Revista Medicina y Salud Pública by Revista Medicina y Salud Pública (MSP)

ESCABIOSIS O SARNA NORUEGA

SE DISFRAZA CON SÍNTOMAS DE PSORIASIS EN UNA PACIENTE DE 75 AÑOS CON PARKINSON EL ANDROGRAFÓLIDO INDUCE DAÑO AL ADN EN LAS CÉLULAS DEL CÁNCER DE PRÓSTATA

EFECTO SECUNDARIO INMUNE POCO COMÚN RELACIONADO CON EL TRATAMIENTO DE INMUNOTERAPIA DEL MELANOMA AVANZADO

PUERTO RICO SE UNE A LOS PAÍSES QUE REALIZAN EL ESTUDIO DE VACUNAS EXPERIMENTALES PARA LA PREVENCIÓN DEL VIH Revista Puertorriqueña de Medicina y Salud Pública

The first IL-17A antagonist to achieve the primary endpoint in a head-to-head trial against Humira® (adalimumab) in PsA 1-5

FOR BIOLOGIC-NAIVE PATIENTS WITH PSORIATIC ARTHRITIS

Superiority to Humira in the percentage of patients simultaneously achieving ACR50 and PASI 100 at week 24, with consistency through week 526

SPIRIT-H2H (BIOLOGIC-NAIVE): Simultaneous achievement of ACR50 and PASI 100

PATIENTS ACHIEVING RESPONSE, NRI (%)

SUPERIOR

CONSISTENT

ACR50 & PASI 100 at week 24

through week 52

39%†

36%* 28%

26%

0 0

WEEK

Taltz (n=283)

Humira (n=283)

*P<.05 vs Humira. P≤.001 vs Humira. Nominal P value: Week 52 measure of ACR50 + PASI 100 was not controlled for type-I error; therefore, no statistical comparisons can be made.

†

All patients had BSA ≥3%; patients with BSA ≥10%, PASI ≥12, and sPGA ≥3 followed the dosing for moderate to severe PsO.7 Primary endpoint=simultaneous achievement of ACR50 and PASI 100 at week 24.

SPIRIT-P1 and -P2: ACR response rates at week 24, NRI8

SPIRIT-P1 and -P2: PASI response rates at week 12, NRI

In SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=107; placebo n=106) and SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=122; placebo n=118), 58% and 53% of Taltz patients, respectively, achieved ACR20 vs 30% and 20% for placebo. Additionally, 40% and 35% of patients receiving Taltz achieved ACR50 vs 15% and 5% for placebo.

In SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=73; placebo n=67), among PsA patients with plaque psoriasis ≥3% BSA, NRI, 75% of patients receiving Taltz achieved PASI 75 at week 12 vs 8% of patients who received placebo. 32% of patients receiving Taltz achieved PASI 100 at week 12 vs 2% of patients who received placebo.9 In SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=68; placebo n=67), among PsA patients with plaque psoriasis ≥3% BSA, 57% of patients receiving Taltz achieved PASI 75 at week 12 vs 10% for placebo. Additionally, 19% of patients receiving Taltz achieved PASI 100 at week 12 vs 6% for placebo.10 Among patients with sPGA ≥3 at baseline, in SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=52; placebo n=41), 75% of patients receiving Taltz achieved sPGA 0,1 at week 12 vs 7% for placebo.9 Additionally, in SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=60; placebo n=55), 63% of patients receiving Taltz achieved sPGA 0,1 vs 4% for placebo.10,11

Primary endpoint=ACR20 response at week 24. Inadequate responders (<20% improvement in tender and in swollen joint counts) at week 16 were analyzed as nonresponders after week 16 until the primary endpoint. NRI of intent-to-treat population through week 24.

Taltz has no boxed warning 2

Revista Puertorriqueña de Medicina y Salud Pública

NRI of intent-to-treat population through week 12. ACR20/50=American College of Rheumatology 20%/50% response; PASI=Psoriasis Area Severity Index; NRI=nonresponder imputation; BSA=body surface area; sPGA=static Physician’s Global Assessment; TNFi=tumor necrosis factor inhibitor; PsA=psoriatic arthritis.

Approved to treat adult patients across the spectrum of axSpA (nr-axSpA, AS) SPIRIT-H2H Trial Design12

SPIRIT-P1 and -P2 Trial Design8,10,13,14

SPIRIT-H2H (N=566) was a phase 4, randomized, open-label, blinded-assessor study evaluating the efficacy and safety of Taltz vs Humira in biologic-naive patients with active psoriatic arthritis and plaque psoriasis BSA ≥3%. The primary efficacy endpoint was the proportion of patients simultaneously achieving ACR50 and PASI 100 at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints with an inadequate response to ≥1 cDMARD. Patients were randomized (1:1) to Taltz or Humira and allowed to continue a stable dose of concomitant cDMARD during the study. For Taltz patients with psoriatic arthritis only (n=234), the initial dose (160 mg as 2 injections) was followed by 80 mg every 4 weeks. Humira patients (n=231) received 40 mg every other week and no initial dose. Patients who met the trial design criteria for moderate to severe psoriasis (BSA ≥10%, PASI ≥12, and sPGA ≥3) in addition to psoriatic arthritis followed the psoriasis dosing regimen: Taltz patients (n=49) received an initial dose of 160 mg (two 80 mg injections), followed by 80 mg every 2 weeks through week 12, then 80 mg every 4 weeks thereafter. Humira patients (n=52) received an initial dose of 80 mg, then 40 mg every other week starting 1 week after the initial dose.

SPIRIT-P1 (N=417) and SPIRIT-P2 (N=363) were phase 3, randomized, doubleblind, placebo-controlled trials to evaluate the efficacy and safety of Taltz compared with placebo in patients with active psoriatic arthritis. Patients in SPIRIT-P1 were biologic-naive. Patients in SPIRIT-P2 were tumor necrosis factor inhibitor (TNFi)experienced, having had an inadequate response and/or intolerance to 1 or 2 prior TNFis. In both trials, the primary efficacy endpoint was the proportion of patients achieving ACR20 response at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints. Patients were randomized to placebo or Taltz 80 mg every 2 or 4 weeks following a 160 mg starting dose. In SPIRIT-P1, an active reference arm of Humira 40 mg every 2 weeks was included. Patients in all study arms were allowed to continue taking stable background medications during the trial. Inadequate responders (as defined by blinded criteria of <20% improvement in tender and in swollen joint counts) at week 16 received rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders in the placebo and Humira arms were re-randomized to Taltz 80 mg every 2 or 4 weeks. NRI methods were used for categorical efficacy analyses during the double-blind treatment period.

cDMARD=conventional disease-modifying antirheumatic drug.

INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS Taltz is indicated for adults with active psoriatic arthritis (PsA), for adults with active ankylosing spondylitis (AS), and for adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. Taltz is also indicated for patients aged 6 years or older with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

CONTRAINDICATIONS

ADVERSE REACTIONS

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

Most common adverse reactions (≥1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. Overall, the safety profiles observed in adult patients with psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and pediatric patients with plaque psoriasis were consistent with the safety profile in adult patients with plaque psoriasis, with the exception of influenza and conjunctivitis in psoriatic arthritis and conjunctivitis, influenza, and urticaria in pediatric psoriasis.

WARNINGS AND PRECAUTIONS Infections Taltz may increase the risk of infection. In clinical trials of adult 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 adult patients with psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and pediatric patients with plaque psoriasis. 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 Patients treated with Taltz may be at an increased risk of inflammatory bowel disease. In clinical trials, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group than the placebo group. During Taltz treatment, monitor patients for onset or exacerbations of inflammatory bowel disease and if IBD occurs, discontinue Taltz and initiate appropriate medical management.

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.

Please see Brief Summary of Prescribing Information on next pages. See Instructions for Use included with the device. IX HCP ISI 07MAY2020 References: 1. Data on file. Lilly USA, LLC. DOF-IX-US-0121. 2. Data on file. Lilly USA, LLC. DOF-IX-US-0122. 3. Data on file. Lilly USA, LLC. DOF-IX-US-0123. 4. Data on file. Lilly USA, LLC. DOF-IX-US-0124. 5. Data on file. Lilly USA, LLC. DOF-IX-US-0125. 6. Data on file. Lilly USA, LLC. DOF-IX-US-0190. 7. Mease PJ, Smolen JS, Behrens F, et al. A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naive patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial. Ann Rheum Dis. 2020;79:123-131. 8. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 9. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76:79-87. 10. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317-2327. Supplementary appendix. 11. Data on file. Lilly USA, LLC. TAL20171127A. 12. Data on file. Lilly USA, LLC. DOF-IX-US-0119. 13. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase 3 trial SPIRIT-P1. Ann Rheum Dis. 2017;76(suppl):1-30. 14. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317-2327.

For more information, please contact a Lilly representative or visit TaltzPSAH2H.com. Taltz® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, and affiliates. Humira® is a registered trademark of AbbVie Biotechnology Ltd. Revista de Medicina y Salud Pública PP-IX-US-3933 05/2020 ©LILLY USA, LLC 2020.Puertorriqueña 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 patients aged 6 years and older 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. Ankylosing Spondylitis—Taltz is indicated for the treatment of adult patients with active ankylosing spondylitis. Non-radiographic Axial Spondyloarthritis—Taltz is indicated for the treatment of adult patients with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. 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 adult 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 pediatric psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis (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—Patients treated with Taltz may be at an increased risk of inflammatory bowel disease. In clinical trials, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group than in the placebo group (Adverse Reactions). During Taltz treatment, monitor for onset or exacerbation of inflammatory bowel disease and if IBD occurs, discontinue Taltz and initiate appropriate medical management. 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: • Infections (Warnings and Precautions) • Hypersensitivity Reactions (Contraindications and Warnings and Precautions) • Inflammatory Bowel Disease (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. Adult 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 subjectyear 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 Placebo Adverse Reactions Taltz 80 mg Q2W Etanerceptb (N=287) (n%) (N=791) (n%) (N=1167) (n%) Injection site reactions 196 (17) 32 (11) 26 (3) Upper respiratory 163 (14) 23 (8) 101 (13) tract infectionsa Nausea 23 (2) 1 (<1) 5 (1) Tinea infections 17 (2) 0 1 (<1) a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection. b 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. 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). Inflammatory Bowel Disease: In adult subjects with plaque psoriasis, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the TALTZ 80 mg Q2W group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period in clinical trials (Warnings and Precautions). 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 subject-year 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. Pediatric Plaque Psoriasis Taltz was evaluated in a placebo-controlled trial in pediatric subjects with moderate-to-severe psoriasis 6 to less than 18 years of age. A total of 171 subjects were studied (115 subjects on Taltz and 56 subjects on placebo). Overall, the safety profile observed in pediatric subjects with plaque psoriasis treated with Taltz every 4 weeks is consistent with the safety profile in adult subjects with plaque psoriasis with the exception of the frequencies of conjunctivitis (2.6%), influenza (1.7%), and urticaria (1.7%). In this clinical trial, Crohn’s disease occurred at a greater frequency in the Taltz group (0.9%) than the placebo group (0%) during the 12-week, placebo-controlled period. Crohn’s disease occurred in a total of 4 Taltz treated subjects (2.0%) in the clinical trial (Warnings and Precautions). 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 adult patients with plaque psoriasis with the exception of the frequencies of influenza (1.3%) and conjunctivitis (1.3%). Ankylosing Spondylitis Taltz was studied in two placebo-controlled trials in patients with ankylosing spondylitis. A total of 566 patients were studied (376 patients on Taltz and 190 on placebo). A total of 195 patients in these trials received Taltz 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the

Taltz® (ixekizumab) injection

Revista Puertorriqueña de Medicina y Salud Pública

IX HCP BS 07MAY2020

safety profile observed in patients with ankylosing spondylitis treated with Taltz Q4W is consistent with the safety profile in adult patients with plaque psoriasis. In adult patients with ankylosing spondylitis, Crohn’s disease and ulcerative colitis, including exacerbations, occurred in 2 patients (1.0%) and 1 patient (0.5%), respectively, in the Taltz 80 mg Q4W group and 1 patient (0.5%) and 0%, respectively, in the placebo group during the 16-week, placebo-controlled period in clinical trials. Of these patients, serious events occurred in 1 patient in the Taltz 80 mg Q4W group and 1 patient in the placebo group (Warnings and Precautions). Non-radiographic Axial Spondyloarthritis Taltz was studied in a placebo-controlled trial in patients with non-radiographic axial spondyloarthritis. A total of 303 patients were studied (198 patients on Taltz and 105 on placebo). A total of 96 patients in this trial received Taltz 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with non-radiographic axial spondyloarthritis treated with Taltz 80 mg Q4W up to Week 16 is consistent with the previous experience of Taltz in other indications. 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 adult 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 adult 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. In pediatric psoriasis subjects treated with ixekizumab at the recommended dosing regimen up to 12 weeks, 21 subjects (18%) developed anti-drug antibodies, 5 subjects (4%) had confirmed neutralizing antibodies associated with low drug concentrations. No conclusive evidence could be obtained on the potential association of neutralizing antibodies and clinical response and/or adverse events due to small number of pediatric subjects in the study. Psoriatic Arthritis Population For subjects treated with Taltz 80 mg every 4 weeks for up to 52 weeks (PsA1), 11% developed anti-drug antibodies, and 8% had confirmed neutralizing antibodies. Ankylosing Spondylitis Population For patients treated with Taltz 80 mg every 4 weeks for up to 16 weeks (AS1, AS2), 5.2% developed anti-drug antibodies, and 1.5% had neutralizing antibodies. Non-radiographic Axial Spondyloarthritis Population Of patients treated with Taltz 80 mg every 4 weeks for up to 52 weeks (nr-axSpA1), 8.9% developed anti-drug antibodies, all of which were low titer. No patient had 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 postapproval 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 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, TNFα, 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.

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 have been established in pediatric subjects aged 6 years to less than 18 years with moderate-to-severe plaque psoriasis. The safety and effectiveness of Taltz in other pediatric indications and for pediatric subjects less than 6 years of age have not been established. 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.

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.

IX HCP BS 07MAY2020

Taltz® (ixekizumab) injection

IX HCP BS 07MAY2020

IX HCP BS 07MAY2020 Revista Puertorriqueña de Medicina y Salud Pública

NOW APPROVED

3/21

cp-186469v1

Revista Puertorriqueña de Medicina y Salud Pública

CONTENIDO

OSTEOARTRITIS, UNA CONDICIÓN METABÓLICA QUE REQUIERE ATENCIÓN TEMPRANA PARA NO LLEGAR A SER LIMITANTE

ESCABIOSIS O SARNA NORUEGA SE DISFRAZA CON SÍNTOMAS DE PSORIASIS EN UNA PACIENTE DE 75 AÑOS CON PARKINSON

EL ANDROGRAFÓLIDO INDUCE DAÑO AL ADN EN LAS CÉLULAS DEL CÁNCER DE PRÓSTATA

RYAN WHITE LA HISTORIA QUE CAMBIÓ LA FORMA DE VER AL SIDA

USO CONCURRENTE DE OPIOIDES Y BENZODIACEPINAS: EL VERDADERO DESAFÍO

EDITOR FUNDADOR Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD PRINCIPAL OFICIAL EJECUTIVO Pedro Carlos Lugo Hernández III, P.A PRESIDENTA Y FUNDADORA Glorybelle Hernández Figueroa, MBA VICEPRESIDENTA Y FUNDADORA Laila Paloma Lugo, MBA CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA, MARKETING Y SERVICIOS 360 Ivelisse Cortés,Yasmin Morell PERIODISTAS Belinda Burgos, Grenda Rivera, Mayra Acevedo, Luis Penchi ARTISTAS GRÁFICOS Natalia Zoé Rivera Torres DIRECTORA AUDIOVISUAL Fabiola Plaza REALIZADORA AUDIOVISIAL Salomé Mateus FOTOS Revista Medicina y Salud Pública DIRECCIÓN GENERAL Carlos Alexis Lugo Marrero DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente Para ventas y otros servicios pueden comunicarse al 787.848.3333, msp@editorialmundo.com o www.medicinaysaludpublica.com Revista Puertorriqueña de Medicina y Salud Pública ISSN 1937-8521 COMITÉ EDITORIAL CIENTÍFICO COMITÉ EDITORIAL Olga Rodríguez, MD - Decana Escuela de Medicina de Ponce (Puerto Rico), Vivian Green, LND, MS, PhD, Sub editora y fundadora (Puerto Rico), José Cordero, MD, MPH - Exdecano Escuela Graduada Salud Pública Recinto de Ciencias Médicas UPR (Puerto Rico), Ángeles Rodríguez, MD, MPH (Puerto Rico), Simón Carlo, MD (Puerto Rico), Bárbara Rosado, MD (Puerto Rico), Idhaliz Flores PhD (Puerto Rico), Jesús Cruz-Correa, MD, FACOG (Puerto Rico), Rafael Bredy, MD, LicMTo, MBE, MS (Puerto Rico), David Caseida, MD, FACOG, (Puerto Rico), José Capriles, MD, MHSA (Puerto Rico) Joaquín Laboy, MD, FACOG (Puerto Rico), Luis Adrian Rivera Pomales, MD, PEMBA, MPH, CMQ (Puerto Rico), Juan Fernández, MS, PhD (Puerto Rico), Nuria Sebate, MD (Puerto Rico), Pedro Amador, MD, MPH (Puerto Rico), Nydia Cappas, PsyD (Puerto Rico), Luis Franco, MD (Puerto Rico), Federico Montealegre, DVM, PhD, Msc (Puerto Rico), Nydia Ortiz, PsyD (Puerto Rico), José Pons, PhD, FPPR (Puerto Rico), Esdrás Vélez, JD, MPH (Puerto Rico), Diego Zavala, MSc, PhD, (Puerto Rico), Ana Torres-Martín, MD (Puerto Rico), Julio Cádiz, MD, MPH (Puerto Rico), Rafael Gómez-Cuevas (Colombia), José Javier Orengo, PhD(c) (España), Cesar A. Del Rey, MD (Panamá), Pedro Serrano, MD, PhD (España), Luis Serra-Majem, MD, PhD (España), José Ramón Calvo, MD, PhD (España). Síguenos en www.medicinaysaludpublica.com, www.facebook.com/revistamsp, en Twitter @revistamsp, en LinkedIn como Revista Puertorriqueña de Medicina y Salud Pública. Las normas editoriales de la Revista Puertorriqueña de Medicina y Salud Pública para la publicación de artículos originales y cartas al editor pueden ser accesadas en la página web: www.medicinaysaludpublica.com, y solicitadas a través de msp@editorialmundo.com. Medicina y Salud Pública es propiedad de publicaciones mundo. Medicina es una publicación de la REVISTA PUERTORRIQUEÑA DE MEDICINA Y SALUD PÚBLICA. Medicina y Salud Pública tiene como política corregir y aclarar cualquier información incorrecta que pueda ser publicada en su revista. Medicina y Salud Pública no asume responsabilidad alguna por los anuncios, artículos y otros servicios anunciados en nuestra publicación. Revista Puertorriqueña de Medicina y Salud Pública

Revista Puertorriqueña de Medicina y Salud Pública

EDITORIAL

40 AÑOS DE SIDA, LA PANDEMIA DE LA SEGUNDA MITAD DEL SIGLO XX

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

l 5 de junio de 2021 se cumplieron 40 años de la primera descripción clínica de casos de lo que posteriormente se denominó el Síndrome de Inmunodeficiencia Adquirida (SIDA). A lo largo de estas cuatro décadas, la A lo largo de estas cuatro décadas, la enfermedad ha pasado de tener una morbimortalidad muy elevada a tratarse con antirretrovirales eficaces con un buen perfil de seguridad. Queda

mucho camino por recorrer, ya que la epidemia no está controlada y el acceso a los tratamientos para todos los sectores socioeconómicos sigue siendo uno de los mayores retos. Según ONUSIDA, hay 76 millones de personas infectadas por VIH y 35 millones de personas han muerto de SIDA. En la actualidad, 38 millones de personas viven con el VIH. Cada año se producen 80.000 nuevas infecciones en Occidente y en Puerto Rico hay diagnosticados 11, 474 seres humanos con la condición. Es por ello que acelerar el progreso para poner fin a esta enfermedad debe ser el objetivo común de cara al 2030. El llamado cobra mayor importancia al conocerse los nuevos datos del Programa de las Naciones Unidas para el VIH-SIDA (ONUSIDA) que demuestran que estas metas no son meras aspiraciones, sino una realidad alcanzable. El informe demuestra que los países con leyes y políticas progresistas y sistemas sanitarios sólidos e inclusivos son los que tienen mejores resultados contra el VIH. Las personas que viven con el VIH en esos países tienen una mayor probabilidad de acceder a servicios eficaces para el VIH, entre ellos las pruebas de detección, la profilaxis previa a la exposición (medicamentos para prevenir el padecimiento), la reducción de daños causados por la enfermedad, el suministro de varios meses de tratamiento para el VIH y un seguimiento y una atención constante y de calidad. Con financiación adecuada, el compromiso auténtico de la comunidad, los enfoques multisectoriales basados en los derechos

humanos y la ciencia como punto de partida para sus estrategias han logrado revertir sus epidemias y salvar vidas. Todos estos elementos son muy valiosos para estar preparados y responder eficazmente a la pandemia contra el VIH, la COVID-19 y muchas otras enfermedades. Sin embargo, ONUSIDA debió destacar también que se agota el tiempo para alcanzar el objetivo de acabar con el sida para el año 2030. El estudio muestra que a nivel mundial el número de personas que reciben tratamiento se ha triplicado. En el 2020, 27,4 millones de los 37,6 millones de personas que vivían con el VIH estaban en tratamiento, frente a los 7,8 millones de 2010. Las muertes relacionadas con el sida también disminuyeron, en gran parte gracias a la implementación de las terapias antirretrovirales, cayendo un 43 % desde 2010 y llegando a las 690.000 en 2020. Al mismo tiempo, se avanzó en la reducción de nuevas infecciones por VIH, pero con un progreso notablemente más lento: se ha logrado una reducción del 30 % desde 2010, con 1,5 millones de nuevas infecciones por VIH en 2020 en comparación con los 2,1 millones de 2010. En el momento actual la investigación sobre el VIH se enfrenta a dos grandes desafíos: alcanzar la curación del VIH mediante nuevas estrategias de tratamiento que permitan eliminar el virus en el paciente infectado y conseguir una vacuna preventiva frente al VIH. Precisamente, las claves para terminar con esta pandemia.

