal toxicity was observed with glucagon administered by injection during the period of organogenesis at doses representing up to 40 times the human dose, based on body surface area (mg/m2) (see Data).

Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of BAQSIMI cannot be directly compared with rates in clinical trials of other drugs and may not reflect the rates observed in practice.

Two similarly designed comparator-controlled trials, Study 1 and Study 2, evaluated the safety of a single dose of BAQSIMI compared to a 1 mg dose of intra-muscular glucagon (IMG) in adult patients with diabetes.

Table 1: Pooled Adverse Reactions (≥2%) in Adult Patients with Type 1 and Type 2 Diabetes in Study 1 and Study 2

Data

BAQSIMI 3 mg (N=153) % Nausea 26.1 Headache 18.3 Vomiting 15.0 Upper Respiratory Tract Irritationa 12.4 a Upper Respiratory Tract Irritation: rhinorrhea, nasal discomfort, nasal congestion, cough, and epistaxis.

Animal Data: In pregnant rats given animal sourced glucagon twice-daily by injection at doses up to 2 mg/kg (up to 40 times the human dose based on body surface area extrapolation, mg/m2) during the period of organogenesis, there was no evidence of increased malformations or embryofetal lethality.

Adverse Reaction

Lactation: Risk Summary There is no information available on the presence of glucagon in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, glucagon is a peptide and would be expected to be broken down to its constituent amino acids in the infant's digestive tract and is therefore, unlikely to cause harm to an exposed infant.

Pediatric Use: The safety and effectiveness of BAQSIMI for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients ages 4 years and above. Use of BAQSIMI for this indication is supported by evidence from a study in 48 pediatric patients from 4 to <17 years of age with type 1 diabetes mellitus. The safety and effectiveness of BAQSIMI have not been established in pediatric patients younger than 4 years of age.

Nasal and ocular adverse reactions with BAQSIMI were solicited through a patient questionnaire.

Table 2: Solicited Nasal and Non-Nasal Adverse Reactions in Adult Patients with Type 1 and Type 2 Diabetes Pooled from Study 1 and 2 Adverse Reactiona

BAQSIMI 3 mg (n=153) % Any increase in symptom severitya Watery eyes 58.8 Nasal congestion 42.5 Nasal itching 39.2 Runny nose 34.6 Redness of eyes 24.8 Itchy eyes 21.6 Sneezing 19.6 Itching of throat 12.4 Itching of ears 3.3 a Subjects were asked to report whether they have the symptom, as well as severity (mild, moderate, severe) at baseline, and after glucagon administration.

Adverse Reactions in Pediatric Patients Aged 4 Years and Above A single dose of BAQSIMI was compared to weight based doses of 0.5 mg or 1 mg of IMG in pediatric patients with type 1 diabetes in Study 3.

Table 3: Adverse Reactions (≥2%) Occurring in Pediatric Patients with Type 1 Diabetes in Study 3 BAQSIMI 3 mg (n=36) % 30.6 25.0 16.7 16.7

Adverse Reaction Vomiting Headache Nausea Upper Respiratory Tract Irritationa a Upper Respiratory Tract Irritation: nasal discomfort, nasal congestion, sneezing.

The estimated background risk of major birth defects and 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.

Geriatric Use: Clinical studies of BAQSIMI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Limited clinical trial experience has not identified differences in responses between the elderly and younger patients.

OVERDOSAGE: If overdosage occurs, the patient may experience nausea, vomiting, inhibition of GI tract motility, increase in blood pressure and pulse rate. In case of suspected overdosing, serum potassium levels may decrease and should be monitored and corrected if needed. If the patient develops a dramatic increase in blood pressure, phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed.

PATIENT COUNSELING INFORMATION Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Recognition of Severe Hypoglycemia: Inform patient and family members or caregivers on how to recognize the signs and symptoms of severe hypoglycemia and the risks of prolonged hypoglycemia. Inform patients to notify their healthcare provider each time a severe hypoglycemic event occurs. Administration: Review the Patient Information and Instructions for Use with the patient and family members or caregivers. Serious Hypersensitivity: Inform patients that allergic reactions can occur with BAQSIMI. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions].

Important Administration Instructions BAQSIMI is for intranasal use only.

Instruct patients and their caregivers on the signs and symptoms of severe hypoglycemia. Because severe hypoglycemia requires help of others to recover, instruct the patient to inform those around them about BAQSIMI and its Instructions for Use. Administer BAQSIMI as soon as possible when severe hypoglycemia is recognized.

Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for BAQSIMI. Emphasize the following instructions to the patient or caregiver: •

Do not push the plunger or test the device prior to administration.

•

Administer BAQSIMI according to the printed instructions on the shrink-wrapped tube label and the Instructions for Use.

•

Administer the dose by inserting the tip into one nostril and pressing the device plunger all the way in until the green line is no longer showing.

The dose does not need to be inhaled.

•

Call for emergency assistance immediately after administering the dose.

•

Do not attempt to reuse BAQSIMI. Each BAQSIMI device contains one dose of glucagon and cannot be reused.

Dosage in Adults and Pediatric Patients Aged 4 Years and Above: The recommended dose of BAQSIMI is 3 mg administered as one actuation of the intranasal device into one nostril. If there has been no response after 15 minutes, an additional 3 mg dose of BAQSIMI from a new device may be administered while waiting for emergency assistance.

Nasal and ocular symptoms with BAQSIMI were solicited through a patient questionnaire in pediatric patients.

Table 4: Solicited Nasal and Non-Nasal Adverse Reactions in Pediatric Patients with Type 1 Diabetes Adverse Reactiona

Watery eyes Nasal congestion Nasal itching BAQSIMI™ (glucagon) nasal powder

Baqsimi, GN HCP BS 24JUL2019_0200 - 10 x 12.75

BAQSIMI 3 mg (n=36) % Any increase in symptom severitya 47.2 41.7 27.8

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA www.baqsimi.com Copyright © 2019, Eli Lilly and Company. All rights reserved.

Additional information can be found at www.BAQSIMI.com, www.lillymedical.com, or call The Lilly Answer Center at 1800-LillyRx (1-800-545-5979.

GN HCP BS 24JUL2019 PP-GN-US-0200

GN HCP BS 24JUL2019

BAQSIMI™ (glucagon) nasal powder

GN HCP BS 24JUL2019

PRINTER VERSION 1 OF 1

Autor Dra. Carmen Serrano, MD, FAAN Neurología, Trastornos de Movimiento Directora del Programa de Residencia de Neurologïa Catedrática, Sección de Neurología, Departamento de Medicina Interna Universidad de Puerto Rico, Recinto de Ciencias Médicas

Tratamientos quirúrgicos y no quirúrgicos en el manejo de la enfermedad de Parkinson

PALABRAS CLAVES

KEYWORDS

Parkinson, síntomas, tratamiento, ejercicio, cirugía

Parkinson, symptoms, treatment, exercise, surgery

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Revista Puertorriqueña de Medicina y Salud Pública

Autor Tania C. Zayas Torres Neuróloga, Especialista en Trastornos de Movimientos Profesora Adjunto

UNA VEZ SE DIAGNOSTICA EL PARKINSON, EXISTEN VARIAS MODALIDADES DE TRATAMIENTO DISPONIBLES. ESTOS INCLUYEN TRATAMIENTOS FARMACOLÓGICOS, TRATAMIENTOS QUIRÚRGICOS Y TRATAMIENTOS NO-FARMACOLÓGICOS COMO EL EJERCICIO Y DIVERSOS TIPOS DE TERAPIA FÍSICA.

DESARROLLO

RESUMEN: La enfermedad de Parkinson es una condición neurodegenerativa caracterizada tanto por síntomas motores como no motores; es la segunda condición neurodegenerativa más común luego del alzhéimer.

El párkinson usualmente comienza entre los 60-64 años de edad, pero puede afectar a personas más jóvenes y es un poco más frecuente en varones.

ABSTRACT: Parkinson disease is a neurodegenerative condition. It has been associated to a deficiency in the neurotransmitter dopamine. Its treatment is multidisciplinary and includes pharmacologic therapies, non-pharmacologic therapies and surgical options.

By maintaining an adequate treatment and adequate support the Parkinson patient can experience a very good quality of life.