Revista Puertorriqueña de Medicina y Salud Pública

ESCABIOSIS O SARNA NORUEGA SE DISFRAZA CON SÍNTOMAS DE PSORIASIS EN UNA PACIENTE DE 75 AÑOS CON PARKINSON a

Revista Puertorriqueña de Medicina y Salud Pública

AUTOR PRIMARIO: Dra. Jeandelize Soto Rosa, del Departamento de Medicina Interna del Mayagüez Medical Center (MMC)

AUTOR SECUNDARIO:

Dr. Jan P. Rosaly

Autores terciarios: Dr. Christian Camacho, Dr. Dannel Díaz, Dra. Miriam Padilla, Dra. Xiomara Cruz, Dr. Milton Carrero

RESUMEN a Sarna Costrosa, también conocida como Sarna Noruega, es una versión severa de sarna humana que puede ocurrir en algunas personas inmunodeprimidas, ancianos, discapacitados o con enfermedades neurológicas. Este tipo de sarna suele presentarse en forma de costras gruesas en la piel, conteniendo una gran cantidad de ácaros y huevos. Es una infestación muy contagiosa y puede propagarse fácilmente tanto por el contacto directo de piel como por la contaminación de artículos. En nuestro caso se describe a una paciente con enfermedad de Parkinson y demencia con cuerpos de Lewy, que desarrolló sarna costrosa en un asilo de ancianos.

ABSTRACT Crust y Scabies, also known as Norwegian Scabies, is a severe version of human scabies that can occur in some immunosuppressed, elderly, disabled, or neurologically ill people. This type of scabies usually appears in the form of thick crusts on the skin, containing a large number of mites and eggs. It is a highly contagious infestation and can be easily spread by both direct skin contact and contamination of items. In our case, we describe a patient with Parkinson's disease and Lewy body dementia, who developed crusty scabies in a nursing home.

PALABRAS CLAVE sarna noruega, psoriasis, parkinson

KEYWORDS crusty scabies, psoriasis, parkinson

Revista Puertorriqueña de Medicina y Salud Pública

La Sarna Costrosa, también conocida como Sarna Noruega, es una versión severa de sarna humana que puede ocurrir en algunas personas inmunodeprimidas, ancianos, discapacitados o con enfermedades neurológicas. Este tipo de sarna suele presentarse en forma de costras gruesas en la piel, conteniendo una gran cantidad de ácaros y huevos. Es una infestación muy contagiosa y puede propagarse fácilmente tanto por el contacto directo de piel como por la contaminación de artículos. Los signos y síntomas más comunes en este tipo de sarna son el sarpullido, prurito y placas hiperqueratósicas. Es importante identificarla ya que solamente el 0.5% de los pacientes presentan este tipo de sarna humana la cual también está asociada a pacientes de Parkinson. Si es identificada en un paciente, este debe recibir un tratamiento médico rápido y agresivo para prevenir algún brote en el área o complicaciones severas. En nuestro caso se describe a una paciente con enfermedad de Parkinson y demencia con cuerpos de Lewy que desarrolló sarna costrosa en un asilo de ancianos. Se trata de una mujer de 75 años sin alergias conocidas y con antecedentes de hipertensión arterial, diabetes mellitus, enfermedad de Parkinson y demencia con cuerpos de Lewy que ingresó a nuestros servicios con diagnóstico de celulitis en la pierna izquierda y sospecha de sarna. La paciente de acuerdo a su hija, vive en un centro de atención de ancianos donde desarrolla una celulitis en la pierna izquierda de varios días de evolución. La celulitis fue previamente tratada por su médico primario con antibióticos, sin ninguna mejoría y empeoramiento del eritema y el edema de la pierna. Durante dos días se observó una formación de ampollas y secreción en el área de la

pierna las cuales fueron la principal causa de acudir a Emergencias Médicas. Además, se relata que la paciente ha venido presentando durante varios años placas hiperqueratósicas entre los dedos de las manos y pies, palmas, axilas y abdomen. Todas estas lesiones son asociadas con prurito generalizado. En adición, estas lesiones cutáneas fueron también tratadas con antifungales y esteroides sin ninguna mejoría. Al tener la alta sospecha de sarna humana se decide solicitar los servicios de infectología para obtener una mejor guía diagnóstica y terapéutica. Luego de examinar al paciente, revisar el registro médico y los estudios de imágenes, se le diagnostica Sarna Noruega. Durante la admisión, en los análisis de laboratorio se pudo observar una eosinofilia persistente, leucocitosis leve y una anemia microcítica (8,5 g / dl). A la paciente se le asigna islamiento por contacto y para el tratamiento médico se utilizó permetrina tópica al 5% por dos dosis con 5 días de intervalo e ivermectina oral 9 mg durante tres dosis los días 1, 2 y 8. La celulitis del pies izquierdo secundaria a la pérdida de integridad de la piel por sarna, se trató con antibióticos de amplio espectro para cubrir Staphylococcus aureus resistente a meticilina (SARM). Se consultó la evaluación del equipo de atención de heridas y luego de varios días de terapia médica, se notó una mejoría clínica. Este caso ilustra los desafíos que

Revista Puertorriqueña de Medicina y Salud Pública

enfrentan los médicos para identificar un diagnóstico tan inusual y como pueden ser necesarias las aplicaciones repetidas de un medicamento tópico tanto así como un tratamiento combinado durante varias semanas. En nuestro caso, el inicio de la medicación oral y del tratamiento tópico fue fundamental para evitar complicaciones como sepsis. Este tipo de lesiones en la piel pueden confundirse con psoriasis o dermatitis, por lo que es esencial el diagnóstico y evaluación multidisciplinaria a tiempo en estos tipos de pacientes. Por lo tanto, este informe refuerza y establece los procedimientos adecuados para el control y tratamiento de infecciones. CONCLUSIÓN Este caso ilustra los desafíos que enfrentan los médicos para identificar un diagnóstico tan inusual y como pueden ser necesarias las aplicaciones repetidas de un medicamento tópico tanto así como un tratamiento combinado durante varias semanas. Esta enfermedad de no ser tratada puede llevar a una propagación inexorable. En nuestro caso, el inicio de la medicación oral y del tratamiento tópico fue fundamental para evitar complicaciones como sepsis. Por lo tanto, este informe refuerza y establece los procedimientos adecuados para el control y tratamiento de infecciones.

AbbVie Aquí. Ahora.

Desarrollando las medicinas del futuro, a la vez que ayudamos a millones a vivir mejor hoy. En AbbVie, trabajamos hacia avances médicos del futuro, a la vez que nos enfocamos en las necesidades diarias de las personas. Porque nunca nos daremos por vencidos ayudando a las personas a vivir sus mejores vidas hoy y mañana. Conozca acerca de nuestro trabajo: herenow.abbvie

Prisca Honore, PhD Científica en inmunología de AbbVie

Revista Puertorriqueña de Medicina y Salud Pública

EL ANDROGRAFÓLIDO INDUCE DAÑO AL ADN EN LAS CÉLULAS DEL CÁNCER DE PRÓSTATA

PALABRAS CLAVE quimioprevención; fitoquímicos; modelo de ratón; Reparación de ADN; la expresión génica KEYWORDS chemoprevention; phytochemicals; mouse model; DNA repair; gene expression RECIBIDO 28 de marzo de 2017 Aceptado: 09 de enero de 2019 Publicado: 01 de febrero de 2019 14

Revista Puertorriqueña de Medicina y Salud Pública

AUTORES Ingrid S. Forestier-Román1,2, Andrés López-Rivas2,3, María M. Sánchez-Vázquez2, Krizia Rohena-Rivera1,2, Gretchen Nieves-Burgos2,3, Humberto Ortiz-Zuazaga4, Carlos A. Torres-Ramos 5 and Magaly Martínez-Ferrer2,6 1 Department of Biochemistry, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA 2 University of Puerto Rico Comprehensive Cancer Center, Division of Cancer Biology, San Juan, Puerto Rico, USA 3 Department of Biology, University of Puerto Rico at Rio Piedras, San Juan, Puerto Rico, USA

4 Department of Computer Sciences, University of Puerto Rico at Rio Piedras, San Juan, Puerto Rico, USA 5 Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA 6 Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, San Juan, Puerto Rico, USA

Correspondencia a: Magaly Martínez-Ferrer, correo electrónico: magaly.martinez1@upr.edu

RESUMEN l cáncer de próstata (CaP) es el cáncer diagnosticado más común y es el tercero c aus a de mo r t alid a d por cáncer en hombres en los EE. UU. Andrografólido, una lactona diterpenoide aislado de Andrographis paniculata, ha demostrado poseer actividad anticancerígena en una variedad de células cancerosas. En este estudio, examinamos la eficacia de Andrographolide en CaP utilizando modelos in vitro e in vivo. Andrógenos independientes (PC3) y andrógenos líneas celulares dependientes (22RV1) fueron tratadas con Andrographolide para determinar la efecto en la motilidad celular, proliferación celular y apoptosis. Disminución de andrografólido Migración de células CaP, menor invasión y aumento de la apoptosis celular in vitro. Tumor El crecimiento se evaluó utilizando un modelo de xenoinjerto ortotópico en el que

las próstatas de ratones SCID fueron inyectados con 22RV1, y los ratones fueron tratados tres veces por semana con Andrographolide 10 mg/kg. Andrographolide disminuyó el volumen del tumor, Expresión de MMP11 y formación de vasos sanguíneos in vivo. Análisis de expresión genética identificado compromiso celular, ciclo celular y "recombinación, replicación y reparación “como las principales funciones moleculares y celulares alteradas en tumores tratados con Andrografólido. Dentro de los genes de reparación del ADN, confirmamos una mayor expresión de genes implicados en la reparación de roturas de doble cadena del ADN. De acuerdo con esta observación, detectó un aumento de γH2AX en tumores tratados con andrografólido y en células en cultivo. En conjunto, estos datos sugieren que Andrographolide inhibe el CaP al promover daño en el ADN.

COPYRIGHT Forestier-Román et al. Este es un artículo de acceso abierto distribuido bajo los términos de Creative Commons Attribution LICENCIA 3.0 (CC BY 3.0) que permite el uso, distribución y reproducción sin restricciones en cualquier medio, siempre que se acredite el autor y la fuente originales. Revista Puertorriqueña de Medicina y Salud Pública

ABSTRACT Prostate cancer (PCa) is the most common diagnosed cancer and is the third cause of cancer mortality in men in the USA. Andrographolide, a diterpenoid lactone isolated from Andrographis paniculata, has shown to possess anticarcinogenic activity in a variety of cancer cells. In this study, we examined the efficacy of Andrographolide in PCa using in vitro and in vivo models. Androgen-independent (PC3) and androgen-dependent (22RV1) cell lines were treated with Andrographolide to determine the effect in cell motility, cell proliferation and apoptosis. Andrographolide decreased PCa cell migration, decreased invasion, and increased cell apoptosis in vitro. Tumor growth was evaluated using an orthotopic xenograft model in which the prostates of SCID mice were injected with 22RV1, and mice were treated three times per week with Andrographolide 10 mg/ kg. Andrographolide decreased tumor volume, MMP11 expression and blood vessels formation in vivo. Gene expression analysis identified cellular compromise, cell cycle, and “DNA recombination, replication and repair” as the major molecular and cellular functions altered in tumors treated with Andrographolide. Within DNA repair genes we confirmed increased expression of genes involved in DNA double strand break repair. Consistent with this observation we detected increased γH2AX in Andrographolide treated tumors and in cells in culture. Taken together, these data suggest that Andrographolide inhibits PCa by promoting DNA damage.

Figura 1: Andrografólido disminuyó la viabilidad celular en células de cáncer de próstata. Las células se incubaron con Andrographolide en las dosis indicadas y la viabilidad celular se determinaron 24 horas o 48 horas después del tratamiento. (A) Andrographolide inhibió el crecimiento de células PC3 después 48 horas; inhibió el crecimiento de células 22RV1 y LNCaP después de 24 horas, pero no inhibió el crecimiento de células RWPE1 después de 24 horas. (B) Porcentaje de inhibición celular se utilizó para determinar el valor de GI50. Los experimentos se realizaron por triplicado. El análisis estadístico se realizó utilizando un factor ANOVA, seguido de la prueba de Dunnett. Media + SEM (* = P <0,05 en comparación con el control). (C) Se determinó el GI50 para cada línea celular.

INTRODUCCIÓN El cáncer de próstata (CaP) es el segundo cáncer diagnosticado con mayor frecuencia en hombres, con 1,1 millones de casos nuevos estimados en 2012 y fue la quinta causa principal de muerte por cáncer en hombres en todo el mundo en 2012[1]. Actualmente, el CaP es el cáncer más común en los hombres, así como una de las principales causas de mortalidad relacionada con el cáncer en los Estados Unidos[2]. Según las estadísticas, uno de cada cinco hombres será diagnosticado con cáncer de próstata[2]. La quimioprevención y prevención con fitoquímicos se ha estudiado ampliamente en cánceres como el de pulmón, colon, mama y próstata. La combinación de productos naturales con el tratamiento estándar de atención es un área emergente de la terapéutica del cáncer con una multitud de beneficios, como la reducción de la dosis, el efecto sinérgico y el retraso en el desarrollo de resistencia a los medicamentos[3-5]. Se sabe que Andrographis paniculata posee una variedad de actividades farmacológicas[6-9]. Se ha informado que el componente principal de esta planta, el andrografólido, tiene potencial terapéutico contra los trastornos hepáticos, la tos y el resfriado común, las infecciones, la inflamación y el cáncer en los seres humanos[7, 8, 10 -15]. Por ejemplo, se ha

Revista Puertorriqueña de Medicina y Salud Pública

demostrado que el andrografólido inhibe el crecimiento de las células cancerosas y su inhibición del crecimiento del 50% varía de 10 a 28 μM, según el tipo de célula cancerosa analizada, que incluye las líneas celulares de cáncer humano SW620 (cáncer de colon), A498 (cáncer de riñón).), NCI / ADR-RES (cáncer de ovario), U251 (glioblastoma), HT29 (cáncer colorrectal), H522 (cáncer de pulmón), M14 (melanoma), SKOV3 (cáncer de ovario) y DU145 (cáncer de próstata)[16]. Por otra parte, informes recientes mostraron que el andrografólido, en concentraciones de 10 a 100 µM, podría inducir la apoptosis en células PC-3 de adenocarcinoma prostático humano y células HL- 60 leucémicas humanas[10, 17, 18]. Estudios anteriores también demuestran que Andrographolide posee una potente actividad anti-angiogénica y, dado que la angiogénesis juega un papel importante en la tumorigénesis, podría tener efectos terapéuticos potenciales[19, 20]. Se ha informado que otros fitoquímicos, como la curcumina, aumentan los niveles de proteínas de los asociados con el daño y la reparación del ADN, como O6-metilguanina-ADN metiltransferasa, BRCA1, mediador del punto de control 1 del daño del ADN, p-p53 y p-H2A .XSer140 en células cancerosas, lo que sugiere que estos fitoquímicos activan una respuesta al daño del ADN[21, 22]. En este estudio, evaluamos el

papel de Andrographolide en el cáncer de próstata utilizando modelos celulares y animales. Pudimos mostrar que el andrografólido disminuyó la motilidad de las células del cáncer de próstata, disminuyó la invasión y aumentó la apoptosis in vitro. Además, el andrografólido disminuyó el crecimiento del tumor de próstata, disminuyó la expresión de la metaloproteinasa 11 de la matriz (MMP11), disminuyó la angiogénesis y los genes de reparación del ADN alterados como BRCA2, ATM, BRIP1 in vivo. Además, sugerimos un posible mecanismo de acción a través del cual Andrographolide inhibe la progresión del cáncer modulando los genes de reparación del ADN. Este es, a nuestro leal saber y entender, el primer estudio que correlaciona el andrografólido con genes de reparación de ADN de doble hebra. RESULTADOS Andrografólido suprime la proliferación de líneas celulares de cáncer de próstata La actividad antiproliferativa de Andrographolide se evaluó usando líneas celulares de cáncer de próstata humano (PC3, 22RV1, LNCaP) y células de próstata humana normales (RWPE1). Las células se trataron con andrografólido 10-25 µM durante 12 horas, 24 horas y 48 horas. La viabilidad celular se midió usando el ensayo MTS. Como se muestra en la Figura 1A, Andrographolide inhibió la proliferación de PC3, 22RV1 y LNCaP en una dosis de manera dependiente. Cuando las células PC3 se trataron con Andrographolide durante 12 y 24 horas, no hubo cambios en la proliferación (Figuras complementarias 1 y 2). Sin embargo, Andrographolide inhibió el crecimiento de células PC3 a las 48 horas de tratamiento (Figura 1A). Las células 22RV1 y LNCaP tratadas con andrografólido durante 12 horas no mostraron cambios en la proliferación (Figuras complementarias 3 y 4). Sin embargo, el andrografólido inhibió la proliferación celular de las células 22RV1 y LNCaP después de 24 horas de tratamiento. (Figura 1A). En consecuencia, los valores de GI50 de Andrographolide se determinaron para las células PC3, 22RV1 y LNCap como 26,2, 24,2 y 28,1 μM, respectivamente (Figura 1B,

1C). Para determinar si el andrografólido era tóxico para las células normales, realizamos el ensayo MTS usando células RWPE1. El andrografólido no inhibió el RWPE1 a las dosis probadas, por lo que no es tóxico para las células prostáticas humanas normales. El andrografólido disminuye la migración y la invasión de las células del cáncer de próstata. Investigamos el efecto de Andrographolide sobre la capacidad de migración de las células PC3 utilizando la herida-ensayo de migración de curación. Para ello, se hirió una monocapa confluente de células PC3 y se dejó migrar durante 12 horas y 24 horas (Figura 2A). A las 12 y 24 horas, la migración de las células PC3 se redujo significativamente en un 10% y un 15%, respectivamente, en las células tratadas con Andrographolide (25 μM) en comparación con el control (P <0,05) (Figura 2B). Las células PC3 tratadas con Andrographolide durante 12 y 24 horas no mostraron una disminución en la proliferación. Así, las células PC3 presentan una inhibición de su capacidad migratoria y no debido a cambios en la proliferación. Las células 22RV1 no se utilizaron para el ensayo de migración porque no crecen en una monocapa confluente. Dado que se ha descubierto que Andrographolide inhibe la invasión celular en otros cánceres, decidimos examinar el efecto de Andrographolide en la invasión celular en el cáncer de próstata utilizando PC3 independiente de andrógenos. El ensayo se realizó utilizando la cámara de Boyden durante 12 hr y 24 hr de tratamiento. Los resultados muestran que Andrographolide (25 μM) redujo la invasión de células PC3 en un 50% después de 12 horas y en un 40% después de 24 horas (Figura 2C, 2D). No se observó una disminución significativa en la línea celular 22RV1 (Figura 5 complementaria). Andrografólido promueve la apoptosis en las células del cáncer de próstata Para evaluar si la disminución de la viabilidad celular también estuvo acompañada de un aumento de la apoptosis, se probaron si andrografólido induce apoptosis en células de cáncer de próstata PC3 y 22RV1. Las células PC3 se trataron con Andrographolide

(25 µM) durante 24 hy 48 h, seguido de un análisis de citometría de flujo para anexina-V. Se observó un aumento del 50% en células apoptóticas después de 48 horas de tratamiento en células PC3 (Figura 3A). Además, la actividad de la caspasa 3/7 se midió por luminiscencia en PC3 y Células 22RV1. Después de 24 horas de tratamiento, se observó un aumento significativo de la actividad de la caspasa 3/7 en la línea celular PC3 (Figura 3B). No se observó ningún aumento significativo en la línea celular 22RV1 (datos no mostrados). Andrografólido inhibe la progresión del ciclo celular Para evaluar la viabilidad y la proliferación de las células PC3, se evaluó la inhibición de la progresión del ciclo celular con andrografólido 25 μM a las 24 y 48 horas en células PC3 mediante citometría de flujo. Las células PC3 tratadas con Andrografólido mostraron una disminución significativa en el número de células en la fase G1 / G0 después de 48 horas de tratamiento y un aumento de la población celular en la fase G2 / M después de 48 horas de tratamiento. (P <0,05). Estos resultados sugieren una detención del ciclo celular en la fase G2 / M (Figura 3C). Para este ensayo, las células 22RV1 no se evaluaron porque crecen en grupos. Andrografólido inhibe la progresión del tumor de próstata en ratones SCID Para probar el efecto del andrografólido sobre la progresión del tumor de próstata, se utilizó un modelo ortotópico SCID para desarrollar tumores en los lóbulos de la próstata anterior utilizando células 22RV1. Una semana después de la inyección de células, los ratones fueron tratados 3 veces por semana, mediante inyecciones intraperitoneales, con vehículo o 10 mg / kg de andrografólido durante cuatro semanas. Los ratones tratados con Andrographolide 10 mg / kg desarrollaron tumores más pequeños en comparación con los tumores de control. Los tumores tratados con Andrographolide 10 mg / kg tenían tres veces menos tumor que los tumores de control (Figura 4A, 4B). Se utilizaron análisis patológicos, histológicos e inmunohistoquímicos de tejido tumoral recolectado para estudiar el efecto del andrografólido en la biología Revista Puertorriqueña de Medicina y Salud Pública

tumoral. Los portaobjetos fueron examinados por un patólogo a baja, media y alta potencia bajo un microscopio óptico compuesto. La evaluación del tumor se realizó según lo descrito por Isaacs y Hukku [23]. Los tumores fueron clasificados en cuatro categorías por grado de diferenciación: bien diferenciado, moderadamente diferenciado, poco diferenciado y anaplásico. Los tumores bien diferenciados se caracterizan por la presencia de estructuras glandulares, luz, membrana basal y estroma. Los tumores moderadamente diferenciados se caracterizan por estructuras glandulares más pequeñas con la luz obstruida por el tumor. Sin embargo, la membrana basal y el estroma permanecieron intactos. Los tumores clasificados como poco diferenciados tienen ausencia de estructuras glandulares, membrana basal y no muestran una relación consistente entre las células tumorales y el estroma. Sin embargo, las células tumorales individuales todavía muestran una proporción normal de núcleo a citoplasma. Los tumores clasificados como anaplásicos carecen de apariencia de tejido. La organización y las células tumorales individuales muestran un tamaño de núcleo irregular y una proporción anormal de núcleo a citoplasma. Todas las muestras de tumores, independientemente del tratamiento, se clasificaron como histológicamente anaplásicas y no mostraron diferencias significativas entre los tratamientos (Figura 4C). Andrografólido disminuye la expresión de M MP11 proliferación y formación de vasos sanguíneos in vivom el efecto de Andrographolide sobre MMP11 fue evaluado para determinar si la expresión de este proteína, involucrada en la descomposición de extracelulares matriz, también se vio afectada por Andrographolide. Para esto, realizamos un ensayo inmunohistoquímico. Nosotros encontramos 18

Figura 2: Andrographolide disminuyó la migración e invasión de células PC3. (A) Se hirió la monocapa confluente de células PC3 rascándola con la punta de una pipeta y se incubaron con o sin andrografólido durante 0, 12 y 24 horas. Se tomaron microfotografías de PC3 tratado con Andrographolide a las 0, 12 y 24 horas. (B) La cuantificación del porcentaje de migración mostró que el andrografólido redujo significativamente la migración celular a las 12 y 24 horas en comparación con el control. (C) Para evaluar el efecto del andrografólido en la invasión, las células PC3 se incubaron durante 12 horas y 24 horas con o sin andrografólido. La invasión se evaluó mediante el método de la cámara de Boyden. Se tomaron microfotografías de PC3 tratado con Andrographolide durante 12 horas y 24 horas. (D) Andrographolide redujo significativamente la invasión celular. Los experimentos se realizaron por triplicado. El análisis estadístico se realizó mediante la prueba t. Media + SEM (* P <0,05).

una disminución en la expresión de MMP11 en tumores tratados (Andrographolide 10 mg / kg) en comparación con el control (Figura 4D). La expresión de los marcadores de proliferación.pH3 and Ki-67 were evaluated to determine the effect of Andrographolide in this cancer hallmark. In this study, we found that Andrographolide decreased the expression of pH3 and Ki-67 in mice tumors when compared to control (Figura 4E). Además, uno de los sellos distintivos del cáncer, angiogénesis, es esencial para la progresión del cáncer ya que la formación de nuevos vasos sanguíneos ayuda a que los tumores crezcan. Para probar el efecto de Andrographolide en la formación de vasos sanguíneos, la expresión de CD31 se midió mediante inmunofluorescencia. En nuestro estudio disminuyó la formación de vasos sanguíneos en tumores de ratones tratados con 10 mg / kg. Se observó andrografólido en comparación con los tratados con control (Figura 5). El andrografólido altera los genes asociados con el compromiso celular, el ciclo celular y la recombinación, replicación y reparación del ADN. El análisis de microarrays se realizó utilizando muestras de tumores de ratones para identificar el efecto de Andrographolide

Revista Puertorriqueña de Medicina y Salud Pública

10 mg / kg de expresión génica. El tratamiento con andrografólido 10 mg / kg alteró significativamente la expresión de 675 genes clasificados en tres amplias funciones moleculares y celulares: compromiso celular, ciclo celular y “recombinación, replicación y reparación del ADN”. Entre la categoría de recombinación, replicación y reparación del ADN, los siguientes genes fueron representado: ATM serina / treonina quinasa (ATM), síndrome de Bloom, RecQ helicasa similar (BLM), cáncer de mama 2, inicio temprano (BRCA2), proteína de interacción BRCA1 Helicasa C-terminal 1 (BRIP1), Claspin (CLSPN), Nibrin (NBN) y socio y localizador de BRCA2 (PALB2) (Tabla 1). Una característica común de estos genes es que están asociados con la vía de reparación de roturas de doble hebra. Para validar que la expresión de este grupo de genes se ve afectada por Andrographolide, realizamos ensayos de PCR en tiempo real. Observamos un aumento en la expresión de genes de reparación de rotura de doble hebra: ATM serina / treonina quinasa (ATM), síndrome de Bloom, RecQ helicasa como (BLM), cáncer de mama 2, inicio temprano (BRCA2), proteína C-terminal que interactúa con BRCA1 helicasa 1 (BRIP1), Nibrina (NBN), socio y localizador de BRCA2 (PALB2) (Tabla 1). Andrographolide aumentó significativamente la expresión de ATM, BRCA2, BRIP1, CLSPN y NBN.