A pesar de que en Puerto Rico no se han recopilado datos epidemiológicos sobre esta enfermedad, se estima que hay alrededor de 15.000 pacientes si se extrapolan los datos de otras poblaciones.

Los síntomas del párkinson son resultado de cambios neurodegenerativos en ciertas regiones del cerebro, los cuales causan una deficiencia en el neurotransmisor llamado dopamina. Sin embargo, hay otros neurotransmisores que también están alterados y provocan el desarrollo de una diversidad de síntomas.

La patología incluye la acumulación de la proteína α-sinucleína y de los llamados cuerpos de Lewy en el cerebro. Se entiende que diversos factores, entre estos genéticos, inflamatorios, ambientales, toxinas, edad, entre otros pueden estar asociados al desarrollo de la enfermedad.

Los síntomas principales incluyen temblor al descanso - cuando la extremidad se encuentra en reposo, rigidez muscular, lentitud en los movimientos y problemas con el balance, la postura y el caminar. El paciente de párkinson puede presentar otros síntomas motores como una expresión facial disminuida, un volumen de voz bajo, dificultad con el tragado, una escritura pequeña, entre otros. Además, el paciente de párkinson puede presentar síntomas no motores como cambios en la conducta, depresión, ansiedad, alucinaciones, cambios en el patrón de sueño, disminución en el olfato, estreñimiento, problemas urinarios, dolor y mareos al levantarse. El diagnóstico de párkinson es principalmente clínico; es decir, se hace utilizando el historial médico y el examen neurológico, ya que un diagnóstico definitivo conllevaría a un análisis de la patología cerebral. Existen varias pruebas que ayudan a establecer el diagnóstico

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MSP ARTÍCULO / ORIGINAL

del paciente como la resonancia magnética cerebral, un estudio de medicina nuclear conocido como Datscan y algunos laboratorios que se pueden realizar para descartar otras condiciones.

Una vez se diagnostica el párkinson, existen varias modalidades de tratamiento disponibles.

Estos incluyen tratamientos farmacológicos, tratamientos quirúrgicos y tratamientos no farmacológicos como el ejercicio y diversos tipos de terapia física. El tratamiento en pacientes con párkinson es individualizado.

Cada paciente debe ser evaluado minuciosamente y, de acuerdo al conjunto de síntomas que presenta y el estadío de la enfermedad en que se encuentra, se diseña el tratamiento que se considere más conveniente. Los fármacos más utilizados y más eficaces hasta ahora para tratar el párkinson son aquellos que contienen levodopa, un químico que se convierte en dopamina al cruzar al cerebro y proveen al neurotransmisor que está deficiente. Existen otros fármacos que estimulan directamente los receptores de dopamina y otros agentes que permiten reducir la degradación de dopamina, por lo que logran que haya mayor cantidad de esta última. La mayoría de estos medicamentos se administran por vía oral. Sin embargo, algunas formulaciones son sublinguales, en forma parche, aromatizador por boca o gel intestinal.

El ejercicio es un componente fundamental para mejorar los síntomas del párkinson.

Diversos estudios sugieren que practicar ejercicio aeróbico, levantar pesas y realizar ejercicios para mejorar el balance confieren ayuda y protección no solamente de manera inmediata sino también a largo plazo. Todo tipo de ejercicio es recomendado, incluyendo caminar, correr una bicicleta estacionaria, ejercicios en el agua, baile, Pilates, yoga, Tai chi, entre otros. Las terapias física, ocupacional, de tragado y habla también son frecuentemente recomendadas para mejorar la movilidad y facilitar las actividades diarias del paciente.

Los equipos asistenciales pueden ser de gran ayuda para pacientes con mayores dificultades motoras. Una evaluación nutricional con una dieta balanceada y evitar la pérdida de peso debe incluirse como parte del plan de manejo.

Se recomienda que la levodopa se ingiera separada de comidas altas en proteínas; así se absorberá con más eficiencia. Es importante que el paciente de párkinson se evalúe de manera regular con su neurólogo y su médico

68

Revista Puertorriqueña de Medicina y Salud Pública

COMO PARTE DE LOS TRATAMIENTOS PARA LA CONDICIÓN DE PARKINSON EXISTEN VARIAS ALTERNATIVAS QUIRÚRGICAS ADEMÁS DE LOS MEDICAMENTOS ORALES.

de cabecera como parte de la medicina preventiva con el fin de atender rápidamente cualquier otra condición médica que se presente. Finalmente, se recomienda orientar al paciente y su cuidador sobre los diversos grupos de apoyo para párkinson existentes en donde tanto el paciente como su cuidador y su familia puedan obtener más información sobre la condición.

Como parte de los tratamientos para la enfermedad de Parkinson existen varias alternativas quirúrgicas, además de los medicamentos orales. Una de esas opciones consiste en la cirugía conocida como Deep brain stimulation (DBS), la cual se ofrece en Puerto Rico. El DBS es un neuroestimulador que utiliza pulsos de alta frecuencia en áreas específicas del cerebro para controlar los síntomas motores del paciente. Para que el paciente sea considerado candidato para este tipo de procedimiento, se toman

en consideración varios factores. Entre ellos se encuentran: la edad del paciente, certeza del diagnóstico, fallo a terapias orales incluyendo fluctuaciones durante el día o discinesias (movimientos involuntarios o erráticos). Es importante tener en consideración que este procedimiento mejora principalmente

síntomas como la rigidez (aumento en tono), temblor y la velocidad de los movimientos en general. Por el contrario, este procedimiento no tiende a mejorar síntomas como problemas de balance o dificultades severas al caminar. Sus beneficios consisten en disminuir las fluctuaciones del diario o los llamados OFF (períodos donde los síntomas resurgen porque el medicamento no está funcionando adecuadamente), disminuir las discinesias y disminuir la frecuencia con la que se toman medicamentos orales. La cirugía brinda beneficios

similares a los que ofrece el medicamento levodopa en el momento óptimo.

El paciente apto para la operación debe tener un diagnóstico de párkinson, respuesta robusta a levodopa, tener fluctuaciones en los síntomas durante el día o presentar efectos secundarios a los medicamentos como las discinesias.

Aquellos pacientes que consideren este procedimiento quirúrgico deben someterse a las siguientes evaluaciones: examen inicial para verificar el diagnóstico, evaluación con o sin levodopa, evaluación neuropsicológica y una evaluación llevada a cabo por un neurocirujano. Por esta razón, el procedimiento conocido como DBS es multidisciplinario, en el cual distintos especialistas intervienen, evalúan al paciente y luego se determina la idoneidad del candidato.

Es importante resaltar que pacientes con cambios cognoscitivos como demencia o con otros tipos de parkinsonismo no pueden ser considerados para esta operación. De igual manera, pacientes con depresión o condiciones psiquiátricas que no estén bien controlados deben ser evaluados y tratados antes de considerados. Finalmente, es de suma importancia que todo profesional de la salud informe a su paciente sobre todos los riesgos y beneficios relacionados a este procedimiento y además atemperar sus expectativas a los fines de entender a cabalidad que el DBS resulta ser otra modalidad de tratamiento y no una cura.

De igual forma, existe otra opción terapéutica para pacientes que no cualifiquen para la cirugía de DBS. Esta alternativa consiste en una infusión de levodopa por medio de una bomba intraduodenal. Dicho artefacto utiliza una infusión de levodopa en gel que es administrada por medio de un tubo que llega al intestino de manera percutánea.

Esta bomba es portable, por lo tanto, se puede tener puesta todo el día durante las actividades regulares del paciente.

La infusión que provee la bomba es continua y se utiliza por un período de hasta 16 horas. Los candidatos a este tratamiento incluyen pacientes con fluctuaciones de sus síntomas o discinesias. Debido a que la infusión es continua, su objetivo es mantener

una cantidad constante de levodopa.

Sus beneficios consisten, aunque no se limitan, a mejorar las fluctuaciones, mejorar la calidad de vida y autonomía del paciente.

ES IMPORTANTE TENER EN CONSIDERACIÓN QUE ESTE PROCEDIMIENTO MEJORA PRINCIPALMENTE SÍNTOMAS COMO LA RIGIDEZ (AUMENTO EN TONO), TEMBLOR Y LA VELOCIDAD DE LOS MOVIMIENTOS EN GENERAL. CONCLUSIÓN En conclusión, la enfermedad del Parkinson es sumamente compleja.

Sin embargo, se han desarrollado una diversidad de tratamientos que consiste en terapias orales, opciones quirúrgicas y no quirúrgicas que ayudan al paciente con párkinson a mejorar sus síntomas, mejorar su autonomía y su calidad de vida. De igual manera, cabe resaltar que continuamente se llevan a cabo estudios clínicos que, en un futuro, pudieran añadir nuevos tratamientos al régimen con el que contamos actualmente.

Finalmente, la actividad física, el apoyo de la familia y de la comunidad junto al manejo médico permiten que el paciente de párkinson mantenga una muy buena calidad de vida.

REFERENCIAS 1.

Fahn, S. Jankovic et al (2011).

Principles and Practice of Movement Disorders. Elsevier Saunders.

2. Marks, W. (2016). Deep Brain Stimulation Management, 2nd Edition. Cambridge University Press 3. Continuum – Movement Disorders – Vol. 22 No. 4 1046-1085 – American Academy of Neurology, Aug 2016

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For your patients with episodic migraine (4-14 migraine headache days [MHDs] per month),

ONE OF THESE IS POSSIBLE WITH EMGALITY®

THE WALRUS THAT

WENT TO THE MOON

THE WOMAN WHO EXPERIENCED

A MONTH OF TOTAL MIGRAINE HEADACHE FREEDOM

Emgality can give some patients the chance to be totally migraine-free for a month1 Emgality demonstrated ≥50%, ≥75%, and 100% reductions in the number of monthly MHDs from baseline for a significantly greater mean percentage of patients vs placebo1 Mean Percentage of Patients Meeting Defined

Mean Percentage of Patients Meeting Defined Levels Levels of Reduction in Monthly MHDs1 of Reduction in Monthly MHDs EVOLVE-1 (over Months 1 to 6)

60

40

80

62%a

Mean Percentage of Patients

Mean Percentage of Patients

80

39% 39%a 19%

20

EVOLVE-2 (over Months 1 to 6)

16%a

60

40

59%a

36% 34%a 18%

20

6% 0

≥50%

100%

≥75%

0

Level of Reduction Emgality 120 mg (N=210)

≥50%

12%a

6%

100%

≥75%

Level of Reduction

Placebo (N=425)

Emgality 120 mg (N=226)

Placebo (N=450)

p<0.001 vs placebo.

a

In REGAIN, in patients with ≥15 headache days per month, Emgality 120 mg was not significantly better than placebo for the mean percentage of patients with ≥75% or 100% reduction from baseline in the number of monthly MHDs over the 3-month treatment period.1

INDICATION Emgality is a calcitonin gene-related peptide antagonist indicated for the preventive treatment of migraine in adults.

SELECT IMPORTANT SAFETY INFORMATION

Contraindications Emgality is contraindicated in patients with serious hypersensitivity to galcanezumab-gnlm or to any of the excipients.

For your patients with ≥15 headache days per month (REGAIN),

28% of patients taking Emgality (N=273) achieved a ≥50% reduction in monthly MHDs from baseline vs 15% with placebo (N=538) over Months 1 to 3 (p<0.001)1 In REGAIN, Emgality 120 mg was not significantly better than placebo for the mean percentage of patients with ≥75% or 100% reduction from baseline in the number of monthly MHDs over the 3-month treatment period.1 For your patients with 4-14 MHDs per month (EVOLVE-1/EVOLVE-2) or ≥15 headache days per month (REGAIN),

Emgality prevented significantly more mean MHDs per month vs placebo (p<0.001)1 EVOLVE-1: 4.7 vs 2.8 (baseline mean: 9.2 vs 9.1)

EVOLVE-2: 4.3 vs 2.3 (baseline mean: 9.1 vs 9.2)

REGAIN: 4.8 vs 2.7 (baseline mean: 19.4 vs 19.6)

Help eligible patients save at EmgalitySavings.com Governmental beneficiaries excluded. Subject to Terms and Conditions.

Study designs1 EVOLVE-1 and EVOLVE-2 were 6-month, double-blind, placebo-controlled studies that enrolled adult patients with episodic migraine (defined as 4-14 MHDs per month) (N=1773). REGAIN was a 3-month, double-blind, placebo-controlled study that enrolled adult patients with chronic migraine (defined as ≥15 headache days per month with ≥8 migraine days per month) (N=1113).

In all 3 studies, patients were randomized to receive once-monthly placebo, Emgality 120 mg after an initial loading dose of 240 mg, or Emgality 240 mg. 240 mg is an unapproved dose.

In EVOLVE-1 and EVOLVE-2, treatments for prevention were not allowed. In REGAIN, a subset of patients (15%) continued 1 concomitant migraine preventive medication. EVOLVE-1 and EVOLVE-2 excluded patients with medication overuse headache. In all 3 studies, patients were allowed to use acute headache treatments including migraine-specific medications (ie, triptans, ergotamine derivatives), nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen during the study. All 3 studies excluded patients with electrocardiogram (ECG) abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening. For each study, the primary endpoint was the mean change from baseline in the number of monthly MHDs over the double-blind treatment period in the intent-to-treat population.

SELECT IMPORTANT SAFETY INFORMATION Hypersensitivity Reactions Hypersensitivity reactions (e.g., rash, urticaria, and dyspnea) have been reported with Emgality in clinical studies. If a serious or severe hypersensitivity reaction occurs, discontinue administration of Emgality and initiate appropriate therapy. Hypersensitivity reactions can occur days after administration and may be prolonged.

Adverse Reactions The most common adverse reactions (incidence ≥2% and at least 2% greater than placebo) in Emgality clinical studies were injection site reactions.

Please see Brief Summary of Prescribing Information on following page. See Instructions for Use included with the device.

GZ HCP SISI 27SEP2018 Reference: 1. Emgality [Prescribing Information].

Indianapolis, IN: Lilly USA, LLC. Emgality® is a registered trademark owned or licensed

by Eli Lilly and Company, its subsidiaries, or affiliates.

PP-GZ-US-0219 02/2019 ©Lilly USA, LLC 2019.

All rights reserved.

MORE IS POSSIBLE

Emgality® (galcanezumab-gnlm) injection, for subcutaneous use Brief Summary: Consult the Package Insert for complete Prescribing Information.

INDICATIONS AND USAGE Emgality is indicated for the preventive treatment of migraine in adults.

CONTRAINDICATIONS Emgality is contraindicated in patients with serious hypersensitivity to galcanezumab-gnlm or to any of the excipients.

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (e.g., rash, urticaria, and dyspnea) have been reported with Emgality in clinical studies. If a serious or severe hypersensitivity reaction occurs, discontinue administration of Emgality and initiate appropriate therapy. Hypersensitivity reactions can occur days after administration and may be prolonged.

ADVERSE REACTIONS 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 with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

In placebo-controlled clinical studies (2 studies in patients with episodic migraine and 1 study in patients with chronic migraine), 705 patients received at least one dose of Emgality 120 mg once monthly and 1451 patients received placebo, during 3 months or 6 months of double-blind treatment. Of the Emgality-treated patients, approximately 85% were female, 77% were white, and the mean age was 41 years at study entry.

The most common adverse reaction was injection site reactions (18% for Emgality vs 13% for placebo). In the studies, 1.8% of patients discontinued double-blind treatment because of adverse events. Injection site reactions include multiple related adverse event terms, such as injection site pain, injection site reaction, injection site erythema, and injection site pruritus.

Immunogenicity As with all therapeutic proteins, there is 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 the incidence of antibodies to galcanezumab-gnlm in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In controlled studies with Emgality up to 6 months (EVOLVE-1, EVOLVE-2, and REGAIN), the incidence of anti-galcanezumab-gnlm antibody development was 4.8% (33/688) in patients receiving Emgality once monthly (32 out of 33 of whom had in vitro neutralizing activity). With 12 months of treatment in an open-label study, up to 12.5% (16/128) of Emgality-treated patients developed anti-galcanezumab-gnlm antibodies, most of whom tested positive for neutralizing antibodies.

Although anti-galcanezumab-gnlm antibody development was not found to affect the pharmacokinetics, safety, or efficacy of Emgality in these patients, the available data are too limited to make definitive conclusions.