Además, también se observó un aumento en la expresión de los genes BLM y PALB2 en tumores tratados con Andrographolide. (Figura 6). Los cebadores utilizados para la confirmación por PCR en tiempo real se enumeran en la Tabla 2. El andrografólido aumenta la fosforilación de la histona H2A en las células del cáncer de próstata Se realizaron estudios de inmunofluorescencia en células 22RV1, PC3 y normales (RWPE1) para determinar el efecto del andrografólido en los niveles de histona H2AX fosforilada (γH2AX), un marcador de roturas de doble hebra del ADN [24]. Encontramos que, 24 horas después del tratamiento con Andrographolide (25 μM), hubo un aumento significativo de 1,6 veces en γH2AX en la línea celular 22RV1 (Figura 7A, 7B). Estos resultados indican que Andrographolide induce roturas de doble cadena del ADN. Para las células PC3, encontramos que hubo un aumento de 0,6 veces en γH2AX cuando se trataron con Andrographolide durante 24 horas (Figura 7C, 7D). Para las células de próstata normales, encontramos que Andrographolide no tiene ningún efecto en los niveles de γH2AX (Figura 7E, 7F). El andrografólido induce daño al ADN en las células PC3 Para evaluar más a fondo la presencia de daño en el ADN en las células tratadas con andrografólido, utilizamos un método de citometría de flujo que detecta ATM fosforilada y γH2AX. El daño al ADN se expresa como el porcentaje de células que muestran simultáneamente ambos marcadores. Las células PC3 tratadas con andrografólido 25 μM durante 24 horas muestran un aumento significativo en el daño del ADN en comparación con las células de control (Figura 8). Para este ensayo, las células 22RV1 no se evaluaron porque crecen en grupos y no pueden ser procesadas por el citómetro de flujo. DISCUSIÓN Se ha demostrado que la andrografólida, cuyo componente principal es la lactona diterpénica, posee propiedades antitumorales. Sin embargo, su mecanismo de acción no se comprende completamente. Se ha observado que Andrographolide inhibe la proliferación de células cancerosas, induce la detención del ciclo celular y promueve la apoptosis[18, 25, 26] . Estudios anteriores demostraron el

potencial de Andrographolide como agente quimiopreventivo al suprimir el crecimiento de las células cancerosas al inhibir NF-κB, PI3K / AKT y otras vías de quinasas e inducir apoptosis[8, 27]. En el cáncer de próstata, se sabe que el andrografólido inhibe las células, viabilidad y migración celular modulando la expresión de CXCL11, CXCR3, CXCR7 e IL-16[28, 29]. Sin embargo, no se ha dilucidado el papel de Andrographolide en la progresión del CaP. En este trabajo, evaluamos los efectos de Andrographolide en CaP usando in vitro e in vivo modelos. Nos centramos en la migración celular, la invasión, el crecimiento tumoral, la proliferación, la angiogénesis, los cambios en la expresión génica y la reparación del ADN. Evaluamos la eficacia de Andrographolide in vitro usando líneas celulares PC3, 22RV1 LNCaP PCa y células de próstata RWPE1. El andrografólido exhibe actividad antiproliferativa en estas células de una manera dependiente de la dosis. Los LNCaP son menos sensibles a este compuesto, en comparación con las células PC3 y 22RV1. Por lo tanto, el andrografólido tiene el potencial de dirigirse a las células CaP que son de naturaleza agresiva. Por el contrario, las mismas dosis no inhibió la proliferación de RWPE1, una línea celular derivada de células prostáticas humanas normales. Observamos que la población celular se mantuvo constante a dosis más altas. Esto sugiere fuertemente que Andrographolide no es tóxico para las células normales de la próstata. La resistencia de las células no cancerosas al andrografólido requerirá un estudio adicional, pero esta característica refuerza la justificación del uso del andrografólido como agente quimioterapéutico. Observamos que el andrografólido inhibe la motilidad y la invasión de las células cancerosas en las células cancerosas de la próstata. Además, los resultados muestran que el andrografólido induce la apoptosis celular a través de cambios en la actividad de la caspasa 3/7. Los estudios han demostrado que la proteína TRAIL es capaz de iniciar la apoptosis mediante la activación de las caspasas-3 y -7[30, 31]. Nuestros resultados muestran que el andrografólido puede frenar la proliferación y estimular la apoptosis en células agresivas de cáncer de próstata específicamente en insensibles a los andrógenos (AI) celular (PC3) ya que las células cancerosas que experimentan la activación del receptor de andrógenos (AR) pueden causar proliferación y bloquear la apoptosis[32]. Además, se llevó a cabo una

Figura 3: Andrographolide aumentó la apoptosis y disminuyó el ciclo celular en las células PC3. Las células PC3 se incubaron durante 24 horas y 48 horas con o sin andrografólido. (A) Se evaluó la apoptosis de las células PC3 usando citometría de flujo (Anexina-V) después de 48 horas y midiendo la actividad de Caspasa 3/7 después de 24 horas. El andrografólido aumentó significativamente la anexina-V en las células PC3 en comparación con el control. (B) El andrografólido aumentó significativamente la actividad relativa de Caspasa 3/7 en la línea celular PC3 en comparación con el control. (C) El ciclo celular se evaluó mediante citometría de flujo en células PC3. El andrografólido (25 μM) redujo significativamente la población celular en la fase G1 / G0 y aumentó la población celular en la etapa G2 / M después de 48 horas de tratamiento. Los experimentos se realizaron por triplicado. El análisis estadístico se realizó mediante la prueba t. Media + SEM (* P <0,05).

Revista Puertorriqueña de Medicina y Salud Pública

citometría de flujo con tinción con anexina V para cuantificar las células apoptóticas. Se observó un aumento de células apoptóticas en pacientes tratados con PC3. Este resultado validó aún más que Andrographolide podría inhibir el crecimiento de células de cáncer de próstata y p ost eriorment e inducir apoptosis. El daño del ADN es un evento molecular que está estrechamente asociado con la detención del ciclo celular y la apoptosis. Hasta la fecha, varios estudios han demostrado que el andrografólido induce eficazmente la detención del ciclo celular en la etapa G0 / G1 en la mayoría de las células cancerosas [10, 33] . Nuestros hallazgos muestran que el andrografólido disminuyó la población celular en la etapa G0 / G1 pero aumentó la población celular en la fase G2 / M. Esta detención puede deberse a que las diferentes actividades de la quinasa dependiente de ciclina (CDK) están reguladas con la asociación de sus parejas de ciclina, quinasas, fosfatasas e inhibidores específicos[34]. La desregulación de ciclinas (D & E) y cdks (2,4 y 6) puede resultar en un crecimiento anormal de células, ya que juegan un papel importante en la progresión de las células a través de la fase G0 / G1 del ciclo celular [35]. Por lo tanto, se necesitan más investigaciones para examinar el mecanismo detallado de la detención del ciclo celular en pacientes tratados con andrografólido, Células de cáncer de próstata PC3. Dado que se ha demostrado que la andrografólida reduce el volumen tumoral de mama, riñón, melanoma y pulmón[3639] , realizamos estudios in vivo. Nuestros datos in vivo mostraron una disminución significativa en los tumores tratados con Andrographolide. La diferenciación, invasión y metástasis tumorales están controladas por múltiples factores durante los procesos de múltiples 20

Figura 4: Andrografólido disminuyó el crecimiento tumoral, la expresión y la proliferación de MMP11. El crecimiento tumoral se evaluó utilizando un modelo ortotópico. Los lóbulos de próstata anteriores se inyectaron con células 22RV1. Se permitió que los tumores se desarrollaran durante 4 semanas y se administró andrografólido tres veces por semana con inyecciones intraperitoneales. El volumen del tumor se determinó con calibre mediciones. (A) Las imágenes representativas de los tumores muestran diferencias de tamaño. (B) Cuantificación del volumen tumoral. Ncontrol = 6, NAndrographolide = 6. Media + SEM (* P <0,05). (C) Imágenes representativas de tumores con vehículo y Andrographolide 10 mg / kg para hematoxilina y eosina (H & E) (D) Medimos la expresión de MMP11 en tumores tratados con Andrographolide 10 mg / kg y control. (E) Se evaluó la expresión de pH3 y Ki-67 en tejido tumoral 22RV1. Vehículo a la izquierda; Andrographolide 10 mg / kg a la derecha. El andrografólido 10 mg / kg redujo la proliferación celular in vivo. El análisis estadístico se realizó mediante la prueba t. Media + SEM (* P <0,05).

Figura 5: Andrografólido disminuyó la expresión de CD31. (A) Se evaluó la expresión de CD31 en tejido tumoral 22RV1. Vehículo a la izquierda; Andrographolide 10 mg / kg a la derecha. Los núcleos se tiñen de azul y los vasos sanguíneos se tiñen de rojo. (B) El andrografólido redujo significativamente la expresión de CD31. Los experimentos se realizaron por triplicado. El análisis estadístico se realizó mediante la prueba t. Media + SEM (* P <0,05).

etapas de composición y degradación de la matriz extracelular (MEC)[40]. Además, los nuevos vasos sanguíneos tumorales secretan varias enzimas proteolíticas que se suman a la compleja imagen de la progresión tumoral. Dado que la metaloproteinasa 11 de la matriz (MMP11) pertenece a un grupo de proteasas dependientes de zinc involucradas en la ECM y la degradación de la membrana basal, medimos su expresión en tumores tratados con Andrographolide[41, 42]. Las MMP promueven

Revista Puertorriqueña de Medicina y Salud Pública

la formación de nuevos vasos sanguíneos y están involucradas en numerosos procesos asociados con el crecimiento, diferenciación, invasión, difusión y metástasis de las células tumorales[41, 42]. Nuestros resultados muestran que Andrographolide disminuye la expresión de MMP11 en el tejido tumoral. Además, nuestros resultados muestran que Andrographolide disminuye el número de vasos sanguíneos, lo que confirma la inhibición observada en el crecimiento tumoral. La contribución de las MMP a la

Figura 6: Andrografólido 10 mg / kg de genes alterados asociados con la reparación del ADN. Resultados de PCR en tiempo real para: ATM serina / treonina quinasa (ATM), síndrome d e Bloom, RecQ helicasa similar (BLM), cáncer de mama 2, inicio temprano (BRCA2), proteína C-terminal de interacción BRCA1 helicasa 1 (BRIP1), Nibrina (NBN) ), socio y localizador de BRCA2 (PALB2). Los experimentos se realizaron por triplicado. El análisis estadístico se realizó mediante la prueba t. Media + SEM (* P <0,05).

angiogénesis no se debe solo a la degradación de la membrana basal que hace que las células endoteliales se desprendan y migren a nuevos tejidos, sino también a la liberación de factores proangiogénicos, unidos a la ECM, como bFGF, VEGF y TGFβ [43]. Además, medimos si Andrographolide inhibió la perfilación in vivo. Observamos que Andrographolide 10 mg / kg disminuyó la expresión de pH3 y Ki-67 en el tejido tumoral. Estos hallazgos son importantes ya que la proliferación es uno de los sellos distintivos del cáncer. Una de las principales mutaciones en el cáncer de próstata incluye el gen PTEN. Se sabe que la pérdida de función en PTEN amplifica la señalización de PI3K y promueve la tumorigénesis en una variedad de modelos experimentales de cáncer. Aunque descubrimos que el andrografólido detiene el ciclo celular en la fase G2 / M, será necesario realizar más estudios para comprender el mecanismo específico por el cual se produce el andrografólido disminuyendo estos dos marcadores de proliferación. Nuest ros exp erimentos de microarrays y PCR en tiempo real indican que el andrografólido induce la expresión de genes

asociados con la reparación de la rotura del ADN de doble hebra en tumores. La expresión de ATM serina / treonina quinasa (ATM), síndrome de Bloom, RecQ helicasa similar (BLM), cáncer de mama 2, inicio temprano (BRCA2), proteína C-terminal que interactúa BRCA1 helicasa 1 (BRIP1), Nibrin (NBN), socio y el localizador de BRCA2 (PALB2) se incrementó en tumores tratados con Andrographolide 10 mg / kg. Se ha sugerido que el BRIP1 puede tener un papel anti-oncogénico, y se ha observado su regulación a la baja en múltiples tipos de cáncer[44]. Dado que BRIP1 tiene una función esencial en la regulación de la progresión del ciclo celular normal y la reparación del ADN, el gen BRIP1 representa un buen candidato para la predicción de la susceptibilidad genética al cáncer[45-48]. Nuestros resultados muestran que Andrographolide aumentó la expresión de BRIP1. BRCA2 juega un papel limitado en los procesos de reparación y recombinación del ADN, pero parece ser un actor clave en la regulación de la actividad de la recombinasa RAD51, una proteína involucrada en la reparación de roturas del ADN bicatenario [49-51]. Demostramos

Figura 7: Andrographolide aumentó la expresión de histona fosfo-H2AX en células de cáncer de próstata. Para evaluar el efecto de Andrographolide en fosfo-H2AX, un marcador de rotura de ADN de doble hebra, 22RV1, PC3 y células prostáticas normales se trataron con 25 μM de Andrographolide y se incubaron durante 24 horas. (A) Imágenes representativas de tinción con fosfo-H2AX para células 22RV1 tratadas con Andrographolide. Vehículo (panel izquierdo); Andrographolide 25 μM (panel derecho). Los núcleos se tiñen con DAPI (azul) y el fosfo-H2AX se tiñe de rojo. (B) El análisis estadístico muestra que el fosfo-H2AX aumentó significativamente en las células 22RV1 cuando se trataron con Andrographolide. (C) Representantes de imágenes de tinción con fosfo-H2AX para células PC3 tratadas con Andrographolide. Vehículo (panel izquierdo); Andrographolide 25 μM (panel derecho). Los núcleos se tiñen con DAPI (azul) y el fosfo-H2AX se tiñe de rojo. (D) El análisis estadístico muestra que el fosfo-H2AX aumentó en las células PC3 cuando se trataron con Andrographolide. (E) Imágenes representativas de tinción con fosfo-H2AX One para células de próstata normal (RWPE1) tratadas con Andrographolide. Vehículo (panel izquierdo); Andrographolide 25 μM (panel derecho). Los núcleos se tiñen con DAPI (azul) y el fosfo-H2AX se tiñe de rojo. (F) El análisis estadístico muestra que los niveles de fosfo-H2AX no cambiaron en las células RWPE1 cuando se trataron con Andrographolide. Los experimentos se realizaron por triplicado. El análisis estadístico se realizó mediante la prueba t. Media + SEM (* P <0,05). Revista Puertorriqueña de Medicina y Salud Pública

que El andrografólido aumentó la expresión del gen BRCA2. Además, nuestros resultados muestran que Andrographolide aumentó la expresión de ataxiatelangiectasia mutada (ATM) en tumores de próstata. ATM es una proteína quinasa de serina / treonina que pertenece a la familia PI3K y funciona como un mediador clave de la respuesta al daño del ADN e induce la detención del ciclo celular[52]. NBN funciona en combinación con las proteínas RAD50 y MRE11 para formar el complejo MRN, responsable de la detección de DSB y la activación posterior de los mecanismos de reparación[53]. En consecuencia, se espera NBN para actuar como un gen supresor de tumores mediante el reclutamiento de ATM [53]. Curiosamente, se demostró que este gen aumenta p or Andro grapholide en tumores. Por otro lado, es bien sabido que las mutaciones BLM conducen al síndrome de Bloom, una enfermedad caracterizada por retraso del crecimiento y predisposición al cáncer [54, 55]. Por lo tanto, una mayor expresión de este gen será esencial para reducir la predisposición al cáncer. Demostramos que Andrographolide aumentó la expresión del gen BLM. PALB2 se encontró como un gen supresor de tumores [56]. En consecuencia, encontramos que Andrographolide aumentó la expresión de este supresor de tumores. Determinamos el estado de fosforilación de la histona H2AX (γH2AX) para confirmar un aumento en las roturas de doble hebra ya que γH2AX funciona como un indicador temprano de las roturas de la doble hebra del ADN (DSB) y de la respuesta resultante (respuesta al daño del ADN [DDR]) [24, 57]. La histona H2AX es un sustrato de varias proteínas quinasas relacionadas con la fosfoinositido 3-quinasa (PIKK), como la ATM, que se considera un mediador fisiológico importante de la fosforilación de H2AX en respuesta a la 22

Figura 8: Andrographolide aumenta el daño del ADN en las células PC3. Las células se incubaron con Andrographolide 25 µM o vehículo (Control) durante 24 horas. El daño del ADN se determinó con un enfoque de citometría de flujo que detecta células que expresan simultáneamente ATM fosforilada y γH2AX. El daño del ADN se presenta en relación con las células de control, que se establece en 1. Los experimentos se realizaron por triplicado. El análisis estadístico se realizó mediante la prueba t. Media ± SEM (* P <0,001).

formación de DSB [58]. Encontramos que Andrographolide aumentó significativamente γH2AX en células 22RV1. Este hallazgo está de acuerdo con el aumento de la expresión de genes de reparación de ADN de rotura de doble cadena después de Andrographolide que informamos. Además, utilizando un método que detecta simultáneamente ATM fosforilada y γH2AX, observamos que Andrographolide induce daño al ADN en las células PC3. Se sabe que la ATM fosforila la quinasa del punto de control 2 (CHK2), que a su vez fosforila el supresor de tumores p53, interrumpiendo su unión a su regulador negativo MDM2. Esto da como resultado la estabilización de la proteína p53 y permite que p53 medie su efecto aguas abajo en la supresión del crecimiento celular [59, 60]. En consecuencia, la activación de los puntos de control del ciclo celular mencionados anteriormente puede dar como resultado la supresión del crecimiento celular y la activación de la apoptosis. Se ha observado que el estado funcional de p53 es importante en la progresión del cáncer de próstata y su respuesta al tratamiento. Se sabe que las células dependientes de andrógenos, 22RV1, tienen la presencia de p53 de tipo salvaje, mientras que se sabe que las células PC3, independientes de andrógenos, son nulas para p53 [61]. Esto puede explicar nuestros hallazgos donde

Revista Puertorriqueña de Medicina y Salud Pública

Andrographolide disminuyó la proliferación de células PC3 después de 48 horas, pero después de 24 horas para la línea 22RV1. En resumen, evaluamos varios sellos distintivos del cáncer como la proliferación, la motilidad celular, el crecimiento tumoral, la angiogénesis y los cambios a nivel genético. Es importante destacar que observamos que Andrographolide aumentó los genes asociados con la reparación del ADN de doble hebra. Este aumento puede explicar el mecanismo por el cual Andrographolide induce una respuesta al daño del ADN que implica supresión del crecimiento celular, detención del ciclo celular y apoptosis. Específicamente, la activación de ATM dependiente de rotura de doble hebra del ADN puede resultar en la activación de p53, que resulta en apoptosis y detención del ciclo celular. Tomados en conjunto, hemos demostrado que Andrographolide es un compuesto anticancerígeno eficaz para el cáncer de próstata al regular genes asociados a roturas de doble cadena como ATM, NBN, BRCA2 BLM, PALB2 y BLM. Este hallazgo innovador es esencial para comprender el mecanismo de acción del andrografólido en el cáncer de próstata. Se necesitan más estudios para delinear los mecanismos por los cuales Andrographolide suprime la progresión del cáncer de próstata in vivo.