Geriatric Use Clinical studies of Emgality did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

DRUG INTERACTIONS Galcanezumab-gnlm is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

DOSING The recommended dosage of Emgality is 240 mg (two consecutive subcutaneous injections of 120 mg each) once as a loading dose, followed by monthly doses of 120 mg injected subcutaneously.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of Emgality in pregnant women. Administration of galcanezumab-gnlm to rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation at plasma exposures greater than that expected clinically did not result in adverse effects on development.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The estimated rate of major birth defects (2.2% - 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.

Animal Data When galcanezumab-gnlm was administered to female rats by subcutaneous injection (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout organogenesis, no adverse effects on embryofetal development were observed. The highest dose tested (250 mg/kg) was associated with a plasma exposure (Cave, ss) 38 times that in humans at the recommended human dose (RHD) of 120 mg.

Administration of galcanezumab-gnlm (0, 30, or 100 mg/kg) by subcutaneous injection to pregnant rabbits throughout the period of organogenesis produced no adverse effects on embryofetal development. The higher dose tested was associated with a plasma Cave, ss 64 times that in humans at the RHD. Administration of galcanezumab-gnlm (0, 30, or 250 mg/kg) by subcutaneous injection to rats throughout pregnancy and lactation produced no adverse effects on pre- and postnatal development. The higher dose tested was associated with a plasma Cave, ss 34 times that in humans at the RHD. Lactation Risk Summary There are no data on the presence of galcanezumab-gnlm in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Emgality and any potential adverse effects on the breastfed infant from Emgality or from the underlying maternal condition.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

If a dose of Emgality is missed, administer as soon as possible. Thereafter, Emgality can be scheduled monthly from the date of the last dose.

Emgality is for subcutaneous use only. Emgality is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer Emgality using the single-dose prefilled pen or single-dose prefilled syringe, including aseptic technique: • Protect Emgality from direct sunlight • Prior to subcutaneous administration, allow Emgality to sit at room temperature for 30 minutes. Do not warm by using a heat source such as hot water or a microwave • Do not shake the product • Inspect Emgality visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use Emgality if it is cloudy or there are visible particles • Administer Emgality in the abdomen, thigh, back of the upper arm, or buttocks subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard • Both the prefilled pen and prefilled syringe are single-dose and deliver the entire contents PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Instructions on Self-Administration: Provide guidance to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the prefilled pen or prefilled syringe correctly. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use Emgality.

Hypersensitivity Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions.

Additional information can be found at www.Emgality.com/hcp.

See Instructions for Use accompanying the device.

GZ HCP BS 28SEP2018

Eli Lilly and Company, Indianapolis, IN 46285, USA ©Lilly USA, LLC 2019.

All rights reserved.

PP-GZ-US-0219 Emgality® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

MSP PUNTO DE VISTA

Erradicación de la hepatitis C en Puerto Rico: ¿una realidad en tiempos de constricción económica?

La hepatitis C se ha convertido en una amenaza alarmante para la salud pública, pues se ha convertido en la causa número uno de enfermedad hepática en etapa terminal y de trasplante de hígado en muchos países. Sin embargo, hace más de cuatro años contamos con opciones simples y noveles de tratamiento oral que han demostrado una eficacia cercana al 100% de cura en la mayoría de pacientes tratados indistintamente del estadio clínico en que se encuentren.

Entonces, ¿cuál es la problemática?

Teóricamente, tanto científica como matemáticamente, la erradicación de la enfermedad es factible. No obstante, requerirá grandes esfuerzos para -en primer lugar- diagnosticar a los pacientes que no están conscientes de su infección, así como de un compromiso real de la arena sociopolítica y cultural para lograr este objetivo mediante la asignación de los recursos necesarios.

Estamos en una coyuntura histórica en la medicina moderna, donde se contempla la posibilidad de erradicar una enfermedad global; y que podría ser posible con herramientas simples de identificación diagnóstica, prevención y vinculación a la atención, manejo y tratamiento oral curativo o seguir drenando el sistema de salud pública con los costos asociados al manejo de pacientes de enfermedad avanzada con cirrosis y pacientes con necesidad de trasplante de hígado.

Desafortunadamente, la hepatitis C todavía no se considera, en muchos países, una prioridad de salud pública a pesar de los grandes esfuerzos de muchos organizaciones científicas y reguladores de la salud, incluida la Organización Mundial de la Salud (OMS). En adición a esto, al menos a nivel doméstico, no se ha identificado ninguna figura o celebridad icónica que pueda elevar la pasión emocional de la conciencia política y comunitaria colectiva como hemos visto con otras enfermedades crónicas y terminales como el VIH y el cáncer, y que además estimule a las partes interesadas en la palestra público-política a asignar los fondos necesarios para aplacar esta epidemia silente.

La OMS, junto al Centro para Control Enfermedades en Atlanta (CDC) y el Departamento de Salud y Recursos Humanos (DHHS, por sus siglas en inglés) han juntado esfuerzos encaminados para que, a nivel global y doméstico en los Estados Unidos y Puerto Rico, se establezcan unas metas de detección, enlace a cuidado y tratamiento mediante la llamada estrategia 90-90-90 para el año 2030, donde se pretende estimular que las estructuras de salud pública y gubernamentales dirijan esfuerzos para lograr dicho cometido.

Autor Dr. Jorge L Santana; FIDSA Profesor de Medicina y Enfermedades Infecciosas Escuela de Medicina de la Universidad de Puerto Rico

Todas las personas dentro de la sociedad civil tenemos el deber de aunar esfuerzos y prosperar con determinación, asociaciones, colaboración y defensa para construir y mantener el apoyo a esta encomienda. Es necesario entablar negociaciones justas y reales con el apalancamiento farmacéutico y del gobierno para reducir aún más el precio de estos medicamentos altamente efectivos.

Podemos y debemos, como individuos dentro de la sociedad civil, estimular la conciencia colectiva con el fin de seleccionar, identificar y diagnosticar a los individuos en riesgo para que podamos sensibilizar a los políticos, las partes interesadas clave y los líderes de opinión sobre la realidad de la respuesta de que una inversión inicial y sustancial segura y sostenida, ayudará a salvar muchas vidas y generará beneficios a largo plazo para la sociedad en conjunto.

Se necesita una defensa comunitaria y política robusta, recurrente y sostenida junto con las personas que viven con la enfermedad para desarrollar e impulsar medidas efectivas que trasciendan la necesidad existente. Si esto va a suceder en nuestras vidas, el tiempo de acción no debe esperar más. La historia siempre nos juzgará por las acciones realizadas u omitidas en el presente.

Revista Puertorriqueña de Medicina y Salud Pública

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THE FIRST AND ONLY ORAL JAK INHIBITOR

FOR MODERATE TO SEVERE UC1,2 APPROVED FOR ADULTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS1

INDICATION • XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC).

• Limitations of Use: Use of XELJANZ in combination with biologic therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

IMPORTANT SAFETY INFORMATION SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing serious infections that may lead to hospitalization or death.

Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections, or with chronic or recurrent infection.

In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily.

Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

The risks and benefits of treatment with XELJANZ/XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.

JAK=Janus kinase; UC=ulcerative colitis.

Please see additional Important Safety Information and brief summary of full Prescribing Information, including BOXED WARNING, on the following pages.