TABLA 1: ANÁLISIS DE MICROARRAYS: GENES ASOCIADOS CON EL CICLO CELULAR Y LA REPARACIÓN DEL ADN ALTERADOS POR ANDROGRAPHOLIDE IN VIVO SÍMBOLO GENÉTICO

DESCRIPCIÓN

CAMBIO DE PLIEGUE

VALOR P

Q VALOR DE PCR-P

ATM

ATM serina / treonina quinasa

2.14

3.07E-02

2.15E-02

BLM

Síndrome de BLM Bloom, RecQ similar a la helicasa

2.49

3.15E-02

3.21E-01

BRCA2

BRCA2 Cáncer de mama 2, inicio temprano

2.23

3.90E-02

1.50E-03

BRIP 1

BRCA1 interactuando proteína C-terminal helicasa 1

2.08

4.35E-02

2.30E-02

CLSPN

Claspin

2.06

2.91E-02

4.28E-02

NBN

Nibrina

2.16

2.94E-02

2.10E-02

PALB2

Socio PALB2 y localizador de BRCA2

2.99

2.47E-03

2.04E-01

MATERIALES Y MÉTODOS Cultivo de células Las células de cáncer de próstata humanas independientes de andrógenos PC3, las células de cáncer de próstata humanas dependientes de andrógenos 22RV1 y LNCaP y las células de próstata humanas normales RWPE-1 se adquirieron de Colección de cultivos (ATCC), (Manassas, VA, EE. UU.). Las líneas celulares PC3, 22RV1 y LNCaP se mantuvieron en Medio RPMI-1640 con L-glutamina (Hyclone, MA, EE. UU.) Suplementado con suero bovino fetal (FBS) al 10%, penicilina 100 U / ml y estreptomicina 100 μg / ml (Gibco, Carlsbad, CA, EE. UU.). Las células RWPE1 se mantuvieron en queratinocitos-SFM suplementado con L-glutamina, 0,05 mg / ml de extracto de pituitaria bovina (BPE) y 5 ng / ml de factor de crecimiento epidérmico (EGF) (Gibco, NY, EE. UU.). Las células se mantuvieron en una atmósfera humidificada con CO2 al 5% a 37 ° C. Solución de andrografólido El andrografólido se obtuvo de Sigma-Aldrich (Saint Louis, MO, EE. UU.), Se disolvió en dimetilsulfóxido (DMSO) a una concentración de 100 mM y luego se diluyó con medio de crecimiento completo hasta la concentración final deseada. Las muestras tratadas con DMSO solo se utilizaron como vehículo.

Viabilidad celular La viabilidad y la proliferación celular se evaluaron utilizando CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) (Promega, Madison, WI, EE. UU.) y se utilizó de acuerdo con las instrucciones del fabricante. Se cultivaron un total de 10.000 células por pocillo de PC3, 22RV1, LNCaP y RWPE1 en una placa de 96 pocillos múltiples. Después las células de 24 horas de incubación se trataron con DMSO (control) y Andrographolide a concentraciones de 10, 15, 20 y 25 µM en medio completo fresco. Se añadió reactivo MTS a las 24 y 48 horas de tratamiento y se incubó durante 2 horas. La absorbancia se midió a 490 nm usando un espectrofotómetro de absorbancia de microplacas xMark (BIORAD, EE. UU.). El GI50 se determinó calculando el porcentaje de inhibición como [(C-T) / C] × 100 (C = control; T = tratamiento) y usando la ecuación de pendiente y = mx + b donde y = 50. El experimento se llevó a cabo por triplicado y los datos se analizaron utilizando GraphPad Prism ANOVA seguido de la comparación de Dunnett con un intervalo de confianza del 95%. Ensayo de migración celular La migración celular se evaluó utilizando el método de raspado (cicatrización de heridas). Las células PC3 se cultivaron en placas de cultivo de tejidos de 6 pocillos hasta una confluencia del 95%. Se hizo un rasguño a través de la monocapa confluente utilizando una punta de

pipeta de plástico estéril de 200 μL. Las células se lavaron suavemente con PBS y se incubaron a 37ºC en RPMI-1640 suplementado con suero bovino fetal al 10% en presencia de vehículo (DMSO) o Andrographolide (25 µM). Las células se fotografiaron con un microscopio Nikon Eclipse TS100 (Nikon, Tokio, Japón) a las 12 y 24 horas de tratamiento con un aumento de 4 ×. Se obtuvieron y analizaron un total de 10 mediciones de distancia dentro de cada herida utilizando el software Image Pro Plus. Las diferencias en el cierre de la herida se normalizaron a 0 horas según el tratamiento y se compararon con el control mediante la prueba T de Student con un intervalo de confianza del 95%. Todos los experimentos fueron realizados por triplicado. Ensayo de invasión celular Se sembraron células PC3 y 22RV1 (4 × 104 / pocillo) en la cámara superior de un sistema transwell (Corning Incorporated, NY, EE. UU.) En medio sin suero, con o sin andrografólido (25 μM) e invasión El ensayo se llevó a cabo de acuerdo con las instrucciones del fabricante. Se añadió medio que contenía suero a la cámara inferior para que actuara como atrayente quimiotáctico. A las 12 y 24 horas de incubación, se retiró la cámara superior y las células no migradas se retiraron con PBS. Las células que migraron a través de la membrana se Revista Puertorriqueña de Medicina y Salud Pública

TABLA 2: SECUENCIAS DE CEBADORES PARA EL ANÁLISIS DE QRTPCR DE GENES AFECTADOS POR ANDROGRAPHOLIDE IN VIVO PRIMER SENTIDO ANTISENTIDO PRIMER

SENSE

ANTISENSE

BRCA2

5'-GAAGCCCTTTGAGAGTGGAA-3'

5'-CTCCATCTGGGCTCCATTTAG-3'

ATM

5'-TGCACTGAAAGAGGATCGTAAA-3'

5'-CAGAGGGAACAAAGTCGGAATA-3'

NBN

5'-CCACACATCATTGGAGGATCA-3'

5'-GTACCTCCATTTCCTGCCTTAG-3'

BRIP1

5'-CAGCTGGAGGCTAATCATATC-3'

5'-CTGGAAGGTAGCACAGAGATTC-3'

CLSPN

5'-GGAGGAGGAATTTGGAGACTTT-3'

5'-TCTTCCAGTGCCAGATCATTAC-3'

BLM

5'-CAGGATGGCTGTCAGGTTATC-3'

5'-GGTAGTAACCCTCCACAGATTTAG-3'

PALB2

5'-CTGGAAGGTGACGTGAAAGA-3'

5'-CAGTACACTGACCGAGAAGTAAG-3'

fijaron con formalina al 10%, se tiñeron con hematoxilina durante la noche, se lavaron con agua desionizada y estas membranas se montaron en portaobjetos. Fotografías con un aumento de 4 × fueron capturados con un microscopio Nikon Eclipse TS100 (Nikon, Tokio, Japón). El número de células invasoras se contó utilizando el software Image Pro Plus. Los resultados se analizaron mediante la prueba T de Student con un intervalo de confianza del 95%. Todos los experimentos fueron realizados por triplicado. Citometría de flujo Los ensayos de ciclo celular, apoptosis y daño del ADN se realizaron usando citometría de flujo con el instrumento Muse® Cell Analyzer (EMD Millipore Merck KGaA, Darmstadt, Alemania). El ciclo celular se ensayó incubando células PC3 (2,5 × 106 células / ml) con DMSO (control) o Andrographolide (25 μM) durante 24 y 48 horas y las células (desprendidas y adheridas) se recogieron y fijaron con etanol al 70%. El kit de ensayo de ciclo celular Muse® se utilizó siguiendo las instrucciones del fabricante. Se utilizó anexina-V para determinar la apoptosis en la línea celular PC3. Las células (1 x 107 células / mL) se incubaron con DMSO (control) o Andrographolide durante 24 y 48 horas y todas las células (desprendidas y unidas) se teñido con el kit Muse® Annexin-V siguiendo las instrucciones del fabricante. Se analizó el daño del ADN 24

incubando células PC3 con DMSO o andrografólido 25 µM durante 24 horas y las células se recogieron, fijaron y permeabilizaron. Las células se evaluaron utilizando el kit MuseTM Multi-Color DNA Damage siguiendo las instrucciones del fabricante. Los experimentos se realizaron por triplicado y los datos se analizaron usando la prueba t de Student GraphPad Prism con un intervalo de confianza del 95%. Ensayo de apoptosis Se midió la actividad de caspasa 3/7 para evaluar la apoptosis en líneas celulares PC3 y 22RV1. Un total de 10,000 se sembraron células por pocillo en una placa de 96 pocillos de paredes blancas. Después de 24 horas de incubación, las células se trataron con DMSO (control) y Andrographolide (10, 15, 20 y 25 µM) en medio completo fresco. Después del tratamiento, se añadió el reactivo Caspase-Glo 3/7 y se incubó a temperatura ambiente durante 60 min. Las actividades de caspasa3/7 se determinaron cuantificando la luminiscencia. Experimentos se realizaron por triplicado y los datos se analizaron utilizando GraphPad Prism ANOVA seguido de la comparación de Dunnett con un intervalo de confianza del 95%. Modelo de ratón ortotópico Todos los estudios en animales se llevaron a cabo de acuerdo con el Comité Institucional de Uso y Cuidado de Animales regulaciones. Se alojaron ratones ICR-SCID macho de siete a ocho semanas (Taconic, Germantown, NY, EE.

Revista Puertorriqueña de Medicina y Salud Pública

UU.) y mantenido en una instalación para animales libre de patógenos. Se utilizó un modelo de xenoinjerto ortotópico en el que se inyectaron 22RV1 (250.000 células) en los lóbulos anteriores de la próstata. Las células suspendidas en PBS se colocaron en 30 µl de colágeno I (Becton Dickinson, Franklin Lakes, NJ, EE. UU.), se dejaron solidificar ligeramente y se inyectaron en los lóbulos prostáticos anteriores. Los ratones se inyectaron intraperitonealmente tres veces por semana. con Andrographolide (10 mg / kg) o vehículo (solución salina). Después de 4 semanas de tratamiento, los tumores se recogieron, midieron y fijaron en formalina tamponada al 10% o se congelaron. Tinción con hematoxilina-eosina Las secciones de tejido tumoral incluidas en parafina (5 μm) se desparafinaron en xileno y se hidrataron utilizando concentraciones descendentes seriadas de alcohol. El tejido se tiñó con hematoxilina seguido de la diferenciación de la tinción con alcohol ácido al 1% v / v (etanol al 80%, agua desionizada al 19%, HCl al 1%), agua amoniacal al 0,3% v / v (NH4 OH al 0,3% en H20 desionizado) y lavado con etanol al 70%. Después de la tinción con eosina (Eosina Y al 0,05% en etanol al 70% ácido acético al 0,005%), las secciones se deshidrataron con diluciones en serie crecientes de etanol y xileno. Los portaobjetos se montaron utilizando medio de montaje permount. n = 5

tumores representativos para el grupo de control yn = 4 tumores representativos para el grupo de Andrographolide 10 mg / kg. Inmunohistoquímica e inmunofluorescencia in vivo Las secciones de tejido tumoral incluidas en parafina se desparafinaron en xileno y se rehidrataron usando un concentración de alcohol. La recuperación de antígenos se realizó utilizando una solución desenmascaradora de antígenos basada en citrato (Vector Laboratories Burlingame, Ca, EE. UU.). La peroxidasa endógena se inactivó con H2O2 al 3% v / v. Las secciones se bloquearon (FBS al 10%) durante 1 hora seguido de una incubación durante la noche con un anticuerpo primario. Los anticuerpos primarios utilizados fueron CD-31 (1:50), MMP11 (1: 500), pH (1: 1000) (Abcam, Cambridge; MA, EE. UU.) Y Ki-67 (1:50) (Vector Laboratories; Burlingame , CA, EE. UU.). Para la inmunofluorescencia, el anticuerpo secundario utilizado fue Alexa-Fluor 594 (anti-conejo) 1: 2000 (Molecular Probes, Life Technologies, Carlsbad, CA, EE. UU.) Y los núcleos se tiñeron con DAPI 1: 5000 (Santa Cruz Biotechnology, Santa Cruz, CA, EE. UU.). Todas las secciones inmunohistoquímicas se detectaron utilizando el sistema Dako Envision-HRP (DAB) (anti-conejo) (Dako; Glostrup, Dinamarca) de acuerdo con las instrucciones del fabricante. Se obtuvieron fotografías digitales usando un microscopio invertido Olympus IX71 (Olympus America, Melville, NY). Análisis de microarrays El perfil de transcripción basado en el chip genético Affymetrix se llevó a cabo en el Centro RCMI de Genómica en Disparidades de Salud y Enfermedades Raras (Universidad de Puerto Rico, Recinto de Ciencias Médicas). Se aisló ARN del tejido tumoral usando RNeasy Mini Kit (Qiagen Inc., Valencia; CA, EE. UU.). El ARN total (100 ng) se convirtió en ADNc y se amplificó usando T7 oligo dT y el kit de síntesis de ADNc GeneChip® WT, el equipo de amplificación de ADNc GeneChip® WT y el módulo de limpieza de muestras GeneChip® exactamente como se describe en la transcripción completa de GeneChip® ( WT) Apéndice del manual del ensayo de etiquetado de objetivos de detección. Se realizaron pasos de control de calidad para asegurar

que el ARN fuera adecuado para ser utilizado en la síntesis de la primera hebra de ADNc (10 μg de ARN). Se realizó un análisis de desplazamiento en gel del WT (Transcripción completa) para evaluar la eficacia de marcado de los ADNc fragmentados. Los datos de la imagen se normalizaron utilizando el software Expression Console proporcionado por Affymetrix. Los valores de expresión génica y la agrupación se realizaron utilizando la Consola de análisis de Transcriptome, también proporcionada por Affymetrix. Los ajustes utilizados para identificar las diferencias en la expresión fueron: un cambio de veces mayor que 2 o menor que –2 y un valor de p menor que 0.05. La identificación de los patrones de expresión génica se realizó con el software Ingenuity Pathway Analysis (IPA) y los parámetros utilizados fueron: un cambio de veces superior a 1,5 o inferior a –1,5 y un valor de p inferior a 0,05. Para identificar las funciones y redes afectadas, utilizamos las secciones "enfermedades y funciones" del software IPA. Los datos se documentaron de acuerdo con las directrices MIAME [62]. Validación de PCR en tiempo real Para validar los resultados de la micromatriz, se realizó una PCR cuantitativa en tiempo real (qRT-PCR) condiciones utilizando el sistema de PCR en tiempo real Step One Plus (Applied Biosystems, Carlsbad; CA, EE. UU.). Los cebadores se diseñaron utilizando la herramienta Primer Quest de Integrated DNA Technologies (IDT). Los cebadores utilizados fueron: ATM serina / treonina quinasa (ATM), síndrome de Bloom, RecQ helicasa similar (BLM), cáncer de mama 2, inicio temprano (BRCA2), proteína C-terminal que interactúa BRCA1 helicasa 1 (BRIP1), Claspin (CLSPN) Nibrin (NBN), y socio y localizador de BRCA2 (PALB2) (Tabla 2). Se ejecutó un BLAST para asegurar la especificidad de las secuencias. La qRT-PCR se realizó en reacciones de 20 μL usando SYBR super mix (Bio-Rad, Hercules, CA, EE. UU.). El ciclo utilizado fue 95 ° C durante 15 segundos y 62 ° C durante 1 minuto o 95 ° C durante 15 segundos y 56 ° C durante 1 minuto. Se examinó la eficacia de la PCR y se recogieron los datos de la curva de fusión para determinar la especificidad de la PCR. El gen de limpieza utilizado fue GAPDH. La cuantificación se realizó utilizando el

ΔΔCt método. No se detectó producto de PCR en las muestras de control en las que se omitió la plantilla. El análisis estadístico se realizó con una prueba U de Mann-Whitney con un intervalo de confianza del 95%. Se utilizaron un total de tres tumores por grupo. Los experimentos fueron realizados por triplicado. Detección por inmunofluorescencia de la fosforilación de histonas H2AX Se trataron células 22RV1, PC3 y RWPE1 con DMSO (control) o Andrographolide a 25 µM durante 24 horas. Las células se fijaron, se permeabilizaron, se bloquearon con FBS (10%) y se tiñeron con DAPI, para visualizar el núcleo, y fosfo-H2AX (1: 400) para medir la cantidad de fosfo-H2AX formada. El anticuerpo secundario usado fue Alexa-Fluor 594. Se obtuvieron fotografías digitales usando un microscopio invertido Olympus IX71 (Olympus America, Melville, NY). Se utilizó Image Pro Plus para determinar una proporción de formación de fosfo - H2A X y células totales. El experimento se realizó por triplicado y los datos se analizaron usando la prueba t de Student GraphPad Prism con un intervalo de confianza del 95%. Detección de daños en el ADN El ensayo de daño del ADN se realizó mediante citometría de flujo utilizando el MUSE Multicolor DNA Damage Kit, siguiendo las instrucciones del fabricante. Las células PC3 se trataron con DMSO (control) o Andrographolide (25 µM) durante 24 horas. El experimento se realizó utilizando 18 muestras, por triplicado, y los datos se analizaron utilizando la prueba t de Student GraphPad Prism con un intervalo de confianza del 95%. Análisis estadístico El análisis estadístico se realizó utilizando el software GraphPad PRISM. Los resultados representan la media ± error estándar de la media (SEM). Las diferencias entre los grupos se analizaron mediante la prueba t de Student o ANOVA de una vía seguida de la prueba de Dunnett. P <0,05 se consideró estadísticamente significativo. Genomics in Health Disparities and Rare Diseases (RCMI, Medical Science Campus, Revista Puertorriqueña de Medicina y Salud Pública

subvenciones 8G12- MD007600 y NIMHD: U54-MD007600) por su ayuda con el procesamiento de muestras para análisis de microarrays. ABREVIATURAS CaP: cáncer de próstata; MMP11: metaloproteinasa 11 de matriz; ATM: ATM serina / treonina quinasa; BLM: síndrome de Bloom, tipo helicasa RecQ; BRCA2: cáncer de mama 2, inicio temprano; BRIP1- proteína C que interactúa con BRCA1: helicasa terminal 1; CLSPN- broche; NBN: nibrina; PALB2: socio y localizador de BRCA2; DSB: Roturas de doble cadena de ADN; γH2AX: H2AX fosforilado; DDR: DNA Damage Respone; FBS: fetal bovino suero; BPE: extracto de pituitaria bovina; DMSO: dimetilsulfóxido; qRT-PCR: PCR en tiempo real; IPA: ingenio Análisis de vías; SEM: Error estándar de la media. CONTRIBUCIONES DE AUTOR Concepción y diseño del estudio: Ingrid Forestier-Román, Magaly Martínez-Ferrer. ADQUISICIÓN DE DATOS Ingrid Forestier-Román, Andrés López-Rivas, María Sánchez, Krizia Rohena, Magaly Martínez-Ferrer. ANÁLISIS E INTERPRETACIÓN DE DATOS Ingrid Forestier- Román, María Sánchez, Krizia Rohena, Gretchen Nieves-Burgos, Andrés López-Rivas, Humberto Ortiz- Zuazaga, Carlos Torres-Ramos, Magaly Martínez-Ferrer. REDACCIÓN DEL ARTÍCULO O REVISIÓN DE IMPORTANCIA Contenido: Ingrid Forestier-Román, María Sánchez, Krizia Rohena, Humberto Ortiz- Zuazaga, Carlos Torres-Ramos, Magaly Martínez-Ferrer. APROBACIÓN FINAL DE LA VERSIÓN A PUBLICAR Magaly Martínez-Ferrer. EXPRESIONES DE GRATITUD Agradecemos la contribución de Adrianna Rivera y Gabriela Fenollal. CONFLICTOS DE INTERÉS Los autores declaran no tener conflictos de intereses. 26

FONDOS Este trabajo fue parcialmente apoyado por la subvención NIGMS - RISE R25GM061838, subvención MARC 5T34GM 0 07821- 39, B e c a N I H INBRE P20 GM103475-17, y fondos institucionales del Centro Integral de Cáncer de la Universidad de Puerto Rico. HOZ fue apoyado en parte por la subvención NIH-NCI U54CA096297. Un agradecimiento especial a la Dra. Carmen Cadilla y Jessica Renta del RCMI Center for Genomics in Health Disparities and Rare Diseases (RCMI, Medical Science Campus, subvenciones 8 G12- M D 0 076 0 0 y NI M H D: U54-MD007600) por su ayuda con el procesamiento de muestras para análisis de microarrays. REFERENCIAS 1. Torre LA, Bray F, Siegel RL, Ferlay J, LortetTieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108. doi: 10.3322/caac.21262. [PubMed] [CrossRef] [Google Scholar] 2. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30. doi: 10.3322/caac.21387. [PubMed] [CrossRef] [Google Scholar] 3. PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board . PDQ Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute; 2012. Available at: https:// www.cancer.gov/about-cancer/treatment/ cam/hp/prostate-supplements-pdq. [Google Scholar] 4. Kallifatidis G, Hoy JJ, Lokeshwar BL. Bioactive natural products for chemoprevention and treatment of castrationresistant prostate cancer. Semin Cancer Biol. 2016;40–41:160–69. doi: 10.1016/j. semcancer.2016.06.003. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 5. Hussain SS, Kumar AP, Ghosh R. Food-based natural products for cancer management: is the whole greater than the sum of the parts? Semin Cancer Biol. 2016;40 –41:233–46. doi: 10.1016/j. semcancer.2016.06.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 6. Li J, Zhang C, Jiang H, Cheng J. Andrographolide inhibits hypoxia-inducible factor-1 through phosphatidylinositol 3-kinase/AKT pathway and suppresses breast cancer growth. Onco Targets Ther. 2015;8:427–35. doi: 10.2147/OTT.S76116. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Revista Puertorriqueña de Medicina y Salud Pública

7. Hsieh YL, Shibu MA, Lii CK, Viswanadha VP, Lin YL, Lai CH, Chen YF, Lin KH, Kuo WW, Huang CY. Andrographis paniculata extract attenuates pathological cardiac hypertrophy and apoptosis in high-fat diet fed mice. J Ethnopharmacol. 2016;192:170– 77. doi: 10.1016/j.jep.2016.07.018. [PubMed] [CrossRef] [Google Scholar] 8. Mishra SK, Tripathi S, Shukla A, Oh SH, Kim HM. Andrographolide and analogues in cancer prevention. Front Biosci (Elite Ed) 2015;7:255–66. doi: 10.2741/e732. [PubMed] [CrossRef] [Google Scholar] 9. Wong SY, Tan MG, Wong PT, Herr DR, Lai MK. Andrographolide induces Nrf2 and heme oxygenase 1 in astrocytes by activating p38 MAPK and ERK. J Neuroinflammation. 2016;13:251. doi: 10.1186/s12974-016-0723-3. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 10. Cheung HY, Cheung SH, Li J, Cheung CS, Lai WP, Fong WF, Leung FM. Andrographolide isolated from Andrographis paniculata induces cell cycle arrest and mitochondrial-mediated apoptosis in human leukemic HL- 60 cells. Planta Med. 2005;71:1106 –11. doi: 10.1055/s-2005-873128. [PubMed] [CrossRef] [Google Scholar] 11. Rajagopal S, Kumar RA, Deevi DS, Sat yanarayana C, Rajagopalan R. A n dro grap ho lid e, a p ot e ntial cancer therapeutic agent isolated from Andrographis paniculata. J Exp Ther Oncol. 2003;3:147–58. doi: 10.1046/j.13594117.2003.01090.x. [PubMed] [CrossRef] [Google Scholar] 12. Khamphaya T, Chansela P, Piyachaturawat P, Suksamrarn A, Nathanson MH, Weerachayaphorn J. Effects of andrographolide on intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats. Eur J Pharmacol. 2016;789:254– 64. doi: 10.1016/j.ejphar.2016.07.032. [PubMed] [CrossRef] [Google Scholar] 13. Sheeja K, Shihab PK, Kuttan G. Antioxidant and anti - inflammator y activities of the plant Andrographis paniculata Nees. Immunopharmacol Immunotoxicol. 2006;28:129–40. doi: 10.1080/08923970600626007. [PubMed] [CrossRef] [Google Scholar] 14. Mittal SP, Khole S, Jagadish N, Ghosh D, Gadgil V, Sinkar V, Ghaskadbi SS. Andrographolide protects liver cells from H2O2 induced cell death by upregulation of Nrf-2/HO-1 mediated via adenosine A2a receptor signalling. Biochim Biophys Acta. 2016;1860:2377–90. doi: 10.1016/j.

bbagen.2016.07.005. [PubMed] [CrossRef] [Google Scholar] 15. Singha PK, Roy S, Dey S. Antimicrobial activit y of Andrographis paniculata. Fitoterapia. 2003;74:692–94. doi: 10.1016/ S0367- 326X(03)0 0159-X . [Pub M e d] [CrossRef] [Google Scholar] 16. Kumar RA, Sridevi K, Kumar NV, Nanduri S, Rajagopal S. Anticancer and immunostimulatory compounds from Andrographis paniculata. J Ethnopharmacol. 20 04;92:291–95. doi: 10.1016/j. jep.2004.03.004. [PubMed] [CrossRef] [Google Scholar] 17. Kim YS, Milner JA. Targets for indole3-carbinol in cancer prevention. J Nutr Biochem. 2005;16:65–73. doi: 10.1016/j. jnutbio.2004.10.007. [PubMed] [CrossRef] [Google Scholar] 18. Zhou J, Zhang S, Ong CN, Shen HM. Critical role of pro-apoptotic Bcl-2 family members in andrographolide induced apoptosis in human cancer cells. Biochem Pharmacol. 2006;72:132–44. doi: 10.1016/j.bcp.2006.04.019. [PubMed] [CrossRef] [Google Scholar] 19. Kumar D, Kumar S, Gorain M, Tomar D, Patil HS, Radharani NN, Kumar TV, Patil TV, Thulasiram HV, Kundu GC. Notch1MAPK Signaling Axis Regulates CD133+ Cancer Stem Cell-Mediated Melanoma Growth and Angiogenesis. J Invest Dermatol. 2016;136:2462–74. doi: 10.1016/j. jid.2016.07.024. [PubMed] [CrossRef] [Google Scholar] 20. Shen K, Ji L, Lu B, Xu C, Gong C, Morahan G, Wang Z. Andrographolide inhibits tumor angiogenesis via blocking VEGFA/VEGFR2-MAPKs signaling cascade. Chem Biol Interact. 2014;218:99–106. doi: 10.1016/j.cbi.2014.04.020. [PubMed] [CrossRef] [Google Scholar] 21. Shang HS, Chang CH, Chou YR, Yeh MY, Au MK, Lu HF, Chu YL, Chou HM, Chou HC, Shih YL, Chung JG. Curcumin causes DNA damage and affects associated protein expression in HeLa human cervical cancer cells. Oncol Rep. 2016;36:2207–15. doi: 10.3892/or.2016.5002. [PubMed] [CrossRef] [Google Scholar] 22. Ting CY, Wang HE, Yu CC, Liu HC, Liu YC, Chiang IT. Curcumin Triggers DNA Damage and Inhibits Expression of DNA Repair Proteins in Human Lung Cancer Cells. Anticancer Res. 2015;35:3867–73. [PubMed] [Google Scholar] 23. Isaacs JT, Hukku B. Nonrandom involvement of chromosome 4 in the progression of rat prostatic cancer. Prostate. 1988;13:165–88. doi: 10.1002/

pros.2990130208. [PubMed] [CrossRef] [Google Scholar] 24. Matthaios D, Foukas PG, Kefala M, Hountis P, Trypsianis G, Panayiotides IG, Chatzaki E, Pantelidaki E, Bouros D, Karakitsos P, Kakolyris S. γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer. Onco Targets Ther. 2012;5:309–14. doi: 10.2147/OTT.S36995. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 25. Shi MD, Lin HH, Lee YC, Chao JK, Lin RA, Chen JH. Inhibition of cell-cycle progression in human colorectal carcinoma Lovo cells by andrographolide. Chem Biol Interact. 2008;174:201–10. doi: 10.1016/j. cbi.2008.06.006. [PubMed] [CrossRef] [Google Scholar] 26. Sat yanarayana C, Deevi DS, Rajagopalan R, Srinivas N, Rajagopal S. DRF 3188 a novel semi-synthetic analog of andrographolide: cellular response to MCF 7 breast cancer cells. BMC Cancer. 2004;4:26. doi: 10.1186/1471-2407-426. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 27. Kayastha F, Madhu H, Vasavada A, Johar K. Andrographolide reduces proliferation and migration of lens epithelial cells by modulating PI3K/Akt pathway. Exp Eye Res. 2014;128:23–26. doi: 10.1016/j. exer.2014.09.002. [PubMed] [CrossRef] [Google Scholar] 28. Mir H, Kapur N, Singh R, Sonpavde G, Lillard JW, Jr, Singh S. Andrographolide inhibits prostate cancer by targeting cell cycle regulators, CXCR3 and CXCR7 chemokine receptors. Cell Cycle. 2016;15:819–26. doi: 10.1080/15384101.2016.1148836. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 29. Chun JY, Tummala R, Nadiminty N, Lou W, Liu C, Yang J, Evans CP, Zhou Q, Gao AC. Andrographolide, an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth. Genes Cancer. 2010;1:868–76. doi: 10.1177/1947601910383416. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 30. Pan MH, Ghai G, Ho CT. Food bioactives, apoptosis, and cancer. Mol Nutr Food Res. 2008;52:43–52. doi: 10.1002/ mnfr.200700380. [PubMed] [CrossRef] [Google Scholar] 31. Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003;22:8628–33. doi: 10.1038/sj.onc.1207232. [PubMed]

[CrossRef] [Google Scholar] 32. Mirochnik Y, Veliceasa D, Williams L, Maxwell K, Yemelyanov A, Budunova I, Volpert OV. Androgen receptor drives cellular senescence. PLoS One. 2012;7:e31052. doi: 10.1371/journal. pone.0031052. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 33. Geethangili M, Rao YK, Fang SH, Tzeng YM. Cytotoxic constituents from Andrographis paniculata induce cell cycle arrest in jurkat cells. Phytother Res. 2008;22:1336–41. doi: 10.1002/ptr.2493. [PubMed] [CrossRef] [Google Scholar] 34. Wang Q, Su L, Liu N, Zhang L, Xu W, Fang H. Cyclin dependent kinase 1 inhibitors: a review of recent progress. Curr Med Chem. 2011;18:2025–43. doi: 10.2174/092986711795590110. [PubMed] [CrossRef] [Google Scholar] 35. Gulappa T, Reddy RS, Suman S, Nyakeriga AM, Damodaran C. Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells. Cancer Lett. 2013;337:177–83. doi: 10.1016/j.canlet.2013.05.014. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 36. Kumar S, Patil HS, Sharma P, Kumar D, Dasari S, Puranik VG, Thulasiram HV, Kundu GC. Andrographolide inhibits osteopontin expression and breast tumor growth through down regulation of PI3 kinase/Akt signaling pathway. Curr Mol Med. 2012;12:952–66. doi: 10.2174/156652412802480826. [PubMed] [CrossRef] [Google Scholar] 37. Zhang M, Xue E, Shao W. Andrographolide promotes vincristineinduced SK-NEP-1 tumor cell death via PI3K-AKT-p53 signaling pathway. Drug Des Devel Ther. 2016;10:3143–52. doi: 10.2147/DDDT.S113838. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 38. Zhang QQ, Zhou DL, Ding Y, Liu HY, Lei Y, Fang HY, Gu QL, He XD, Qi CL, Yang Y, Lan T, Li JC, Gong P, et al. Andrographolide inhibits melanoma tumor growth by inactivating the TLR4/NF-κB signaling pathway. Melanoma Res. 2014;24:545–55. doi: 10.1097/CMR.0000000000000117. [PubMed] [CrossRef] [Google Scholar] 39. Lai YH, Yu SL, Chen HY, Wang CC, Chen HW, Chen JJ. The HL J1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer. Carcinogenesis. 2013;34:1069–80. doi: 10.1093/carcin/bgt005. [PubMed] [CrossRef] [Google Scholar] 40. Liu P, Wang X, Hu CH, Hu TH. Revista Puertorriqueña de Medicina y Salud Pública

Bioinformatics analysis with graph-based clustering to detect gastric cancer-related pathways. Genet Mol Res. 2012;11:3497– 504. doi: 10.4238/2012.September.26.5. [PubMed] [CrossRef] [Google Scholar] 41. Hansmann F, Herder V, Kalkuhl A, Haist V, Zhang N, Schaudien D, Deschl U, Baumgärtner W, Ulrich R. Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler's murine encephalomyelitis. Acta Neuropathol. 2012;124:127– 42. doi: 10.1007/s00401-012-0942-3. [PubMed] [CrossRef] [Google Scholar] 42. Griner SE, Joshi JP, Nahta R. Growth differentiation factor 15 stimulates rapamycinsensitive ovarian cancer cell growth and invasion. Biochem Pharmacol. 2013;85:46– 58. doi: 10.1016/j.bcp.2012.10.007. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 43. McCawley LJ, Matrisian LM. Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol. 2001;13:534– 40. doi: 10.1016/S0955-0674(00)00248-9. [PubMed] [CrossRef] [Google Scholar] 44. Zou W, Ma X, Hua W, Chen B, Huang Y, Wang D, Cai G. BRIP1 inhibits the tumorigenic properties of cervical cancer by regulating RhoA GTPase activity. Oncol Lett. 2016;11:551–58. doi: 10.3892/ ol.2015.3963. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 45. Rafnar T, Gudbjartsson DF, Sulem P, Jonasdottir A, Sigurdsson A, Jonasdottir A, Besenbacher S, Lundin P, Stacey SN, Gudmundsson J, Magnusson OT, le Roux L, Orlygsdottir G, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011;43:1104–07. doi: 10.1038/ ng.955. [PubMed] [CrossRef] [Google Scholar] 46. Song H, Ramus SJ, Kjaer SK, Hogdall E, Dicioccio RA, Whittemore AS, McGuire V, Hogdall C, Jacobs IJ, Easton DF, Ponder BA, Dunning AM, Gayther SA, Pharoah PD. Tagging single nucleotide polymorphisms in the BRIP1 gene and susceptibility to breast and ovarian cancer. PLoS One. 2007;2:e268. doi: 10.1371/journal. pone.0000268. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 47. Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, Wiegant WW, Elghalbzouri-Maghrani E, Steltenpool J, Rooimans MA, Pals G, Arwert F, Mathew CG, Zdzienicka MZ, et al. The DNA helicase BRIP1 is defective in Fanconi anemia

complementation group. J. Nat Genet. 2005;37:934–35. doi: 10.1038/ng1625. [PubMed] [CrossRef] [Google Scholar] 48. Narayan G, Arias-Pulido H, Nandula SV, Basso K, Sugirtharaj DD, Vargas H, Mansukhani M, Villella J, Meyer L, Schneider A, Gissmann L, Dürst M, Pothuri B, Murty VV. Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer. Cancer Res. 2004;64:2994–97. doi: 10.1158/00085472.CAN-04-0245. [PubMed] [CrossRef] [Google Scholar] 49. Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25:5864–74. doi: 10.1038/sj.onc.1209874. [PubMed] [CrossRef] [Google Scholar] 50. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–82. doi: 10.1016/ S0 092- 8674(02)0 0615 - 3. [Pub M ed] [CrossRef] [Google Scholar] 51. Boulton SJ. Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans. 2006;34:633–45. doi: 10.1042/ BST0340633. [PubMed] [CrossRef] [Google Scholar] 52. Geißler AL, Geißler M, Kottmann D, Lutz L, Fichter CD, Fritsch R, Weddeling B, Makowiec F, Werner M, Lassmann S. ATM mutations and E-cadherin expression define sensitivit y to EGFR-targeted therapy in colorectal cancer. Oncotarget. 2017;8:17164 –90. doi: 10.18632/ oncotarget.15211. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 53. Rosinha A, Assis J, Dias F, Nogueira A, Pereira D, Maurício J, Teixeira AL, Medeiros R. DNA repair system and renal cell carcinoma prognosis: under the influence of NBS1. Med Oncol. 2015;32:255. doi: 10.1007/s12032-015-0701-0. [PubMed] [CrossRef] [Google Scholar] 54. Hann DM, Baker F, Roberts CS, Witt C, McDonald J, Livingston M, Ruiterman J, Ampela R, Crammer C, Kaw O. Use of complementar y therapies among breast and prostate cancer patients during treatment: a multisite study. Integr Cancer Ther. 2005;4:294–300. doi: 10.1177/1534735405282109. [PubMed] [CrossRef] [Google Scholar] 55. Hanada K, Hickson ID. Molecular genetics of RecQ helicase disorders. Cell Mol Life Sci. 2007;64:2306–22. doi: 10.1007/s00018-007-7121-z. [PubMed]

Revista Puertorriqueña de Medicina y Salud Pública

[CrossRef] [Google Scholar] 56. Park JY, Zhang F, Andreassen PR. PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochim Biophys Acta. 2014;1846:263–75. doi: 10.1016/j.bbcan.2014.06.003. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 57. Mariotti LG, Pirovano G, Savage KI, Ghita M, Ottolenghi A, Prise KM, Schettino G. Use of the γ-H2AX assay to investigate DNA repair dynamics following multiple radiation exposures. PLoS One. 2013;8:e79541. doi: 10.1371/journal. pone.0079541. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 58. Podhorecka M, Skladanowski A, Bozko P. H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy. J Nucleic Acids. 2010;2010:920161. doi: 10.4061/2010/920161. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 59. El-Deiry WS. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ. 2001;8:1066–75. doi: 10.1038/ sj.cdd.4400943. [PubMed] [CrossRef] [Google Scholar] 60. Kastan MB, Lim DS. The many substrates and functions of ATM. Nat Rev Mol Cell Biol. 2000;1:179–86. doi: 10.1038/35043058. [PubMed] [CrossRef] [Google Scholar] 61. Chappell WH, Lehmann BD, Terrian DM, Abrams SL, Steelman LS, McCubrey JA. p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3. Cell Cycle. 2012;11:4579– 88. doi: 10.4161/cc.22852. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 62. Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, et al. Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet. 2001;29:365– 71. doi: 10.1038/ng1201-365. [PubMed] [CrossRef] [Google Scholar]

Revista Puertorriqueña de Medicina y Salud Pública

As soon as you diagnose mCSPC or nmCRPC...

INDICATIONS ERLEADA® (apalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with: • Metastatic castration-sensitive prostate cancer (mCSPC) • Non-metastatic castration-resistant prostate cancer (nmCRPC) IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Cerebrovascular and 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, 5 patients (0.5%) treated with ERLEADA® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies. In the SPARTAN study, cerebrovascular events occurred in 4.7% of patients treated with ERLEADA® and 0.8% of patients treated with placebo. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA® and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA® , and 2 patients (0.2%) treated with placebo died from a cerebrovascular event. Cerebrovascular and ischemic cardiovascular events, including

Janssen Biotech, Inc. ©30 Janssen Biotech, Inc. 2021 1/21 cp-145357v4

Revista Puertorriqueña de Medicina y Salud Pública

events leading to death, occurred in patients receiving ERLEADA®. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. 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 bonetargeted 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 two randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA®. Advise patients of the risk of developing a seizure while receiving ERLEADA® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA® have not been established in females. Based on its mechanism of action, ERLEADA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA® [see Use in Specific Populations (8.1, 8.3)]. ADVERSE REACTIONS Adverse Reactions — The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA®-treated patients (≥2% over placebo) from the randomized 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%)

START EARLY ® WITH ERLEADA TO PUSH BACK ON PROGRESSION

mCSPC

In the TITAN study*†:

��% reduction

in the risk of death

nmCRPC

(ERLEADA + ADT vs placebo + ADT; median overall survival was not estimable in either arm; HR=0.67; 95% CI: 0.51, 0.89; P=0.0053) ®

��YEAR improvement

in median MFS1

(ERLEADA® + ADT vs placebo + ADT; 40.5 months vs 16.2 months; HR=0.28; 95% CI: 0.23, 0.35; P<0.0001)

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. 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, vBCRP, 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.

cp-50507v3

Rash — In 2 randomized studies (SPARTAN and TITAN), 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®. Hypothyroidism — In 2 randomized studies (SPARTAN and TITAN), 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)].

In the SPARTAN study‡§:

of metastases were excluded. Patients were randomized 1:1 to receive ERLEADA® 240 mg orally once daily or placebo orally once daily. All patients in the TITAN trial received a concomitant GnRH analog or had a prior bilateral orchiectomy. The dual primary endpoints were overall survival and rPFS.1,2 † All patients who enrolled in the TITAN study started ADT for mCSPC ≤6 months prior to randomization.2 ‡ Study Design: SPARTAN was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of patients with nmCRPC (N=1207). Patients had a PSA doubling time ≤10 months and serum testosterone levels <50 ng/dL. All patients enrolled were confirmed to be non-metastatic by blinded central imaging review. 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. Patients were randomized 2:1 to receive ERLEADA® 240 mg orally once daily or placebo orally once daily. All patients in the SPARTAN trial received a concomitant GnRH analog or had a bilateral orchiectomy. The primary endpoint was metastasis-free survival (MFS), defined as the time from randomization to the time of first evidence of blinded independent central review-confirmed distant metastasis, defined as new bone or soft tissue lesions or enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first. Secondary endpoints were time to metastasis, progression-free survival, time to symptomatic progression, overall survival, and time to initiation of cytotoxic chemotherapy.1,3 § In the SPARTAN study, conventional imaging (technetium-99m bone scans and CT scans) was used to confirm that patients were non-metastatic at screening for inclusion. Patients with pelvic lymph nodes <2 cm in short axis (N1) located below the iliac bifurcation at screening were allowed in the study. All patients in SPARTAN had a PSA doubling time ≤10 months at study entry.1,3

ADT = androgen deprivation therapy; AR = androgen receptor; CI = conﬁdence interval; CT = computed tomography; GnRH = gonadotropin-releasing hormone; HR = hazard ratio; mCSPC = metastatic castration-sensitive prostate cancer; MFS = metastasis-free survival; nmCRPC = non-metastatic castration-resistant prostate cancer; PSA = prostate-speciﬁc antigen; rPFS = radiographic progression-free survival; SPARTAN = Selective Prostate Androgen Receptor Targeting with ARN-509; TITAN = Targeted Investigational Treatment Analysis of Novel Antiandrogen. *Study Design: TITAN was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of patients with mCSPC (N=1052). Patients had newly diagnosed mCSPC or relapsed metastatic disease after an initial diagnosis of localized disease. Patients with visceral (ie, liver or lung) metastases as the only sites

Please see Brief Summary of full Prescribing Information for ERLEADA® on subsequent pages. References: 1. ERLEADA® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. 2. Chi KN, Agarwal N, Bjartell A, et al; for the TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. 3. Smith MR, Saad F, Chowdhury S, et al; for the SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.

Visit erleadahcp.com31

Revista Puertorriqueña de Medicina y Salud Pública

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 Cerebrovascular and Ischemic Cardiovascular Events Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. 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, 5 patients (0.5%) treated with ERLEADA, and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. In the SPARTAN study, cerebrovascular events occurred in 4.7% of patients treated with ERLEADA and 0.8% of patients treated with placebo [see Clinical Trials Experience]. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack 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].

Revista Puertorriqueña de Medicina y Salud Pública

ERLEADA® (apalutamide) tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Cerebrovascular and 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. 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 Musculoskeletal and connective tissue disorders Arthralgiaa Skin and subcutaneous tissue disorders Rashb Pruritus Vascular disorders Hot flush Hypertension a b

0.4

0.9

28 11

6 <1

9 5

0.6 <1

23 18

0 8

16 16

0 9

Per the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3 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

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 %

0.4

0.6

Hematology White blood cell decreased Chemistry Hypertriglyceridemiaa a

Placebo N=527

Does not reflect fasting values

ERLEADA® (apalutamide) tablets

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 33 months (range: 0.1 to 75 months) in patients who received ERLEADA and 11 months (range: 0.1 to 37 months) in patients who received placebo. Twenty-four patients (3%) who were treated with ERLEADA died from adverse reactions. The reasons for death with ≥ 2 patients included infection (n=7), myocardial infarction (n=3), cerebrovascular event (n=2), and unknown reason (n=3). 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 ERLEADAtreated 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 3: Adverse Reactions in SPARTAN (nmCRPC)

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)

System/Organ Class Adverse reaction General disorders and administration site conditions Fatiguea,b Musculoskeletal and connective tissue disorders Arthralgiab Skin and subcutaneous tissue disorders Rashc Metabolism and nutrition disorders Decreased appetited Peripheral edemae Injury, poisoning and procedural complications Fallb Fracturef Investigations Weight decreasedb Vascular disorders Hypertension Hot flush Gastrointestinal disorders Diarrhea Nausea

ERLEADA N=803 All Grades Grade 3-4 % %

Placebo N=398 All Grades Grade 3-4 % %

0.3

12 11

0.1 0

9 9

0 0

16 12

2 3

9 7

0.8 0.8

0.3

25 14

14 0

20 9

12 0

20 18

1 0

15 16

0.5 0

Includes fatigue and asthenia Per the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3 c 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 d Includes appetite disorder, decreased appetite, early satiety, and hypophagia e Includes peripheral edema, generalized edema, edema, edema genital, penile edema, peripheral swelling, scrotal edema, lymphedema, swelling, and localized edema f 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 a b

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ERLEADA included hypothyroidism (8% versus 2% on placebo), pruritus (6% versus 2% on placebo), and heart failure (2% versus 1% on placebo).