■

O R A L DOSING 1

Not an injection, not an infusion

■

R APID REMISSION 1,3

Significantly more patients taking XELJANZ 10 mg twice daily vs placebo achieved remissiona as early as Week 8 • OCTAVE 1: 18% (88/476) vs 8% (10/122), respectively; P<0.01 • OCTAVE 2: 17% (71/429) vs 4% (4/112), respectively; P<0.001 Rapid reduction in rectal bleeding and stool frequency1 • Decreases in rectal bleeding and stool frequency Mayo subscores were observed as early as Week 2 in patients treated with XELJANZ

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S U STAINED EFFICACY 1,3

Significantly more patients taking XELJANZ achieved remissiona and sustained corticosteroid-free remissionb vs placebo in a 52-week study • Remission: 41% on XELJANZ 10 mg twice daily (80/197) and 34% on XELJANZ 5 mg twice daily (68/198) vs 11% on placebo (22/198); P<0.0001 for XELJANZ 10 mg and 5 mg • Sustained corticosteroid-free remission: 47% on XELJANZ 10 mg twice daily (26/55) and 35% on XELJANZ 5 mg twice daily (23/65) vs 5% on placebo (3/59); P<0.0001 for XELJANZ 10 mg and 5 mg

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Study Designs for OCTAVE 1, OCTAVE 2, and OCTAVE Sustain (UC-I, UC-II, and UC-III): In 2 identical, 8-week induction studies, 1139 patients with moderate to severe UC (598 and 541 patients, respectively) were randomized to XELJANZ 10 mg twice daily or placebo (4:1 ratio). The primary endpoint was remission.a In a 52-week maintenance study, 593 patients who had completed the induction studies and achieved clinical response were rerandomized to XELJANZ 10 mg twice daily, XELJANZ 5 mg twice daily, or placebo (1:1:1 ratio). The primary endpoint was remission.a Sustained corticosteroid-free remissionb was a key secondary endpoint.1 IMPORTANT SAFETY INFORMATION (cont’d) SERIOUS INFECTIONS (cont’d) Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. a

Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy.

Malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily dosing in the UC long-term extension study.

Other malignancies were observed in clinical studies and the post-marketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Remission was rigorously defined as a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0.1 Sustained corticosteroid-free remission was defined as remission (a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0) and not taking corticosteroids for at least 4 weeks prior to the visit at both Week 24 and Week 52 among patients in remission at baseline.1 UC=ulcerative colitis.

b

IMPORTANT SAFETY INFORMATION (cont’d) GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. XELJANZ/ XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).

HYPERSENSITIVITY Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

LABORATORY ABNORMALITIES Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ/ XELJANZ XR treatment in patients with a count less than 500 cells/ mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.

Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ/ XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks.

There were no clinically relevant changes in LDL/HDL cholesterol ratios.

Manage patients with hyperlipidemia according to clinical guidelines.

Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy.

VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy.

PATIENTS WITH GASTROINTESTINAL NARROWING Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.

HEPATIC and RENAL IMPAIRMENT Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.

For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily, reduce to XELJANZ 5 mg once daily.

For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily.

ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with rheumatoid arthritis (RA) with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in RA patients.

Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials for ulcerative colitis were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

USE IN PREGNANCY Available data with XELJANZ/XELJANZ XR use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryofetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.

References: 1. XELJANZ [prescribing information]. New York, NY: Pfizer Inc; October 2018. 2. Pfizer announces U.S. FDA approves XELJANZ® (tofacitinib) for the treatment of moderately to severely active ulcerative colitis [press release]. New York, NY: Pfizer Inc; May 30, 2018. https://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_u_s_fda_approves_xeljanz_ tofacitinib_for_the_treatment_of_moderately_to_severely_active_ ulcerative_colitis-0. Accessed January 22, 2019. 3. Data on file. Pfizer Inc, New York, NY.

Please see additional Important Safety Information on the previous pages and brief summary of full Prescribing Information, including BOXED WARNING, on the following pages.

PP-XUC-USA-1001-01 © 2019 Pfizer Inc. All rights reserved. Printed in USA/March 2019

XELJANZ® (tofacitinib)/XELJANZ® XR (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease.

Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ/XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virusassociated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

INDICATIONS AND USAGE Rheumatoid Arthritis XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Psoriatic Arthritis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ulcerative Colitis XELJANZ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC).

• Limitations of Use: Use of XELJANZ in combination with biologic therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal

herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

In the UC population, XELJANZ treatment with 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily.

Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ/ XELJANZ XR in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended.

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ/ XELJANZ XR. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea.

Malignancy and Lymphoproliferative Disorders Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. During the 2 PsA controlled clinical studies there were

3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily.

In Phase 2B, controlled dose-ranging trials in denovo renal transplant patients, all of whom received induction therapy with basiliximab, highdose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated posttransplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.

Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids.

XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Hypersensitivity Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/ XELJANZ XR. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections • Malignancy and Lymphoproliferative Disorders • Gastrointestinal Perforations • Laboratory Abnormalities Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Rheumatoid Arthritis The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily.

The recommended dose for XELJANZ XR is 11 mg once daily.

The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials.

In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that

follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long- term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections.

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patientyears) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patientyears for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patientyears) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient- years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Laboratory Abnormalities Lymphopenia In the controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/ mm3 were associated with an increased incidence of treated and serious infections.

Neutropenia In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.

Liver Enzyme Elevations Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.

In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

• Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

• Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.

Serum Creatinine Elevations In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment.

The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocolspecified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below.

Common Adverse Reactions* in Clinical Trials of XELJANZ for theTreatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0-3 Months) XELJANZ XELJANZ 5 mg 10 mg Twice Placebo Twice Daily Daily** N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Upper respiratory tract infection

4

4

3

Preferred Term

Nasopharyngitis

4

3

3

Diarrhea

4

3

2

Headache

4

3

2

Hypertension

2

2

1

N reflects randomized and treated patients from the seven clinical trials. * reported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. ** the recommended dose of XELJANZ for the treatment of rheumatoid arthritis is 5 mg twice daily.

Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies RA-I through V. Psoriatic Arthritis XELJANZ 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA).

Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker.

Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.

Study PsA-II (NCT01882439) had a duration of 6 months and enrolled patients who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo controlled period.

In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline.

The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in rheumatoid arthritis patients.

Ulcerative Colitis XELJANZ has been studied in patients with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose ranging UC-V) and an open-label long term extension study (UC-IV). Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

Induction Trials (Study UC-I, UC-II, and UC-V): Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater than that reported in patients receiving placebo in the 3 induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.

Maintenance Trial (Study UC-III): Common adverse reactions reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported in patients receiving placebo are shown in the table below.

Common Adverse Reactions* in UC Patients during the Maintenance Trial (Study UC-III) XELJANZ XELJANZ 5 mg 10 mg Placebo Twice Daily Twice Daily Preferred Term

N = 198 (%)

N = 196 (%)

N = 198 (%)

Nasopharyngitis

10

14

6

Elevated cholesterol levels**

5

9

1

Headache

9

3

6

Upper respiratory tract infection

7

6

4

Increased blood creatine phosphokinase

3

7

2

Rash

3

6

4

Diarrhea

2

5

3

Herpes zoster

1

5

1

Gastroenteritis

3

4

3

Anemia

4

2

2

Nausea

1

4

3

* reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported for placebo. ** includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed more often in patients treated with XELJANZ 10 mg twice daily. Four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer.

Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC. Postmarketing Experience Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed).

DRUG INTERACTIONS The table below includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ/XELJANZ XR and instructions for preventing or managing them.

Clinical Relevant Interactions Affecting XELJANZ and XELJANZ XR When Coadministered with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

Moderate CYP3A4 Inhibitors Coadministered with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact

Decreased exposure to tofacitinib and may result in loss of or reduced clinical response

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact

Risk of added immunosuppression; coadministration with biologic DMARDs or potent immunosuppressants has not been studied in patients with rheumatoid arthritis, psoriatic arthritis, or UC.

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

USE IN SPECIFIC POPULATIONS All information provided in this section is applicable to XELJANZ and XELJANZ XR as they contain the same active ingredient (tofacitinib).

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/XELJANZ XR during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.

Risk Summary Available data with XELJANZ/ XELJANZ XR use in pregnant women are insufficient

to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy (see Clinical Considerations). In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).

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

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats).

Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/ skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

Lactation Risk Summary There are no data on the presence of tofacitinib in human milk, the effects on a breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with XELJANZ/XELJANZ XR, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives).

Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.

Females and Males of Reproductive Potential Contraception Females In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 5 mg twice daily and 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryofetal findings. However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential.

Infertility Females Based on findings in rats, treatment with XELJANZ/XELJANZ XR may result in reduced fertility in females of reproductive potential.

It is not known if this effect is reversible.

Pediatric Use The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established.

Geriatric Use Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older.

The frequency of serious infection among XELJANZtreated subjects 65 years of age and older was higher than among those under the age of 65.

Of the 1156 XELJANZ treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Use in Diabetics As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.

Renal Impairment Moderate and Severe Impairment XELJANZ-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function. Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis).