ERLEADA N=803 Laboratory Abnormality Hematology Anemia Leukopenia Lymphopenia Chemistry Hypercholesterolemiaa Hyperglycemiaa Hypertriglyceridemiaa Hyperkalemia a

Placebo N=398

All Grades %

Grade 3-4 %

All Grades %

Grade 3-4 %

70 47 41

0.4 0.3 2

64 29 21

0.5 0 2

76 70 67 32

0.1 2 2 2

46 59 49 22

0 1 0.8 0.5

Does not reflect fasting values

Rash In the combined data of two randomized, placebo-controlled clinical studies, SPARTAN and TITAN, 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, SPARTAN and TITAN, 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 was initiated in 5% of patients treated with ERLEADA. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted [see Drug Interactions]. Post-Marketing Experience The following additional adverse reactions have been identified during postapproval use of ERLEADA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis 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].

Revista Puertorriqueña de Medicina y Salud Pública

ERLEADA® (apalutamide) tablets

P-gp, BCRP or OATP1B1 Substrates Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. At steady-state, apalutamide reduced the plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a BCRP/ OATP1B1 substrate). Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The safety and efficacy of ERLEADA have not been established in females. Based on its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy [see Clinical Pharmacology (12.1) in Full Prescribing Information]. There are no human data on the use of ERLEADA in pregnant women. ERLEADA is not indicated for use in females, so animal embryo-fetal developmental toxicology studies were not conducted with apalutamide. Lactation Risk Summary The safety and efficacy of ERLEADA have not been established in females. There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production. Females and Males of Reproductive Potential Contraception Males Based on the mechanism of action and findings in an animal reproduction study, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. [see Use in Specific Populations]. Infertility Males Based on animal studies, ERLEADA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Pediatric Use Safety and effectiveness of ERLEADA in pediatric patients have not been established. Geriatric Use Of the 1327 patients who received ERLEADA in clinical studies, 19% of patients were less than 65 years, 41% of patients were 65 years to 74 years, and 40% were 75 years and over. No overall differences in effectiveness were observed between older and younger patients. Of patients treated with ERLEADA (n=1073), Grade 3-4 adverse reactions occurred in 39% of patients younger than 65 years, 41% of patients 65-74 years, and 49% of patients 75 years or older. Falls in patients receiving ERLEADA with androgen deprivation therapy was elevated in the elderly, occurring in 8% of patients younger than 65 years, 10% of patients 65-74 years, and 19% of patients 75 years or older. OVERDOSAGE There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop ERLEADA, undertake general supportive measures until clinical toxicity has been diminished or resolved. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Cerebrovascular and Ischemic Cardiovascular Events • Inform patients that ERLEADA has been associated with cerebrovascular and ischemic cardiovascular events. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular or a cerebrovascular event occur [see Warnings and Precautions]. Falls and Fractures • Inform patients that ERLEADA is associated with an increased incidence of falls and fractures [see Warnings and Precautions]. Seizures • Inform patients that ERLEADA has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they experience a seizure [see Warnings and Precautions].

Rash • Inform patients that ERLEADA is associated with rashes and to inform their healthcare provider if they develop a rash [see Adverse Reactions]. Dosage and Administration • Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with ERLEADA. • Instruct patients to take their dose at the same time each day (once daily). ERLEADA can be taken with or without food. Each tablet should be swallowed whole. • Inform patients that in the event of a missed daily dose of ERLEADA, they should take their normal dose as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose [see Dosage and Administration (2.1) in Full Prescribing Information]. • Instruct patients who have difficulty swallowing tablets whole to mix the recommended dose of ERLEADA tablets with applesauce. Do not crush tablets [see Dosage and Administration (2.3) in Full Prescribing Information]. Embryo-Fetal Toxicity • Inform patients that ERLEADA can be harmful to a developing fetus. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. Advise male patients to use a condom if having sex with a pregnant woman [see Warnings and Precautions]. Infertility • Advise male patients that ERLEADA may impair fertility and not to donate sperm during therapy and for 3 months following the last dose of ERLEADA [see Use in Specific Populations].

Revista Puertorriqueña de Medicina y Salud Pública

Foros Educativos MSP

en Artritis

+Excelencia Profesional “Diálogos Educativos en Artritis” una innovadora estrategia Telemedicina, que garantiza verdaderos resultados, para los equipos médicos y sus pacientes

Revista Puertorriqueña de Medicina y Salud Pública

EFECTO SECUNDARIO INMUNE POCO COMÚN RELACIONADO CON EL TRATAMIENTO DE INMUNOTERAPIA DEL MELANOMA AVANZADO

Revista Puertorriqueña de Medicina y Salud Pública

Corzo-Gomez J. MD ¹; Carreras-Cruz E. MD ¹; Quiñones-Morales O. MD ¹; Lozada Costas J. MD, FACP ²; García-Ricardo F. MD ³ Medical Intern. Specialist and Sun Specialist. Rotatory Internship Program Director Hospital Auxilio Mutuo, San Juan, Puerto Rico

1 2 3

RESUMEN

ABSTRACT

l melanoma es uno de los cánceres más comunes, tanto en hombres como en mujeres y su incidencia aumenta con la edad. La mayoría de los melanomas son superficiales, se limitan solo a la epidermis y pueden permanecer durante años, y durante esta etapa son curables solo mediante escisión. Sin embargo, los melanomas con infiltración en la dermis tienen un mayor riesgo de malignidad y complicaciones, como enfermedad avanzada y metástasis. Un melanoma maligno avanzado de la piel, que además presentaba una masa paótida positiva para malignidad. Posteriormente a la radioterapia, el paciente fue tratado con Nivolumab, un anticuerpo monoclonal que inhibe selectivamente la actividad de muerte celular programada (PD) en los receptores de células T, causando un síndrome similar a la miastenia, un efecto secundario inmunológico poco común pero grave.

Melanoma is one of the most common cancers, in both men and women, and its incidence increases with age. Most melanomas are superficial, limited only to the epidermis, and can remain for years, and during this stage they are curable only by excision. However, melanomas with infiltration into the dermis have an increased risk of malignancy and complications, such as advanced disease and metastasis. An advanced malignant melanoma of the skin, which also presented a positive paotid mass for malignancy. Following radiation therapy, the patient was treated with Nivolumab, a monoclonal antibody that selectively inhibits programmed cell death (PD) activity at T-cell receptors, causing a myasthenia-like syndrome, a rare but serious immune side effect.

PALABRAS CLAVE inmunoterapia, melanoma, melanoma avanzado, cáncer

KEYWORDS immunotherapy, melanoma, advanced melanoma, cancer

Revista Puertorriqueña de Medicina y Salud Pública

SENSIBILIDAD APROXIMADA DE LAS PRUEBAS CONFIRMATORIAS DE MIASTEMIA GRAVIS

DESCRIPCIÓN DEL CASO Este es el caso de un paciente masculino de 78 años con antecedentes de exposición intensa al sol. Fue diagnosticado de melanoma maligno hace 25 años en la región de la frente, resuelto con exéresis, también tuvo en 2015 lesiones en el párpado medial izquierdo y la muñeca lateral izquierda. En noviembre de 2017 el paciente comenzó a notar tumefacción de la zona periauricular izquierda. Una tomografía computarizada de cuello mostró una masa parotídea y posteriormente se realizó una biopsia con aguja fina que arrojó positivo para malignidad y S100 +. Se realizó parotidectomía y disección de cuello y el informe anatomopatológico confirmó el diagnóstico de melanoma maligno. La estadificación fue IIIC sin metástasis. El paciente se inició en radioterapia que fue bien tolerada y completada. Posteriormente, se planificó la inmunoterapia con Nivolumab 240 mg cada 14 días durante un año. Sin embargo, después de 4 dosis de tratamiento, el paciente comenzó a quejarse de debilidad generalizada, disfagia y ptosis con el posterior empeoramiento de los síntomas. Se sospechó un síndrome similar a miastenia, se suspendió Nivolumab y se inició prednisona. El paciente mostró una leve mejoría de los síntomas tras una semana de tratamiento con prednisona y se decidió consulta neurológica. En investigaciones posteriores, se lo encontró con anticuerpos del receptor de acetilcolina y se confirmó el diagnóstico de síndrome similar a la miastenia, probablemente secundario a inmunoterapia. Continuó con tratamiento con 38

PORCENTAJE POSITIVO DE MIASTENIA GENERALIZADA

PORCENTAJE DE MIASTENIA OCULAR POSITIVA

Anticuerpos AChR

80-90

40-55

Anticuerpos MuSK (pacientes in AChR antobody negativos)

40-50

<10

Estimulación nerviosa repetitiva

<50

Electromiografía de fibra única

92-99

80-95

Porcentaje positivo de miastenia generalizada

29%

Anticuerpos AChR

16%

24%

31%

Anticuerpos MuSK

prednisona y se añadió piridostigmina. En las evaluaciones posteriores, el paciente informa una mejora continua. DISCUSIÓN El síndrome similar a la miastenia es una consecuencia poco frecuente y potencialmente mortal con una tasa de mortalidad de hasta el 30% y puede ser un efecto secundario de la inmunoterapia de los inhibidores de los puntos de control inmunitarios como Nivolumab ³. Nivolumab es un anticuerpo inhibidor de punto de control inmunitario (ICI) IgG4 totalmente humano de muerte programada 1 (PD-1) que bloquea selectivamente la interacción del receptor PD-1 en las células T con ligandos PD-L1 y PD-L2 que provocan una regulación negativa sobre la activación y proliferación de células T ². La miastenia grave es un efecto secundario que afecta al sistema nervioso periférico, que se presenta en aproximadamente el 0,5% de los casos que reciben tratamiento con ICI y causa neuropatías periféricas y miositis ³. El período de tiempo medio desde la administración del fármaco hasta el inicio clínico de la miastenia grave es de aproximadamente 28 días ³.

Revista Puertorriqueña de Medicina y Salud Pública

Porcentaje de miastemia ocular positivo

26%

Estimulación nerviosa repetitiva

24%

45%

Electromiografía de fibra única

CONCLUSIÓN La miastenia grave secundaria al tratamiento con inmunoterapia es una complicación rara que amenaza con vivir en vida e incluso cuando es rara, una complicación que amenaza con vivir es rara e incluso cuando es rara, se puede observar en el 0,5% de los casos que reciben tratamiento con ICI. Es importante que los médicos tengan en cuenta este efecto secundario para el reconocimiento rápido y la interrupción temprana de la terapia que causa el síndrome. Además, el tratamiento adecuado del síndrome puede disminuir la mortalidad y morbilidad a largo plazo de esta afección. REFERENCIAS: https://cancerimmunolres.aacrjournals.org/ content/2/9/846.full https://www.nejm.org/doi/full/10.1056/ nejmoa1412082 https://w w w.ncbi.nlm.nhi.gov/pmc/ articles/PMC7457047/pdflfnmol-13-00156. pdf https://www.uptodate.com

We’ve only scratched the surface on understanding the JAK/STAT pathway’s role in atopic dermatitis (AD)1-3 Key cytokines, including IL-4, IL-13, IL-22, IL-31, and TSLP, contribute to this chronic, relapsing-remitting inflammatory skin disease. Many of these cytokines are also thought to contribute to itch, a symptom responsible for much of the disease burden.4-8 By inhibiting the JAK/STAT pathway, it may be possible to decrease signaling of key cytokines that drive AD inflammation, itch, and skin barrier disruption.9,10 IL=interleukin; JAK=Janus kinase; STAT=signal transducer and activator of transcription; TSLP=thymic stromal lymphopoietin.

Let’s explore more about the JAK/STAT pathway in AD at scratchingtheADsurface.com

Pﬁzer does not currently have any JAK inhibitors approved for the treatment of AD. References: 1. Bao L, Shi V, Chan L, et al. IL-4 regulates chemokine CCL26 in keratinocytes through the Jak1, 2/Stat6 signal transduction pathway: Implication for atopic dermatitis. Mol Immunol. 2012;50(1-2):91-97. 2. Kamijo H, Miyagaki T, Hayashi Y, et al. Increased IL-26 expression promotes T helper type 17- and t helper type 2-associated cytokine production by keratinocytes in atopic dermatitis. J Invest Dermatol. 2020;140(3):636-644. 3. Mucha S, Baurecht H, Novak N, et al. Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. J Allergy Clin Immunol. 2020;145(4):1208-1218. 4. Gittler JK, Shemer A, Suárez-Fariñas M, et al. Progressive activation of TH 2/TH 22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130(6):1344-1354. 5. Katoh N, Ohya Y, Ikeda M, et al. Clinical practice guidelines for the management of atopic dermatitis 2018. J Dermatol. 2019;46(12):1053-1101. 6. Paller AS, Kabashima K, Bieber T. Therapeutic pipeline for atopic dermatitis: end of the drought? J Allergy Clin Immunol. 2017;140(3):633643. 7. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396(10247):345-360. 8. He H, Guttman-Yassky E. JAK inhibitors for atopic dermatitis: an update. Am J Clin Dermatol. 2019;20(2):181-192. 9. Hammarén HM, Virtanen AT, Raivola J, Silvennoinen O. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine. 2019;118:48-63. 10. Renert-Yuval Y, Guttman-Yassky E. New treatments for atopic dermatitis targeting beyond IL-4/IL-13 cytokines. Ann Allergy Asthma Immunol. 2020;124(1):28-35. PP-A2D-GLB-0052-01 © 2021 Pfizer Inc. All rights reserved. February 2021 Revista Puertorriqueña de Medicina y Salud Pública

RESPUESTA A LA INMUNOTERAPIA DE RESCATE CON AGENTE ÚNICO EN PACIENTES CON VHC Y PACIENTE CON LINFOMA DIFUSO DE CÉLULAS B GRANDES

FIGURA 1

PALABRAS CLAVE inmunoterapia, VHC, linfoma, células B grandes, LDCBG, linfoma no Hodgkin (LNH) KEYWORDS immunotherapy, HCV, lymphoma, large B cells, LDCBG, non-Hodgkin lymphoma (NHL)

FIGURA 2

FIGURA 3

Revista Puertorriqueña de Medicina y Salud Pública

BLANCO AZCUY, R. MD1; RUIZ LÓPEZ, H. MD1; ALMAGUER ÁLVAREZ, L. MD1 AROCHO GONZÁLEZ, K. MD2; CABANILLAS ESCALONA, F. MD2 & GARCÍA RICARDO, F. MD3 1. Medical Intern 2. Atending physician and subspecialist 3. Rotatory Internship Program Director Hospital Auxilio Mutuo - San Juan, Puerto Rico

LABORATORIOS

PATOLOGÍA

CARGA VIRAL Y MARCADORES

MASA ABDOMINAL

HCV RNA (cantidad)

2,630,000 IU/mL

CD 20

HCV Log

6.42

CD 10

AST

417

C-myc

ALT

490

Bcl-2

B2 macroglobulin

5.6 mg/L

Ki-67

90%

LDH

399

FISH

Neg MYC reordenamiento

ASPIRACIÓN Y BIOPSIA DE MÉDULA ÓSEA Negativa para la afectación del linfoma

RESUMEN El linfoma difuso de células B grandes (LDCBG) es el subtipo histológico más común de linfoma no Hodgkin (LNH) 25%. Se ha informado que la adición de Rituximab en el régimen R-CHOP puede agregar hepatotoxicidad, favoreciendo la reactivación del VHC o la aceleración de la inflamación hepática viral. Las complicaciones más frecuentes son la descompensación hepática. Con la adición de Rituximab, se han descrito brotes de hepatitis en el 26% al 33%, siendo significativamente más frecuentes que en la serie control de pacientes con LDCBG VHC negativo (2% -3%). Los niveles de ARN-VHC caen drásticamente en el momento del aumento de las transaminasas, lo que sugiere que la causa del daño hepático es una reacción inmune contra el virus; los hepatocitos se ven afectados como espectadores inocentes.

ABSTRACT Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL) 25 %. It has been reported that the addition of Rituximab in the R-CHOP regimen may add hepatotoxicity, favoring HCV reactivation or acceleration of viral liver inflammation. Most frequent complications is hepatic decompensation. With the addition of Rituximab, hepatitis flares have been described in 26% to 33%, being significantly more frequent than in control series of patients with HCV-negative DLBCL (2%-3%). HCV-RNA levels dramatically falls at the time of increase of the transaminases, suggesting that the cause of liver damage is an immune reaction against virus, hepatocytes are affected as innocent bystanders.

DESCRIPCIÓN DEL CASO IPH: Varón de 62 años que se vieron en su estado de salud habitual hasta abril de 2018 cuando comenzó c / o saciedad precoz y pérdida involuntaria de peso de 20 libras, fiebre y sudores nocturnos. PMH, alergias, historial social: sin complicaciones Examen físico: sin complicaciones La TC abdominopélvica mostró una gran masa de 12,9 cm craneocaudal x 13,4 cm transversal x 13,1 cm AP. En junio de 2018, una biopsia con aguja gruesa e inmunohistoquímica fue compatible con el tipo DLBCL-GCB (tabla 1). No hay evidencia de enfermedad en la biopsia de médula ósea. La gastroscopia mostró una ulceración gástrica que también fue positiva para DLCL (fig. 1). Se encontró que tenía hepatitis C durante el examen de rutina antes de la quimioterapia con

Revista Puertorriqueña de Medicina y Salud Pública

transaminasas elevadas y carga viral alta (Tabla 1). Fue tratado en otro lugar con el régimen R-CHOP durante 6 ciclos desde julio de 2018 hasta octubre de 2018. En diciembre de 2018, una PET reveló una masa de 12,1 x 3,7 x 6,5 cm que involucraba el bazo y el estómago y todavía tenía sudores nocturnos. Se interpretó como enfermedad refractaria y se recomendó GROC más lenalidomida. Desafortunadamente, el paciente no pudo recibir tratamiento para su hepatitis C debido a problemas con el seguro. Para evitar un mayor compromiso hepático y proporcionar un tratamiento rápido, se inició lenalidomida como agente único. Después de 4 rondas, el paciente ya no presentaba síntomas. Laboratorios normales, excepto LDH y transaminasas que tuvieron una tendencia decreciente. Una tomografía computarizada de abdomen y pelvis con reestadificación no mostró evidencia de enfermedad (Fig. 2 y 3). DISCUSIÓN En este caso se expone a un paciente con sintomatología general y gran masa abdominal con biopsia inmunohistoquímica compatible con tipo DCBCL-GCB y ulceración gástrica positiva para DLCL. También se encontró hepatitis C durante un examen de rutina. Después del tratamiento con el régimen R-CHOP durante 6 ciclos, un examen PET reveló una masa que involucraba el bazo y el estómago, interpretada como enfermedad refractaria y se recomendó el tratamiento con GROC más lenalidomida, pero no pudo recibir tratamiento para su hepatitis C para evitar un mayor compromiso hepático. Se inició lenalidomida como monoterapia. Afortunadamente, después de 4 rondas, la tomografía computarizada del abdomen y la pelvis no mostró evidencia de enfermedad, la LDH y las transaminasas tuvieron una tendencia a la baja. Se sabe que la lenalidomida en combinación con rituximab puede ser eficaz como terapia de segunda

línea, pero hay poca evidencia de una terapia de rescate de agente único con lenalidomida. CONCLUSIÓN Las células T juegan un papel importante en el control de la infección por el virus de la hepatitis C (VHC). Los fármacos inmunomoduladores que afectan a las células T, como la talidomida y la lenalidomida, se utilizan en el tratamiento de algunos cánceres hematológicos. La lenalidomida es hasta 1000 veces más potente que la talidomida para estimular la proliferación de células T, la producción de interferón-γ e interleucina-2. Recientemente se informó sobre la reactivación del VHC con brote de hepatitis después de la terapia con talidomida (Mahale et al., Open Forum Infect Dis. 2015); sin embargo, aún no se ha estudiado el efecto de la lenalidomida sobre la viremia por VHC. HCV-infected cancer patients treated with lenalidomide at MD Anderson Cancer Center (November 2012 to March 2016) were studied. HCV-RNA levels were measured before and after lenalidomide use. The conclusion in this study are unlike thalidomide, lenalidomide does not cause HCV reactivation. On the disagreeing, this agent seems to inhibit HCV replication. Nuestro caso muestra un posible tratamiento muy relevante para pacientes con opciones de tratamiento limitadas por comorbilidades. REFERENCIAS Arora, M., Gowda, S., & Tuscano, J. (2016). A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma. Therapeutic Advances in H e m a t o l o g y, 7(4), 20 9-221. doi:10.1177/2040620716652861 Hosry, J., Samaniego, F., Turturro, F., Economides, M. P., & Torres, H. A. (2016). Effect of Lenalidomide on Hepatitis C Viremia in Cancer Patients: A Case Series. Blood, 128(22), 5691. Kritharis, A., Coyle, M., Sharma, J., & Evens, A. M. (2015). Lenalidomide

Revista Puertorriqueña de Medicina y Salud Pública

in non-Hodgkin lymphoma: biological perspectives and therapeutic o p p o r t unitie s. B l o o d, 125(16), 2471-2476. doi:10.1182/blood-2014-11567792 Witzig, T. E., Wiernik, P. H., Moore, T., Reeder, C., Cole, C., Justice, G., … Vose, J. M. (2009). Lenalidomide Oral Monotherapy Produces Durable Responses in Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma. Journal of Clinical Oncolo gy, 27(32), 5404-5409. doi:10.1200/ jco.2008.21.1169 AGRADECIMIENTO ESPECIAL Caroll J. Vazquez Arroyo, MD Suzzette Florez & Sonia Milan, Coordinadoras Kyria E. Echevarría Alicea, Coordinador de Programa

"Las células T juegan un papel importante en el control de la infección por el virus de la hepatitis C (VHC). Los fármacos inmunomoduladores que afectan a las células T, como la talidomida y la lenalidomida, se utilizan en el tratamiento de algunos cánceres hematológicos. La lenalidomida es hasta 1000 veces más potente que la talidomida para estimular la proliferación de células T, la producción de interferón-γ e interleucina-2"

Revista Puertorriqueña de Medicina y Salud Pública

PATIENTS PRESCRIBED SYNTHROID MAY NOT ALWAYS GET SYNTHROID Based on Synthroid Consumer Awareness, Attitude and Usage Study

37%

of patients who think they are on Synthroid are actually not.1

†

Mistaken generic users defined as those who reported taking Synthroid but were not taking a pill with the word “SYNTHROID” embossed on it. From a 2018 national online survey of 501 adults diagnosed with hypothyroidism and currently taking LT4 products.

Tablets may not represent exact 25 shown 50not actual 75size and 88 100 112color.125

mcg orange

mcg white

mcg violet

mcg olive

mcg yellow

mcg rose

mcg brown

137 mcg turquoise

150 mcg blue

175 mcg lilac

200 mcg pink

300 mcg green

Tablets shown not actual size and may not represent exact color.

INDICATION2

Hypothyroidism SYNTHROID® (levothyroxine sodium) tablets, for oral use is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid Stimulating Hormone, TSH) Suppression SYNTHROID is indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Limitation of Use SYNTHROID is not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients, as there are no clinical benefits and over-treatment with SYNTHROID may induce hyperthyroidism. SYNTHROID is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

IMPORTANT SAFETY INFORMATION2

WARNING: Thyroid hormones, including SYNTHROID, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects. • SYNTHROID is contraindicated in patients with uncorrected adrenal insufficiency. • In the elderly and in patients with cardiovascular disease, SYNTHROID should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease. If cardiac symptoms develop or worsen, the SYNTHROID dose should be reduced or withheld for one week and restarted at a lower dose. • Patients with coronary artery disease who are receiving SYNTHROID should be monitored closely during surgical procedures for cardiac arrhythmias. Monitor patients during concomitant administration of SYNTHROID and Revista Puertorriqueña de and Medicina y Salud Pública sympathomimetic agents for signs symptoms of coronary insufficiency. 44

• Use of oral thyroid hormone is not recommended in myxedema coma. Products formulated for IV administration should be used to treat myxedema coma. • Patients with adrenal insufficiency should be treated with replacement glucocorticoids prior to initiating treatment with SYNTHROID. Failure to do so may precipitate an acute adrenal crisis when thyroid hormone therapy is initiated. • SYNTHROID has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of overor under-treatment. • Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing SYNTHROID. • Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in postmenopausal women. To mitigate this risk, patients receiving SYNTHROID should be given the minimum dose necessary that achieves the desired response. • Adverse reactions associated with SYNTHROID therapy are primarily those of hyperthyroidism due to therapeutic overdosage. • Many drugs and some foods affect thyroid hormone pharmacokinetics and metabolism and may alter the therapeutic response to SYNTHROID. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs. Administer at least 4 hours Please see thedrugs following brief summary of full Evaluate before or after that arepages knownfor to interfere with absorption. Prescribing Information. the need for dose adjustments when regularly administering within one hour For morefoods information a copy of fullPrescribers Prescribing of certain that may or affect absorption. should consult appropriate reference sources additional information Information call AbbVie at for 800-241-1643 or visiton drug or food interactions with SYNTHROID. Synthroid.com. • SYNTHROID should not be discontinued during pregnancy, and hypothyroidism diagnosed during pregnancy should be promptly treated. TSH levels may increase during pregnancy, so TSH should be monitored and SYNTHROID dose adjusted as needed.

THE IMPORTANCE OF DAW-1

HOW PRESCRIPTION PROTECTION MAY IMPACT PATIENT COST WHEN PRESCRIBING SYNTHROID

WITH DAW-1

WITHOUT DAW-1

Levothyroxine A Manufacturer 1

PHARMACY ADJUDICATION: DAW-1 (PRESCRIBER PREFERENCE)

Levothyroxine B Manufacturer 2

Levothyroxine C Manufacturer 3

Levothyroxine D Manufacturer 4

PHARMACY ADJUDICATION: SUBSTITUTABLE (DAW-0) MAY BE DISPENSED AS: GENERIC SUBSTITUTE

DISPENSED AS: BRANDED PRODUCT

IF PATIENT THEN REQUESTS BRAND

PATIENT COST ON PLAN: BRAND CO-PAY1

The Food and Drug Administration (FDA) has determined that certain levothyroxine products are therapeutically equivalent. The FDA has determined that drugs that are classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the reference product.3

SAFETY CONSIDERATIONS2

• SYNTHROID should not be used for the treatment of obesity or for weight loss. • SYNTHROID is contraindicated in patients with uncorrected adrenal insufficiency. • In the elderly and in patients with cardiovascular disease, SYNTHROID should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease. Patients with coronary artery disease who are receiving SYNTHROID should be closely monitored for cardiac arrhythmias during surgical procedures. • Oral thyroid hormone is not recommended in myxedema coma; only products formulated for IV administration should be used.

PHARMACY ADJUDICATION: DAW-2 (PATIENT PREFERENCE)

PATIENT COST ON PLAN: HIGHER BRAND CO-PAY 1, 4 PATIENT CALLS OFFICE

PATIENT ACCEPTS GENERIC

PATIENT PAYS HIGHER BRAND CO-PAY

• Patients with adrenal insufficiency should be treated with replacement glucocorticoids prior to initiating SYNTHROID. • SYNTHROID is a narrow therapeutic index drug requiring careful titration. • Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control. Carefully monitor glycemic control after starting, changing, or discontinuing SYNTHROID. • Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in postmenopausal women. REFERENCES: 1. Synthroid Consumer Awareness, Attitude And Usage Report 2018. 2. Synthroid [package insert]. North Chicago, IL: AbbVie Inc. 3. US Food and Drug Administration. Approved Drug Products with Therapeutic Equivalence Evaluations 39th ed. 2020. https://www.fda.gov/media/71474/download. Accessed date: December 8, 2020. 4. Some plans set a “DAW-2 Penalty” price, which may be as high as the Non-Formulary Co-Pay plus the dfference between the cost of the Brand Name Drug and the available Generic.

Please see additional Important Safety Information, including BOXED Warning regarding inappropriate treatment for obesity or for weight loss, on the adjacent page. Please see the following pages for brief summary of full prescribing information. ©2020 AbbVie Inc. North Chicago, IL 60064 US-SYNT-200381 December 2020 Printed in Puerto Rico Revista Puertorriqueña de Medicina y Salud Pública

SYNTHROID® (sin-throyd) (levothyroxine sodium) tablets, USP WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS Thyroid hormones, including SYNTHROID, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects [see Adverse Reactions, Drug Interactions, and Overdosage]. INDICATIONS AND USAGE Hypothyroidism SYNTHROID is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression SYNTHROID is indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Limitations of Use: • SYNTHROID is not indicated for suppression of benign thyroid nodules hyperthyroidism [see Warnings and Precautions]. • SYNTHROID is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. CONTRAINDICATIONS SYNTHROID is contraindicated in patients with uncorrected adrenal [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate SYNTHROID therapy in this population at lower doses than those recommended in younger individuals or in patients without . cardiac disease Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive SYNTHROID therapy. Monitor patients receiving concomitant SYNTHROID and sympathomimetic agents for If cardiac symptoms develop or worsen, reduce the SYNTHROID dose or withhold for one week and restart at a lower dose. Myxedema Coma Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma. Acute Adrenal Crisis in Patients with Concomitant Adrenal Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may prior to initiating treatment with SYNTHROID [see Contraindications]. Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism SYNTHROID has a narrow therapeutic index. Over- or undertreatment with SYNTHROID may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and glucose and lipid metabolism. Titrate the dose of SYNTHROID carefully and monitor response to titration to avoid these effects. Monitor for the presence of drug or food interactions when using SYNTHROID and adjust the dose as necessary [see Drug Interactions]. Worsening of Diabetic Control Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing SYNTHROID [see Drug Interactions]. Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in postmenopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Administer the minimum dose of SYNTHROID that achieves the desired clinical and biochemical response to mitigate this risk. ADVERSE REACTIONS Adverse reactions associated with SYNTHROID therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions, Overdosage]. They include the following: • General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating • Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia • Musculoskeletal: tremors, muscle weakness, muscle spasm • Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest • Respiratory: dyspnea • Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests • Dermatologic:

Revista Puertorriqueña de Medicina y Salud Pública

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

• Endocrine: decreased bone mineral density • Reproductive: menstrual irregularities, impaired fertility Seizures have been reported rarely with the institution of levothyroxine therapy. Adverse Reactions in Children Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height. Hypersensitivity Reactions Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur. DRUG INTERACTIONS Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to SYNTHROID (see Tables 1-4 below). Table 1. Drugs That May Decrease T4 Absorption (Hypothyroidism) by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class

Effect

Phosphate Binders (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum)

Phosphate binders may bind to levothyroxine. Administer SYNTHROID at least 4 hours apart from these agents.

Orlistat

Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.

Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol) Ion Exchange Resins

Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.

Proton Pump Inhibitors Sucralfate Antacids

Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.

Table 2. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class

Effect

These drugs may increase serum thyroxineEstrogen-containing oral binding globulin (TBG) concentration. contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid

These drugs may decrease serum TBG concentration.

Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. Salicylates (> 2 g/day)

Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.

Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-

These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.

- Fenamates

Table 3. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements. Drug or Drug Class Phenobarbital Rifampin

Effect Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.

Table 4. Drugs That May Decrease Conversion of T4 to T3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class

Effect

Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day)

In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.

Glucocorticoids (e.g., Dexamethasone > 4 mg/day)

Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).

Other drugs: Amiodarone

Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.

Antidiabetic Therapy Addition of SYNTHROID therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued [see Warnings and Precautions]. Oral Anticoagulants SYNTHROID increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the SYNTHROID dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. Digitalis Glycosides SYNTHROID may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and SYNTHROID may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. SYNTHROID may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on SYNTHROID may result in increased SYNTHROID requirements. Ketamine Concurrent use of ketamine and SYNTHROID may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. Sympathomimetics Concurrent use of sympathomimetics and SYNTHROID may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may are administered to patients with coronary artery disease. Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients. Drug-Food Interactions Consumption of certain foods may affect SYNTHROID absorption thereby SYNTHROID from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. Drug-Laboratory Test Interactions Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias 1 in 9000.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Experience with levothyroxine use in pregnant women, including data from post-marketing studies, have not reported increased rates of major birth defects or miscarriages [see Data]. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and SYNTHROID dosage adjusted during pregnancy [see Clinical Considerations]. There are no animal studies conducted with levothyroxine during pregnancy. SYNTHROID should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. 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 Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development. Dose Adjustments During Pregnancy and the Postpartum Period Pregnancy may increase SYNTHROID requirements. Serum TSH levels should be monitored and the SYNTHROID dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the SYNTHROID dosage should return to the pre-pregnancy dose immediately after delivery. Data Human Data Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women. Lactation Risk Summary Limited published studies report that levothyroxine is present in human of levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid should be considered along with the mother’s clinical need for SYNTHROID and any potential adverse effects on the breastfed infant from SYNTHROID or from the underlying maternal condition. Pediatric Use The initial dose of SYNTHROID varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient’s clinical and laboratory parameters. In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue SYNTHROID administration for a trial period, but only after the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, and use laboratory test results and clinical assessment to guide diagnosis and treatment, if warranted. Congenital Hypothyroidism Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate SYNTHROID therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients.

cardiac overload, arrhythmias, and aspiration from avid suckling. Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. Acquired Hypothyroidism in Pediatric Patients Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height. Geriatric Use Because of the increased prevalence of cardiovascular disease among the elderly, initiate SYNTHROID at less than the full replacement dose [see Warnings and Precautions]. Atrial arrhythmias can occur in elderly patients. levothyroxine overtreatment in the elderly. OVERDOSAGE The signs and symptoms of overdosage are those of hyperthyroidism [see Adverse Reactions]. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Reduce the SYNTHROID dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s medical status. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org. PATIENT COUNSELING INFORMATION Inform the patient of the following information to aid in the safe and effective use of SYNTHROID: Dosing and Administration • Instruct patients to take SYNTHROID only as directed by their healthcare provider. • Instruct patients to take SYNTHROID as a single dose, preferably on an empty stomach, one-half to one hour before breakfast. • Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine. Instruct patients not to take SYNTHROID tablets within 4 hours of these agents. • Instruct patients to notify their healthcare provider if they are pregnant or breastfeeding or are thinking of becoming pregnant while taking SYNTHROID. Important Information • Inform patients that it may take several weeks before they notice an improvement in symptoms. • Inform patients that the levothyroxine in SYNTHROID is intended to replace a hormone that is normally produced by the thyroid gland. Generally, replacement therapy is to be taken for life. • Inform patients that SYNTHROID should not be used as a primary or adjunctive therapy in a weight control program. • Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations.

• Instruct patients to notify their physician of any other medical conditions they may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking SYNTHROID. If they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. If patients are taking anticoagulants, their clotting status should be checked frequently. • Instruct patients to notify their physician or dentist that they are taking SYNTHROID prior to any surgery. Adverse Reactions • Instruct patients to notify their healthcare provider if they experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event. • months of SYNTHROID therapy, but this is usually temporary. AbbVie Inc. North Chicago, IL 60064, U.S.A. © 2020 AbbVie Inc. Ref: 20063914 Revised: July 2020 LAB-3951 MASTER

US-SYNT-200381

Revista Puertorriqueña de Medicina y Salud Pública

Ryan White

La historia que cambió la forma de ver el sida Por: Francisco Ernesto Lugo Guevarra Redactor y colaborador de Medicina y Salud Pública

48 56

Revista Puertorriqueña de Medicina y Salud Pública

SUMPLEMENTO ESPECIAL

El adolescente fue diagnosticado en 1984, cuando tenía sólo 13 años. Fue víctima de hostigamiento y discriminación, pero su lucha no fue en vano y ayudó a crear conciencia sobre la enfermedad. En su honor el Congreso de los Estados Unidos aprobó el mayor avance legislativo contra el sida, el acta Ryan White. Revista Puertorriqueña de Medicina y Salud Pública

En los años ochenta no solo la cultura pop y de grandes avances tecnológicos influyeron dramáticamente en la historia sino que, esta manifestación cultural ayudaron con tratamientos contra enfermedades hasta ese momento desconocidas. En una época donde la codicia era bien vista entró al escenario la caridad cuando un centenar de estrellas como Michael Jackson, Bob Dylan, Stevie Wonder, Bruce Springsteen y Lionel Richard le abrieron los ojos al mundo con «We Are the World» («Somos el mundo») una canción escrita por Jackson y Richie.

En los años ochenta no solo la cultura pop y de grandes avances tecnológicos influyeron dramáticamente en la historia, sino que esta manifestación cultural ayudaron con tratamientos contra enfermedades hasta ese momento desconocidas. En una época donde la codicia era bien vista entró al escenario la caridad cuando un centenar de estrellas como Michael Jackson, Bob Dylan, Stevie Wonder, Bruce Springsteen y Lionel Richard le abrieron los ojos al mundo con «We Are the World» («Somos el mundo») una canción escrita por Jackson y Richie. La canción producida por Quincy Jones cambia la mentalidad de la caridad y el altruismo y lo convierte en una verdadera revolución de hacer el bien. Los beneficios obtenidos por la canción fueron donados a una campaña humanitaria para intentar acabar con la tremenda hambruna en Etiopía. Al mismo tiempo, intérpretes latinos como Rubén Blades utilizaban la música como arma para combatir la pobreza e iluminar la hambruna casi bíblica en Africa. Pero el activismo de las celebridades no era suficiente y pronto tendrían que abrir los ojos igual que el mundo sobre una comunidad en crisis que hasta el momento el gobierno de Estados Unidos ignoraba. Puerto Rico no era la excepción. La protesta comercializada despierta a una comunidad en una crisis de proporciones epidémicas que los politicos y las autoridades eligen ignorar. Un despiadado enemigo andaba en las calles y nadie lo conocía. Era impactante. Uno de los principales noticieros de la televisión estadounidense presentaba la noticia confundiendo el diagnóstico del síndrome de inmunodeficiencia con cáncer y vinculándolo solo con homosexuales, lo que fomenta el discrimen y el desconocimiento. “Se detectó una forma rara y mortal de cáncer en 41 hombres homosexuales y la situación preocupa a los funcionarios de salud pública”, dijo la presentadora. Una enfermedad que comenzaba a cobrar cientos de vidas con un diagnóstico totalmente desapercibido. La gente moría en todos lados y ya no se trataba de una enfermedad de homosexuales. Pero el miedo al sida levanta una muralla entre los que la padecen y los que no. La polarización arropa a todos los sectores, incluyendo a la propia familia de los pacientes que llegaban a rechazarlos y a dejarlos desamparados a pesar de que ya estaban desahuciados por la medicina. La figura de Rud Hudson abría las portadas de los periódicos del mundo entero, pero, un gran sector de la ciencia reitera que se trata de una enfermedad que solo se transmitía por contacto sexual entre hombres homosexuales.

El mundo requiere de un valiente niño de trece años, Ryan Whithe, para comenzar a derribar aquella muralla de prejuicios. Ryan, un adolescente de Indiana, Estados Unidos, se convirtió en un referente mundial a causa del sida después de ser expulsado de su escuela. El adolescente padecía hemofilia, un trastorno hemorrágico hereditario en el cual la sangre no se coagula de manera adecuada. La hemofilia es causada por una mutación o cambio en uno de los genes que da las instrucciones para producir las proteínas del factor de la coagulación necesarias para formar un coágulo de sangre. Este cambio o mutación puede hacer que las proteínas de la coagulación no funcionen correctamente o que directamente no estén presentes. Estos genes se localizan en el cromosoma X. Los hombres tienen un cromosoma X y un cromosoma Y (XY) y las mujeres tienen dos cromosomas X (XX).

50% de probabilidad de los hijos tendrá hemofilia XY

Key 50 58

Revista Puertorriqueña de Medicina y Salud Pública

La madre es portadora del gen de la hemofilia XX

Padre no tiene hemofilia xy

No tiene hemofilia

50% de probabilidad hijas sea portador del gen de la hemofilia XX Portador del gen de la hemofilia

Tiene hemofilia

SUPLEMENTO ESPECIAL

EL CROMOSOMA X CONTIENE MUCHOS GENES QUE NO ESTÁN PRESENTES EN EL CROMOSOMA Y. ESO SIGNIFICA QUE LOS HOMBRES TIENEN SOLO UNA COPIA DE LA MAYORÍA DE LOS GENES DEL CROMOSOMA X, MIENTRAS QUE LAS MUJERES TIENEN DOS COPIAS. POR LO TANTO, LOS HOMBRES PUEDEN TENER UNA ENFERMEDAD COMO LA HEMOFILIA SI HEREDAN UN CROMOSOMA X AFECTADO QUE TENGA UNA MUTACIÓN EN EL GEN DEL FACTOR VIII O DEL FACTOR IX.

Ronald Reagan, expresidente de los EE.UU., Ryan White y Nancy Reagan, ex primera dama.

Michael Jackson y Ryan White.

White se contagia de sida en 1984 debido al uso de un producto que se utilizaba para ayudar a la coagulación sanguínea. Factor VII es el agente coagulante que tiene la sangre. De esta manera es que el joven contrae el sida derribando los mitos sobre el contagio de la enfermedad. Ya no se trataba de homosexuales ni de usuarios de drogas. Sin embargo, las vías de transmisión del sida aún no estaban claras ni tan siquiera para la medicina y, al tratar de volver a su escuela muchos padres y profesores se manifestaron en contra. Una larga batalla legal contra su escuela y la cobertura de los medios de comunicación, hicieron de White una celebridad y portavoz sobre la investigación del sida. Apareció frecuentemente en los medios de comunicación junto a celebridades como el cantante Elton John y sobre todo con Michael Jackson. Sorprendiendo a sus médicos, Ryan White vivió cinco años más sobre el tiempo que le fue pronosticado y falleció poco antes de acabar sus estudios de secundaria en abril de 1990. En el transcurso de la década de 1980 y de 1990 la percepción social de la enfermedad cambió, gracias en parte, a White y otras personalidades relevantes con sida, como la súper estrella de la NBA Magic Johnson. En 1990 el Congreso de los Estados Unidos aprobó el mayor avance legislativo contra el sida hasta la fecha, el acta Ryan White CARE, en su honor, poco después de la muerte del joven.

Rob Lowe y Ryan White.

Madre de Ryan White y Elton John.

En 1990 el Congreso de los Estados Unidos aprobó el mayor avance legislativo contra el sida hasta la fecha, el acta Ryan White CARE, en su honor, poco después de la muerte del joven.

Revista Puertorriqueña Puertorriqueña de de Medicina Medicina yy Salud Salud Pública Pública Revista

51 59

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

IN A PHASE 3 TRIAL VENCLEXTA + AZACITIDINE WAS PROVEN TO HELP

NEWLY DIAGNOSED AML

PATIENTS LIVE LONGER1 National Comprehensive Cancer Network® (NCCN®) Recommendations* for Venetoclax + Azacitidine2 • For patients ≥60 years of age who are not candidates for intensive induction chemotherapy in first-line AML

THE ONLY CATEGORY 1 PREFERRED RECOMMENDATION FOR PATIENTS WITH OR WITHOUT ACTIONABLE MUTATIONS† For additional recommendations on venetoclax combination-based regimens, including in actionable mutations, see NCCN.org. * See NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for AML, Version 2.2021, for complete recommendations. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. † Actionable mutations include IDH1/2 and FLT3. IDH=isocitrate dehydrogenase; FLT=fms-like tyrosine kinase.

Select Important Safety Information • Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA. Assess all patients for risk, including evaluation of tumor burden and comorbidities, and provide prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA follow dose modification guidance in the Prescribing Information. • Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during ramp-up phase, and requires VENCLEXTA dose adjustment. • Grade 3 or 4 neutropenia occurred in patients treated with VENCLEXTA. Monitor blood counts and for signs of infection; manage as medically appropriate. • Baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles. • Fatal and serious infections such as pneumonia and sepsis have occurred in patients with VENCLEXTA. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution. • Do not administer live attenuated vaccines prior to, during, or after treatment until B-cell recovery occurs. • VENCLEXTA may cause embryo-fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after the last dose.

Visit venclextahcp.com/aml to learn more about VENCLEXTA in newly diagnosed AML

Please see additional Important Safety Information on following pages.

52 Please see Brief Summary of full Prescribing Information on the pages following this advertisement. Revista Puertorriqueña de Medicina y Salud Pública

VEN+AZA demonstrated superior overall survival (OS) vs PBO+AZA1 Median OS was extended by 5.1 months in patients treated with VEN+AZA vs PBO+AZA Difference in mOS

1.0

34%

Probability of no event

REDUCTION IN RISK OF MORTALITY

HR=0.66 95% CI: (0.52, 0.85); P<0.001

95% CI: (11.9, 18.7) 0.5

95% CI: (7.4, 12.7)

14.7

9.6

VEN+AZA

PBO+AZA

0.0 0

Time (months) Number of patients at risk VEN+AZA 286

219

198

168

143

117

101

PBO+AZA 145

109

• Median follow-up for OS was approximately 20.5 months (range: <0.1-30.7 months)3 – Median follow-up was estimated using reverse Kaplan-Meier methodology VIALE-A: A randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine (VEN+AZA, N=286) vs placebo with azacitidine (PBO+AZA, N=145) in adults with newly diagnosed AML who were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy. The primary endpoint was OS. Patients received VENCLEXTA 400 mg daily or placebo in combination with azacitidine 75 mg/m2 for 1-7 days per cycle until disease progression or unacceptable toxicity.1 VENCLEXTA + low-dose cytarabine (LDAC) (VIALE-C phase 3 trial): Efficacy of VEN+LDAC regimen was based on CR rate and duration of CR with supportive evidence of rate of CR+CRh, duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. In the VIALE-C trial, VEN+LDAC did not significantly improve OS versus placebo plus LDAC.1 CI=confidence interval; mOS=median overall survival; HR=hazard ratio; CR=complete remission; CR+CRh=complete remission and complete remission with partial hematologic recovery.