• Rheumatoid arthritis and psoriatic arthritis patients with moderate or severe renal impairment receiving XELJANZ XR should switch to XELJANZ and adjust the dosage.

Mild impairment No dosage adjustment is required in patients with mild renal impairment.

Hepatic Impairment Severe Impairment XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.

Moderate Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function. Higher blood concentrations may increase the risk of some adverse reactions. Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate hepatic impairment.

• Rheumatoid arthritis and psoriatic arthritis patients receiving XELJANZ XR should switch to XELJANZ and adjust the dosage.

Mild Impairment No dosage adjustment of XELJANZ/XELJANZ XR is required in patients with mild hepatic impairment.

Hepatitis B or C Serology The safety and efficacy of XELJANZ/XELJANZ XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

OVERDOSAGE There is no specific antidote for overdose with XELJANZ/XELJANZ XR. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

In a study in subjects with end stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)].

However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus limits the value of hemodialysis for treatment of overdose with XELJANZ/XELJANZ XR. This brief summary is based on XELJANZ®/ XELJANZ® XR (tofacitinib) Prescribing Information LAB-0445-16.0 Issued: October 2018 © 2018 Pfizer Inc. All rights reserved. October 2018

2019

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha

Actividad

Puerto Rico

Lugar

Coordinador o Contacto

Comentarios

Fecha 31 de mayo al 2 de junio 2019

Cursos ObligatoriosMayagüez

Club de Leones Mayagüez, PR

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CURSO

6 al 8 de junio 2019

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7 al 8 de junio 2019

Caribbean Congress on Emergency Medicine- Colegio de Emergenciólogos de PR

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CONGRESO

7 al 9 de junio 2019

Cursos Obligatorios- San Juan

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CURSO

6 al 9 de junio de 2019

Convención Anual-Sociedad Puertorriqueña de Oftalmología

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20 al 22 de junio 2019

Sociedad Dermatológica de PR2019 Summer Meeting

Caribe Hilton Hotel San Juan, PR

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21 al 23 de junio 2019

Convención anual-Asociación Puertorriqueña de Medicina Física y Rehabilitación

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21-23 de junio 2019

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CONVENCIÓN

22 de junio 2019

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28 al 30 de junio 2019

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12 al 14 de julio 2019

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27 al 28 de julio 2019

Simposium Compulsory Credits for Recertification

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2 al 3 de agosto 2019

ASCO Annual Convention 2019

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9 al 10 de agosto 2019

Convención Anual-Sociedad de Cirujanos Vasculares de PR

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CONVENCIÓN

17 de agosto 2019

Puerto Rico Cancer Conference Series: Colon & Rectal Cancer in 2019

Caribe Hilton Hotel San Juan, PR

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CONFERENCIAS

23 al 24 de agosto 2019

Convención anual-Sociedad de Nefrología de PR

Hotel Marriot Condado San Juan, PR

Business Planners Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

24 de agosto 2019

Simposio anual-Asociación de Gastroenterología y Hepatología Pediátrica de PR

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SIMPOSIO

24 de agosto 2019

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24 de agosto 2019

Update in GI Cancer SymposiumAsociación Puertorriqueña de Gastroenterología

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SIMPOSIO

24 Y 25 de agosto 2019

Risk Management Summit

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30 de agosto al 2 de septiembre 2019

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CONVENCIÓN

31 de agosto al 2 de septiembre 2019

Convención Anual-Asociación de Médicos Pediatras Región Oeste (AMPRO)

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7 de septiembre 2019

2nd Cardiovascular Innovation Forum 2019- Asociación de Cardiólogos del Noroeste

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FORO

7 de septiembre 2019

Update in the Treatment of Liver Diseases- Asociación Puertorriqueña de Gastroenterología

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SIMPOSIO

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CURSO

13 al 15 de septiembre 2019

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21 de sep36ta Conferencia de Epilepsia tiembre del Caribe 2019

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21 de sep- Excellence in Nursing- Sociedad Puertorriqueña de Asistentes tiembre de Gastroenterología 2019

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81

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20 al 22 de septiembre 2019

8th Respiratory Congress- Coalición de Asma y otras Condiciones Respiratorias Crónicas de PR

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CONGRESO

26 al 28 de septiembre 2019

Puerto Rico Urological Association Annual Convention 2019

Sheraton Convention Center Hotel San Juan, PR

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CONVENCIÓN

5 de octubre 2019

4TH EP Symposium- ACC PR Chapter

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SIMPOSIO

11 al 14 Octubre 2019

Convención anual Asociación de Hematología y Oncología Médica de PR (AHOMPR)

Puerto Rico

Germaine Quiñones 787-608-1477 ahomprgq@gmail.com

11 al 13 de octubre 2019

Academy for Physicians 2019 Workshop-Best Practice of Acupuncture

Club Rotario de Río Piedras San Juan, PR

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CURSO

11 al 14 de octubre 2019

Convención anual-Sociedad de Médicos Graduados de la Escuela de Medicina RCM

San Juan Marriot Resort San Juan, PR

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CONVENCIÓN

26 de octubre 2018

Asociación de Médicos Alergistas de PR

Embassy Suites Hotel San Juan, PR

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CONVENCIÓN

25 al 27 de octubre 2019

Convención anual- Puerto Rico HIV Embassy Suites Dorado Treaters Association de Mar Dorado, PR

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CONVENCIÓN

8 al 10 de Noviembre 2019

Convención Anual-Asociación Médica de Pediatras Región Este (AMPRE)

San Juan Marriot Stellaris Resort San Juan, PR

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CURSO

22 al 24 de Noviembre 2019

Convención-Sociedad Puertorriqueña de Neumología

Wyndham Rio Mar Río Grande, PR

Business Planners Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

12 al 15 de diciembre 2019

SPED AACE Congress

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Educational Partners (787) 646-0780 vperez@epcpr.com

CONGRESO

13 al 15 de diciembre 2019

Convención anual- Colegio de Médicos Cirujanos de Puerto Rico

Centro de Convenciones San Juan, PR

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CONVENCIÓN

CONVENCIÓN

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2019

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Internacional

MSP Somos Ciencia

Fecha

Actividad

Lugar

Coordinador o Contacto

18 al 21 de

XVII Congreso de la Sociedad Cu-

Palacio de Convenciones

Sociedad Cubana de Ginecología

junio 2019

bana de Ginecología y Obstetricia

La Habana, Cuba

y Obstetricia www.ginecobstcuba.com

4 al 6 de julio Congreso Colombiano de 2019

de Pediatría

12 de julio de Advanced Surgical Skills for Expo2019 20 al 28 de julio 2019

sure in Trauma (ASSET) 2019 AMHE Medical Convention

Centro de Convenciones Plaza Mayor Medellín, Colombia New York, NY La Habana, Cuba

Sociedad Colombiana de Pediatría www.scp.com.co ACS 718-334-5724 galera@nychhc.org AMHE-Marie Bruno (202)-681-3506 / www.amhe.org

Comentarios CONGRESO

CONGRESO

CONGRESO CONVENCIÓN

American College of Ob2 de agosto

Tools for Effective Ob-Gyn Practice

stetricians and Gynecol-

The American College of Obstetricians

de 2019

Management

ogists

and Gynecologists/ www.acog.org

CONFERENCIAS

Washington, DC Congreso Sociedad

Frei Caneca

Latinoamericana de Cardiología

Convention Center

Intervencionista (SOLACI)

Sao Paulo, Brazil

7 al 10 de

XV Encuentro Latinoamericano

Cento de convenciones

agosto de

de Cirujanos de Cadera y Rodilla

Las Americas

2019

ELCCR

Cartagena Colombia

1 al 3 de agosto 2019

9 al 10 de agosto de 2019

VI Simposio Nacional de Crianza y Salud

Estelar Paipa Hotel & Centro de Convenciones Paipa Boyacá, Colombia

SOLACI www.solacicongress.org ELCCR direccion@elccr.org Sociedad Colombiana de Pediatría www.scp.com.co

14 al 17 de

LIV Congreso Curso Internacional

Country Club

Sociedad Colombiana de Urología

agosto 2019

de Urología 2019

Barranquilla, Colombia

www.scu.org.co

Hotel Cosmos 100

Sociedad Colombiana de Pediatría

Bogotá, Colombia

www.scp.com.co

20 al 21 de septiembre

V Simposio Nacional de Nutrición

2019 21 de

Puerto Rico Cancer Conferences

septiembre

at Florida: Management Head

de 2019

and Neck Cancers

19 al 21 de septiembre de 2019

6to Simposio Internacional de Pie y Tobillo

Embassy Suites by Hilton Orlando International Drive Orlando, FL Cartagena Colombia

CONGRESO

CONGRESO

SIMPOSIO

CONGRESO

SIMPOSIO

High Education Health 787-964-6394

CONFERENCIAS

heh@hehpr.com/www.hehpr.com Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

SIMPOSIO

Revista Puertorriqueña de Medicina y Salud Pública

83

Fecha

Actividad

5 al 6 de octubre de 2019 25 al 30

Lugar

ACR 2019 Imaging Informatics Summit

Washington, DC

Coordinador o Contacto

American College of Radiology (ACR) www.acr.org

Comentarios

CONVENCIÓN

American College of Gastroen-

San Antonio, TX

American College of Gastroenterology

terology 2019 Annual meeting

USA

https://gi.org

27 al 30 de octubre de 2019

ACEP Scientific Assembly 2019

Colorado Convention Center Denver, Colorado

American College of Emergency Physicians (ACEP) www.acep.org

CONFERENCIAS

27 al 31 de octubre de 2019

Clinical Congress 2019- American College of Surgeons

Moscone Convention Center San Francisco, CA

American College of Surgeons www.facs.org

CONGRESO

8 al 3 de noviembre 2019

American College of Rheumatology 2019 Annual Meeting

Atlanta, GA USA

American College of Rheumatology www.rheumatology.org

CONVENCIÓN

24 al 26 de noviembre de 2019

Congreso Internacional de Medicina Deportiva

Cartagena Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

CONGRESO

21 de noviembre de 2019

1er Curso Nacional de Ortopedia para Médicos Generales

Bucaramanga Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

CURSO

22 al 24 de noviembre de 2019

14 Encuentro Nacional de Residentes de Ortopedia y Traumatología

Bucaramanga Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

CURSO

2 al 7 de diciembre de 2019

Emergency Medicne Basic Research Skills

Irving, TX

American College of Emergency Physicians (ACEP) www.acep.org/embrs

CONGRESO

13 de diciembre de 2019

Quality and Safety for Leaders in Women’s Health Care

New York, NY

The American College of Obstetricians and Gynecologists / www.acog.org

CONFERENCIAS

de octubre 2019

BUSCA LOS EVENTOS MÉDICOS DE PUERTO RICO EN: MEDICINAYSALUDPUBLICA.COM

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CONVENCIÓN

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Servicio de Noticias Científicas de Medicina y Salud Pública de Puerto Rico

Doctor Fernando Joglar

CONVENCIÓN ANUAL DE LA SOCIEDAD PUERTORRIQUEÑA DE NEFROLOGÍA Durante la Convención Anual de la Sociedad de Nefrología de Puerto Rico, su presidente, el Dr. Josué Castresana resaltó la importancia del cuidado renal que deben tener los pacientes diabéticos pues en varios casos cuando asisten a un consultorio ya presentan nefropatía diabética y en ese caso, la opción es ayudarlo para que el proceso para desarrollar la ERC sea más lento.

CONVENCIÓN DE LA SOCIEDAD DE CIRUJANOS VASCULARES Y ENDOVASCULARES DE PUERTO RICO (SCVEPR) La Sociedad de Cirujanos Vasculares y Endovasculares de Puerto Rico (SCVEPR) celebró su convención anual número 14, donde su presidente, el doctor Fernando Joglar, destacó la oferta de los cursos de educación continua –para un total de 11 créditos- que fue el eje de la agenda del encuentro. Además, el encuentro incluyó conferencias sobre enfermedades del sistema venoso, del sistema exterior periferal, enfermedades de la aorta, y trajeron lo último sobre las técnicas y lo que se está haciendo ahora, así como los temas de controversia en el mundo de la cirugía vascular a Puerto Rico.

Dra. Sylvia Arce Cardona

CONVENCIÓN ANUAL DE LA ASOCIACIÓN DE MÉDICOS PEDIATRAS DE LA REGIÓN OESTE (AMPRO) Destacando los logros bajo su presidencia en la Asociación de Médicos Pediatras de la Región Oeste (AMPRO); la Dra. Sylvia Arce Cardona, dirigió su trigésima séptima convención, que se llevó a cabo en Mayagüez. Temas tan diversos como enfermedades inflamatorias de intestinos, artritis, artralgias, soplos y cernimiento neonatal, manejo quirúrgico de epilepsia en niños, el niño con problemas al caminar, prevención de diabetes, manejo clínico de perlesía cerebral, espasticidad, obesidad, dermatitis atòpica, normas de vacunación, albinismo, enfermedades pulmonares raras y anemia hemolítica, fueron parte de la oferta de esta convención.

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CONVENCIÓN “CARIBE GYN 2019” Con un repertorio de las más destacadas actividades de investigación y avances científicos relacionados al cuidado de la salud de la mujer, se desarrolló la convención “CARIBE GYN 2019” en Ponce, Puerto Rico. Manejo no quirúrgico del prolapso de órganos pélvicos, lesiones ováricas y cirugía en la población pediátrica, diagnósticos de imágenes mamarias, uso del cabestrillo uretral para casos de incontinencia urinaria y el manejo del sangrado posmenopáusico, son solo algunos de los temas que se pusieron sobre la mesa en este encuentro cargado de educación continua, especialmente para los ginecólogos y obstetras

www.medicinaysaludpublica.com

Servicio de Noticias Científicas de Medicina y Salud Pública de Puerto Rico

Dr. Leonardo Hormaza, gastroenterólogo pediátrico y presidente Asociación de Gastroenterología y Hepatología Pediátrica de Puerto Rico.

Dr David Blas, Presidente entrante Academia Puertorriqueña de Neurología

CONVENCIÓN ANUAL DE LA ACADEMIA PUERTORRIQUEÑA DE NEUROLOGÍA La convención anual de la Academia Puertorriqueña de Neurología contó con la participación de más de 200 profesionales de la salud. Entre las conferencias más destacadas se encontraron las novedades sobre la esclerosis múltiple, las nuevas modalidades en la epilepsia, lo que se debe saber sobre la esclerosis lateral amiotrófica y las actualizaciones en el manejo de la migraña crónica.

SIMPOSIO ANUAL DE LA ASOCIACIÓN DE GASTROENTEROLOGÍA Y HEPATOLOGÍA PEDIÁTRICA DE PUERTO RICOS La Asociación de Gastroenterología y Hepatología Pediátrica de Puerto Rico realizó la novena edición de su Simposio anual, en su continuo esfuerzo por educar a los pediatras y médicos generalistas del país sobre las condiciones digestivas y que afectan el hígado de la población infantil. Según el doctor Leonardo Hormaza, presidente de la asociación, más allá de ofrecer conferencias sobre investigaciones y novedades en cuanto a tratamientos, este año también quisieron enfocarse en otros aspectos que afectan a los niños con condiciones gastrointestinales, entre estos el manejo psicológico de los niños.

Dr. Eduardo Canto, presidente de la Asociación Puertorriqueña de Urología.

SIMPOSIO ANUAL DE LA ASOCIACIÓN DE GASTROENTEROLOGÍA Y HEPATOLOGÍA PEDIÁTRICA DE PUERTO RICO La Asociación de Gastroenterología y Hepatología Pediátrica de Puerto Rico realizó la novena edición de su Simposio anual, en su continuo esfuerzo por educar a los pediatras y médicos generalistas del país sobre las condiciones digestivas y que afectan el hígado de la población infantil. Según el doctor Leonardo Hormaza, presidente de la asociación, más allá de ofrecer conferencias sobre investigaciones y novedades en cuanto a tratamientos, este año también quisieron enfocarse en otros aspectos que afectan a los niños con condiciones gastrointestinales, entre estos el manejo psicológico de los niños.

Dr. Rogelio Mercado, dermatólogo

CONVENCIÓN DE DERMATÓLOGOS DE PUERTO RICO Sociedad de Dermatólogos de Puerto Rico desarrolló su la convención anual, donde su vicepresidente, el doctor Rogelio Mercado, compartió información relevante acerca de una enfermedad con alta prevalencia en la isla: la dermatitis atópica.

El galeno indicó que se trata de una enfermedad multifactorial, donde la genética es un componente importante pero no es el único, también intervienen “condiciones alérgicas o atópicas” y entre ellas señala el asma o la rinitis.

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ENTREVISTA EXCLUSIVA / MSP

IMPLANTES MAMARIOS PROVOCAN LA APARICIÓN DE UN NUEVO LINFOMA

ción y los pacientes pueden presentar varios síntomas, entre los que se encuentran: •

•

EN EXCLUSIVA CON LA REVISTA PUERTORRIQUEÑA DE MEDICINA Y SALUD PÚBLICA (MSP), LA DRA. MARIA ELENA ARTZE, RADIÓLOGA DE CLEVELAND CLINIC FLORIDA, HABLÓ ACERCA DE UN NUEVO LINFOMA QUE HA SURGIDO A PARTIR DE LOS IMPLANTES MAMARIOS. 88

Se trata del linfoma anaplásico de células grandes relacionado o asociado al implante mamario y se encuentra en algunos pacientes que tienen implantes.

“No es un cáncer de seno y eso es importante saberlo. La presentación el diagnóstico y el tratamiento es totalmente diferente, es un linfoma que está asociado con los implantes”, explicó la galena.

Aunque este linfoma puede manifestarse un año después de la cirugía, el promedio es de siete a diez años después de la interven-

Revista Puertorriqueña de Medicina y Salud Pública

• •

Un seno más grande que el otro y que ha cambiado de tamaño repentinamente Dolor en el área del implante Sentir masas en el área del implante Se pueden sentir ganglios en las axilas u otros lugares

“Si la paciente tiene un implante y sabe que la superficie del implante es de textura o rugosidad y los síntomas aparecen de repente debe ir al médico lo más rápido posible”, manifestó la radióloga.

Este linfoma se desarrolla en todo tipo de implante. Sin embargo, en implantes con superficie texturizada existe mayor riesgo de desarrollar este linfoma que aquellos con una

EL TRATAMIENTO DEPENDE EXCLUSIVAMENTE DE LA GRAVEDAD DEL LINFOMA. SI LLEGARA A SER NECESARIA LA CIRUGÍA, SE DEBE SACAR EL IMPLANTE CON TODA LA CÁPSULA Y LAS CÉLULAS.

superficie de textura lisa. Además, es importante que el paciente sepa qué tipo de implante, ya que la prótesis texturizada de la compañía Allergan, especialmente el Biocell, tiene seis veces más riesgo que otros implantes. Sin embargo, es indispensable resaltar que la compañía Allergan ya se retiró del mercado y estas prótesis no se siguen distribuyendo.

Como recomendaciones generales la doctora Artze puntualiza los siguientes aspectos: •

•

•

Conservar la Ficha de Implante (describe los datos de la prótesis mamarias), que fue entregada junto con la historia clínica.

Visitar al especialista, inclusive si no ha presentado sintomatología clínica o deterioro de las prótesis, para determinar conjuntamente las acciones a seguir, en función de las circunstancias médicas y estéticas particulares de cada persona.

Ante evidencia clínica de ruptura de los implantes mamarios, se deberán retirar de manera inmediata a través de los servicios médicos de urgencias.

El tratamiento depende exclusivamente de la gravedad del linfoma. Si llegara a ser necesaria la cirugía, se debe sacar el implante con toda la cápsula y las células. Sin embargo, si el diagnóstico no se da a tiempo puede terminar en metástasis y en ese caso se necesitaría radiación o quimioterapia.

Es importante reconocer que el linfoma no es la única causa, la causa más común es la ruptura del implante, se rompe la cápsula y el líquido se acumula entre la cápsula y el implante, produciendo infección y hematomas.

Este diagnóstico se puede confundir sólo con un seroma (ruptura del implante), sin embargo un seroma con los síntomas descritos anteriormente en un paciente con implantes puede ser un potencial linfoma.

“El médico tiene que estar atento, ya que no se puede

confundir con un seroma o una ruptura del implante cuando en realidad tiene un linfoma, porque en ese caso el paciente no tendrá un tratamiento adecuado y puede llegar a una metástasis”, afirmó la Dr. Artze.

El linfoma anaplásico de células grandes es un linfoma de células T que aparece sólo en personas con prótesis mamarias, siendo esta la primera vez que se clasifica un linfoma.

“Es importante que el paciente que quiere colocarse implantes sepa toda la información necesaria por medio del cirujano tratante acerca de su cirugía e implantes. Además, para los pacientes con prótesis no se recomienda quitar los implantes si no siente síntomas, sólo se deben quitar si al paciente se le detecta alguna anomalía” concluyó la Dr. Artze.

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112 mcg rose

125 mcg brown

137 mcg turquoise

150 mcg blue

175 mcg lilac

200 mcg pink

300 mcg green

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A CIENCIA CIERTA

DR. ALMODÓVAR: EJEMPLO DE EXCELENCIA EN LA PRÁCTICA ONCOLÓGICA DE UNA NUEVA GENERACIÓN

E

l mayor sueño de todo padre es ver a un hijo cumplir sus metas, pero, esta vez, no solo el vástago logró convertirse en médico, sino que cumplió el sueño de su padre, convirtiéndose en neurocirujano oncólogo y director del Servicio de Neuro-Oncología del Hospital HIMA San Pablo de Caguas en Puerto Rico.

“Mi papá es médico y empezó a hacer la residencia en Neurocirugía, sin embargo, por situaciones familiares no logró terminar. Es por eso que me hacía mucha ilusión darle a él la satisfacción de ver a su hijo realizarse como neurocirujano. Tanto así, que cuando terminé la subespecialidad en Neurocirugía Oncológica, una de las cosas que hice fue llevar a mi papá a trabajar 94

conmigo, para que él pudiese tener esa cercanía con la especialidad que tanto le gustaba”, explicó el Dr. Almodóvar, quien es graduado de Biología y Medicina de la Universidad de Puerto Rico.

Además de cumplir el sueño de su padre, otra razón por la que decidió escoger la neurocirugía, es porque la considera una especialidad extremadamente retadora, debido a la complejidad del cerebro humano y todos los principios físicos, químicos y mecánicos que es necesario conocer para tratarlo.

Es así como el Dr. Almodóvar ha dedicado su vida a llevar a cabo una práctica médica que genera valor en la vida de sus pacientes y la comunidad médico-científica, a través de grandes aportes a la oncología puertorriqueña;

Revista Puertorriqueña de Medicina y Salud Pública

dentro de los que se incluye el inició del programa Gamma Knife en Puerto Rico, que consiste en la remoción de tumores sin afectar tejido benigno en el cerebro.

Además, mientras realizaba un año de investigación en la Universidad Central del Caribe en Bayamón, llevó a cabo experimentos relacionados a la electrofisiología cerebral, para estudiar la conectividad de las neuronas o células cerebrales, frente a estímulos de compuestos aditivos. Así pues, alineado a ese interés científico, hizo un año de investigación en el área de nanotecnología médica, que se concentraba en lograr sintetizar compuestos que pudieran combinarse con ciertas moléculas, para llevarlas de una manera dirigida al tratamiento de células cancerosas.

Actualmente el Dr. Almodóvar mantiene más viva que nunca su pasión por la neurocirugía, realizando una práctica médica de alto nivel y focalizando su conocimiento y creatividad en el desarrollo de instrumentos y nuevas tecnologías de alto impacto, tanto para los pacientes como para los especialistas médicos del área oncológica.

This is what BPH medications do for patients.

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1. McVary K T, Rogers T, Roehrborn CG. Rezūm water vapor thermal therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia: 4-year results from randomized controlled study. Urology. 2019 Apr; 126:171–179.

2. McVary KT, Gange SN, Gittelman MC, et al. Erectile and ejaculatory function preserved with convective water vapor energy treatment of LUTS secondary to BPH: randomized controlled study. J Sex Med. 2016 Jun;13(6):924-33.

Caution: U.S. Federal law restricts this device to sale by or on the order of a physician.

All images are the property of Boston Scientific. All trademarks are the property of their respective owners. © 2019 Boston Scientific Corporation or its affiliates. All rights reserved. URO-562404-AB APR 2019