Select Important Safety Information Tumor Lysis Syndrome • Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA. • VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.

Revista Puertorriqueña de Medicina y Salud Pública

Important Safety Information Tumor Lysis Syndrome • Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA. • VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase. • In patients with AML who followed the current 3-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 1.1% in patients who received VENCLEXTA in combination with azacitidine. In patients with AML who followed a 4-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 5.6% and included deaths and renal failure in patients who received VENCLEXTA in combination with low-dose cytarabine. • The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. • Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA follow dose modification guidance in the Prescribing Information. • Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase, and requires VENCLEXTA dose adjustment. Neutropenia • In patients with AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles. • Monitor complete blood counts throughout the treatment period. For severe neutropenia, interrupt dosing or reduce duration based on remission status and occurrence. Consider supportive measures including antimicrobials and growth factors (e.g., G-CSF). Infections • Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with VENCLEXTA. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution and resume at same or reduced dose based on occurrence. Immunization • Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective. Embryo-Fetal Toxicity • VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose. Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone • In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials. Adverse Reactions • In patients with AML receiving combination therapy with azacitidine, the most frequent serious adverse reactions (≥5%) were febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). The most common adverse reactions (≥30%) of any grade were neutrophils decreased (98%), platelets decreased (94%), lymphocytes decreased (91%), hemoglobin decreased (61%), nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with azacitidine, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%). 54

Revista Puertorriqueña de Medicina y Salud Pública

• In patients with AML receiving combination therapy with decitabine, the most frequent serious adverse reactions (≥10%) were sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). The most common adverse reactions (≥30%) of any grade were febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexia (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%), and vomiting (31%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment. • In patients with AML receiving combination therapy with low-dose cytarabine, the most frequent serious adverse reactions (≥10%) were pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). The most common adverse reactions (≥30%) of any grade were platelets decreased (97%), neutrophils decreased (95%), lymphocytes decreased (92%), hemoglobin decreased (63%), nausea (42%), and febrile neutropenia (32%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%). Drug Interactions • Concomitant use with a P-gp inhibitor or a strong or moderate CYP3A inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions. Resume the VENCLEXTA dosage that was used prior to concomitant use of a P-gp inhibitor or a strong or moderate CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor. • Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A. • Avoid concomitant use of strong or moderate CYP3A inducers. • Monitor international normalized ratio (INR) more frequently in patients receiving warfarin. • Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA. Lactation • Advise nursing women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose. Females and Males of Reproductive Potential • Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose. • Based on findings in animals, VENCLEXTA may impair male fertility. Hepatic Impairment • Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for signs of adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Please see Brief Summary of full Prescribing Information on the pages following this advertisement. References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.2.2021. © National Comprehensive Cancer Network, Inc 2020. All rights reserved. Accessed November 19, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.

VENCLEXTA® and its design are registered trademarks of AbbVie Inc. Distributed and marketed by AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064 Marketed by Genentech USA, Inc., 1 DNA Way, South San Francisco, CA 94080-4990 ©2020 AbbVie Inc. and Genentech USA, Inc. US-VENA-200310/December 2020

Revista Puertorriqueña de Medicina y Salud Pública Printed in USA55

DO NOT RE-SIZE US-VENA-200310

VENCLEXTA® (venetoclax tablets) INDICATIONS AND USAGE Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Acute Myeloid Leukemia VENCLEXTA is indicated in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. CONTRAINDICATIONS Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during the ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions]. WARNINGS AND PRECAUTIONS Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA [see Adverse Reactions]. VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients, and during reinitiation after dosage interruption in patients with CLL/SLL. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase. TLS, including fatal cases, has been reported after a single 20 mg dose of VENCLEXTA. In patients with CLL/SLL who followed the current (5-week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL/SLL monotherapy trials. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure [see Adverse Reactions]. In patients with AML who followed the current 3-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 1.1% in patients who received VENCLEXTA in combination with azacitidine (VIALE-A). In patients with AML who followed a 4-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 5.6% and included deaths and renal failure in patients who received VENCLEXTA in combination with low-dose cytarabine (VIALE-C) [see Adverse Reactions]. The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL. Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow dose modification guidance in the full Prescribing Information. Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase of VENCLEXTA. For patients with CLL/SLL, coadministration of VENCLEXTA with strong CYP3A inhibitors at initiation and during the 5-week ramp-up phase is contraindicated [see Contraindications]. For patients with AML, reduce the dose of VENCLEXTA when coadministered with strong CYP3A inhibitors at initiation and during the 3- or 4-day ramp-up phase. For patients with CLL/SLL or AML, reduce the dose of VENCLEXTA when coadministered with moderate CYP3A4 inhibitors or P-gp inhibitors [see Drug Interactions]. Neutropenia In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with VENCLEXTA in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients [see Adverse Reactions]. In patients with AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine. Neutropenia can recur with subsequent cycles. Monitor complete blood counts throughout the treatment period. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Infections Fatal and serious infections, such as pneumonia and sepsis, have occurred in patients treated with VENCLEXTA [see Adverse Reactions]. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution. Immunization Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations may be less effective. Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of venetoclax to pregnant animals at exposures equivalent to that observed in patients at a dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose [see Use in Specific Populations] Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Revista Puertorriqueña de Medicina y Salud Pública 5620065599 Venclexta PB-7.5 x 10.5(3.5).indd 1

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Tumor Lysis Syndrome [see Warnings and Precautions] • Neutropenia [see Warnings and Precautions] • Infections [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. In CLL/SLL, the safety population reflects exposure to VENCLEXTA as monotherapy in patients in M13-982, M14-032, and M12-175 and in combination with obinutuzumab or rituximab in patients in CLL14 and MURANO. In this CLL/SLL safety population, the most common adverse reactions (≥20%) for VENCLEXTA were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. In AML, the safety population reflects exposure to VENCLEXTA in combination with decitabine, azacitidine, or low-dose cytarabine in patients in M14-358, VIALE-A, and VIALE-C. In this safety population, the most common adverse reactions (≥30% in any trial) were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA in Combination with Obinutuzumab The safety of VENCLEXTA in combination with obinutuzumab (VEN+G) (N=212) versus obinutuzumab in combination with chlorambucil (GClb) (N=214) was evaluated in CLL14, a randomized, open-label, actively controlled trial in patients with previously untreated CLL. Patients randomized to the VEN+G arm were treated with VENCLEXTA and obinutuzumab in combination for six cycles, then with VENCLEXTA as monotherapy for an additional six cycles. Patients initiated the first dose of the 5-week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and once completed, continued VENCLEXTA 400 mg orally once daily for a total of 12 cycles. The trial required a total Cumulative Illness Rating Scale (CIRS) >6 or CLcr <70 mL/min, hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system. The median duration of exposure to VENCLEXTA was 10.5 months (range: 0 to 13.5 months) and the median number of cycles of obinutuzumab was 6 in the VEN+G arm. Serious adverse reactions were reported in 49% of patients in the VEN+G arm, most often due to febrile neutropenia and pneumonia (5% each). Fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection. In the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%. Neutropenia led to discontinuation of VENCLEXTA in 2% of patients, dose reduction in 13%, and dose interruption in 41%. Table 1 presents adverse reactions identified in CLL14. Table 1. Adverse Reactions (≥10%) in Patients Treated with VEN+G in CLL14 VENCLEXTA + Obinutuzumab + Obinutuzumab Chlorambucil (N = 212) (N = 214) All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Blood and lymphatic system disorders a 60 56 62 52 Neutropenia Anemiaa 17 8 20 7 Gastrointestinal disorders Diarrhea 28 4 15 1 Nausea 19 0 22 1 Constipation 13 0 9 0 Vomiting 10 1 8 1 General disorders and administration site conditions 21 2 23 1 Fatiguea Infections and infestations Upper respiratory 17 1 17 1 tract infectiona aIncludes multiple adverse reaction terms. Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+G are presented below: Blood and lymphatic system disorders: febrile neutropenia (6%) Infection and infestations (all include multiple adverse reaction terms): pneumonia (9%), urinary tract infection (6%), sepsis (4%) Metabolism and nutrition disorder: tumor lysis syndrome (1%) During treatment with VENCLEXTA monotherapy after completion of VEN+G, the adverse reaction that occurred in ≥10% of patients was neutropenia (26%). The grade ≥3 adverse reactions that occurred in ≥2% of patients were neutropenia (23%) and anemia (2%). Table 2 presents laboratory abnormalities CLL14. Adverse Reaction

Table 2. New or Worsening Clinically Important Laboratory Abnormalities (≥10%) in Patients Treated with VEN+G in CLL14

Laboratory

Abnormalitya

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

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

Hematology Leukopenia 90 46 89 41 Lymphopenia 87 57 87 51 Neutropenia 83 63 79 56 Thrombocytopenia 68 28 71 26 Anemia 53 15 46 11 Chemistry Blood creatinine increased 80 6 74 2 Hypocalcemia 67 9 58 4 Hyperkalemia 41 4 35 3 Hyperuricemia 38 38 38 38 aIncludes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown. Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+G included neutropenia (32%), leukopenia and lymphopenia (10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia (2%). VENCLEXTA in Combination with Rituximab The safety of VENCLEXTA in combination with rituximab (VEN+R) (N=194) versus bendamustine in combination with rituximab (B+R) (N=188) was evaluated in MURANO. Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily, in combination with rituximab for 6 cycles followed by VENCLEXTA monotherapy, for a total of 24 months after ramp-up. At the time of analysis, the median duration of exposure to VENCLEXTA was 22 months and the median number of cycles of rituximab was 6 in the VEN+R arm. Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab were reported in 2% (4/194) of patients. In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. Neutropenia and thrombocytopenia each led to discontinuation of VENCLEXTA in 3% of patients. Neutropenia led to dose interruption of VENCLEXTA in 46% of patients. Table 3 presents adverse reactions identified in MURANO. Table 3. Adverse Reactions (≥10%) in Patients Treated with VEN+R in MURANO VENCLEXTA + Bendamustine + Rituximab Rituximab (N = 194) (N = 188) Adverse Reaction All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Blood and lymphatic system disorders 65 62 50 44 Neutropeniaa 16 11 23 14 Anemiaa Gastrointestinal disorders Diarrhea 40 3 17 1 Nausea 21 1 34 1 Constipation 14 <1 21 0 Infections and infestations 39 2 23 2 Upper respiratory tract infectiona 18 2 10 2 Lower respiratory tract infectiona a Pneumonia 10 7 14 10 General disorders and administration site conditions a 22 2 26 <1 Fatigue aIncludes multiple adverse reaction terms. Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+R are presented below: Blood and lymphatic system disorders: febrile neutropenia (4%) Gastrointestinal disorders: vomiting (8%) Infections and infestations: sepsis (<1%) Metabolism and nutrition disorders: tumor lysis syndrome (3%) During treatment with VENCLEXTA monotherapy after completion of VEN+R combination treatment, adverse reactions that occurred in ≥10% of patients were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%). The Grade 3 or 4 adverse reactions that occurred in ≥2% of patients were neutropenia (12%) and anemia (3%). Table 4 presents laboratory abnormalities identified in MURANO.

/21/Dec2020 2:56 PM

DO NOT RE-SIZE US-VENA-200310

Table 4. New or Worsening Clinically Important Laboratory Abnormalities (≥10%) in Patients Treated with VEN+R in MURANO

Laboratory Abnormality

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

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

Hematology Leukopenia 89 46 81 35 Lymphopenia 87 56 79 55 Neutropenia 86 64 84 59 Anemia 50 12 63 15 Thrombocytopenia 49 15 60 20 Chemistry Blood creatinine increased 77 <1 78 1 Hypocalcemia 62 5 51 2 Hyperuricemia 36 36 33 33 Hyperkalemia 24 3 19 2 aIncludes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown. Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia (6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), hypoglycemia (2%), and hypermagnesemia (2%). VENCLEXTA as Monotherapy The safety of VENCLEXTA was evaluated in pooled data from three single-arm trials (M13-982, M14-032, and M12-175). Patients received VENCLEXTA 400 mg orally once daily after completing the ramp-up phase (N=352). The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks. In the pooled dataset, the median age was 66 years (range: 28 to 85 years), 93% were White, and 68% were male. The median number of prior therapies was 3 (range: 0 to 15). Serious adverse reactions were reported in 52% of patients, with the most frequent (≥5%) being pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most often (2 patients) from septic shock. Adverse reactions led to treatment discontinuation in 9% of patients, dose reduction in 13%, and dose interruption in 36%. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia. The most frequent adverse reaction (≥5%) leading to dose reductions or interruptions was neutropenia (8%). Table 5 presents adverse reactions identified in these trials. Table 5. Adverse Reactions Reported in ≥10% (All Grades) or ≥5% (Grade ≥3) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy VENCLEXTA (N = 352) Adverse Reaction All Grades Grade ≥3 (%) (%) Blood and lymphatic system disorders 50 45 Neutropeniaa Anemiaa 33 18 a 29 20 Thrombocytopenia Lymphopeniaa 11 7 Febrile neutropenia 6 6 Gastrointestinal disorders Diarrhea 43 3 Nausea 42 1 18 3 Abdominal paina Vomiting 16 1 Constipation 16 <1 13 <1 Mucositisa Infections and infestations 36 1 Upper respiratory tract infectiona Pneumoniaa 14 8 11 2 Lower respiratory tract infectiona General disorders and administration site conditions a 32 4 Fatigue 22 2 Edemaa Pyrexia 18 <1 Musculoskeletal and connective tissue disorders 29 2 Musculoskeletal paina Arthralgia 12 <1 Respiratory, thoracic, and mediastinal disorders 22 0 Cougha 13 1 Dyspneaa Nervous system disorders Headache 18 <1 14 0 Dizzinessa Skin and subcutaneous tissue disorders 18 <1 Rasha Adverse reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms.

20065599 Venclexta PB-7.5 x 10.5(3.5).indd 2

Table 6 presents laboratory abnormalities reported throughout treatment that were new or worsening from baseline. The most common (>5%) Grade 4 laboratory abnormalities observed with VENCLEXTA monotherapy were hematologic laboratory abnormalities, including neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%). Table 6. New or Worsening Laboratory Abnormalities in ≥40% (All Grades) or ≥10% (Grade 3 or 4) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy Laboratory Abnormality

VENCLEXTA (N = 352) All Gradesa Grade 3 or 4 (%) (%)

Hematology Leukopenia 89 42 Neutropenia 87 63 Lymphopenia 74 40 Anemia 71 26 Thrombocytopenia 64 31 Chemistry Hypocalcemia 87 12 Hyperglycemia 67 7 Hyperkalemia 59 5 AST increased 53 3 Hypoalbuminemia 49 2 Hypophosphatemia 45 11 Hyponatremia 40 9 aIncludes laboratory abnormalities that were new or worsening, or worsening from baseline unknown. Important Adverse Reactions in CLL/SLL Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA. CLL14 The incidence of TLS was 1% (3/212) in patients treated with VEN+G [see Warnings and Precautions]. All three events of TLS resolved and did not lead to withdrawal from the trial. Obinutuzumab administration was delayed in two cases in response to the TLS events. MURANO The incidence of TLS was 3% (6/194) in patients treated with VEN+R. After 77/389 patients were enrolled in the trial, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures. All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days. All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 4. Monotherapy Studies (M13-982 and M14-032) In 168 patients with CLL treated according to recommendations described in sections 2.1 and 2.2, the rate of TLS was 2%. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L), or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm and/or absolute lymphocyte count (ALC) ≥25 x 109/L. All events resolved within 5 days. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures was observed in these patients. All patients had CLcr ≥50 mL/min. Laboratory abnormalities relevant to TLS were hyperkalemia (17% all Grades, 1% Grade ≥3), hyperphosphatemia (14% all Grades, 2% Grade ≥3), hypocalcemia (16% all Grades, 2% Grade ≥3), and hyperuricemia (10% all Grades, <1% Grade ≥3). In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting doses, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. After this experience, TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised. Acute Myeloid Leukemia VENCLEXTA in Combination with Azacitidine The safety of VENCLEXTA in combination with azacitidine (VEN+AZA) (N=283) versus placebo in combination with azacitidine (PBO+AZA) (N=144) was evaluated in VIALE-A, a double-blind, randomized trial, in patients with newly diagnosed AML. At baseline, patients were ≥75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients were randomized to receive VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or placebo in combination with azacitidine. Among patients who received VEN+AZA, the median duration of exposure to VENCLEXTA was 7.6 months (range: <0.1 to 30.7 months). Serious adverse reactions were reported in 83% of patients who received VEN+AZA, with the most frequent (≥5%) being febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). Fatal adverse reactions occurred in 23% of patients who received VEN+AZA, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%). Adverse reactions led to permanent discontinuation of VENCLEXTA in 24% of patients, dose reductions in 2%, and dose interruptions in 72%. Adverse reactions which led to discontinuation of VENCLEXTA in ≥2% of patients were sepsis (excluding fungal; 3%) and pneumonia (2%). The most frequent adverse reaction leading to dose reduction was pneumonia (0.7%). Adverse reactions which required a dose interruption in ≥5% of patients included febrile neutropenia (20%), neutropenia (20%), pneumonia (14%), sepsis (excluding fungal; 11%), and thrombocytopenia

(10%). Among patients who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for absolute neutrophil count (ANC) <500/microliter. Table 7 presents adverse reactions identified in VIALE-A. Table 7. Adverse Reactions (≥10%) in Patients with AML Who Received VEN+AZA with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+AZA in VIALE-A

Adverse Reaction

VENCLEXTA + Azacitidine (N = 283)

Placebo + Azacitidine (N = 144)

All Grade 3 All Grade 3 Grades or 4 Grades or 4 (%) (%) (%) (%)

Gastrointestinal disorders Nausea

Diarrheaa

<1 3

Vomitingb

Stomatitisc

Abdominal paind

Blood and lymphatic system disorders Febrile neutropenia

Musculoskeletal and connective tissue disorders Musculoskeletal paine

General disorders and administration site conditions Fatiguef

Edemag

Vascular disorders Hemorrhageh

Hypotensioni

Sepsisl (excluding fungal)

Urinary tract infectionm

Metabolism and nutrition disorders Decreased appetitej

Skin and subcutaneous tissue disorders Rashk Infections and infestations

Respiratory, thoracic and mediastinal disorders Dyspnean

Nervous system disorders Dizzinesso aIncludes

diarrhea and colitis. vomiting and hematemesis. cIncludes stomatitis, mouth ulceration, mucosal inflammation, cheilitis, aphthous ulcer, glossitis, and tongue ulceration. dIncludes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. eIncludes arthralgia, back pain, pain in extremity, musculoskeletal pain, bone pain, myalgia, neck pain, non-cardiac chest pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, spinal pain, and musculoskeletal discomfort. fIncludes fatigue and asthenia. gIncludes edema peripheral, edema, generalized edema, eyelid edema, face edema, penile edema, periorbital edema, and swelling. hIncludes epistaxis, hematuria, conjunctival hemorrhage, hemoptysis, hemorrhoidal hemorrhage, gingival bleeding, mouth hemorrhage, hemorrhage intracranial, vaginal hemorrhage, cerebral hemorrhage, gastrointestinal hemorrhage, muscle hemorrhage, skin hemorrhage, upper gastrointestinal hemorrhage, anal hemorrhage, eye hemorrhage, gastritis hemorrhagic, hemorrhage, hemorrhage urinary tract, hemorrhagic diathesis, hemorrhagic stroke, hemorrhagic vasculitis, lower gastrointestinal hemorrhage, mucosal hemorrhage, penile hemorrhage, post procedural hemorrhage, rectal hemorrhage, retinal hemorrhage, shock hemorrhagic, soft tissue hemorrhage, subdural hemorrhage, tongue hemorrhage, urethral hemorrhage, vessel puncture site hemorrhage, vitreous hemorrhage, and wound hemorrhage. iIncludes hypotension and orthostatic hypotension. jIncludes decreased appetite and hypophagia. kIncludes rash, rash maculo-papular, rash macular, drug eruption, rash papular, rash pustular, eczema, rash erythematous, rash pruritic, dermatitis acneiform, rash morbilliform, dermatitis, eczema asteatotic, exfoliative rash, and perivascular dermatitis. lIncludes sepsis, escherichia bacteremia, escherichia sepsis, septic shock, bacteremia, staphylococcal bacteremia, klebsiella bacteremia, staphylococcal sepsis, streptococcal bacteremia, enterococcal bacteremia, klebsiella sepsis, pseudomonal bacteremia, pseudomonal sepsis, urosepsis, bacterial sepsis, clostridial sepsis, enterococcal sepsis, neutropenic sepsis, and streptococcal sepsis. mIncludes urinary tract infection, escherichia urinary tract infection, cystitis, urinary tract infection enterococcal, urinary tract infection bacterial, pyelonephritis acute, and urinary tract infection pseudomonal. nIncludes dyspnea, dyspnea exertional, and dyspnea at rest. oIncludes dizziness and vertigo. bIncludes

Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 7 or <10% are presented below: Hepatobiliary disorders: cholecystitis/cholelithiasisa (4%) Infections and infestations: pneumoniab (33%) Metabolism and nutrition disorders: tumor lysis syndrome (1%) Nervous system disorders: headachec (11%)

Revista Puertorriqueña de Medicina y Salud Pública

/21/Dec2020 2:56 PM

DO NOT RE-SIZE US-VENA-200310

Investigations: weight decreased (13%). aIncludes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis chronic. bIncludes pneumonia, lung infection, pneumonia fungal, pneumonia klebsiella, atypical pneumonia, lower respiratory tract infection, pneumonia viral, lower respiratory tract infection fungal, pneumonia hemophilus, pneumonia pneumococcal, and pneumonia respiratory syncytial viral. cIncludes headache and tension headache. Table 8 presents laboratory abnormalities identified in VIALE-A. Table 8. New or Worsening Laboratory Abnormalities (≥10%) in Patients with AML Who Received VEN+AZA with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+AZA in VIALE-A

Laboratory Abnormality

Hematology Neutrophils decreased Platelet decreased Lymphocytes decreased Hemoglobin decreased Chemistry Bilirubin increased Calcium decreased Sodium decreased Alkaline phosphatase increased

VENCLEXTA + Placebo + Azacitidine Azacitidine All Grade 3 All Grade 3 Grades or 4 Grades or 4 (%) (%) (%) (%) 98 94 91 61 53 51 46 42

98 88 71 57 7 6 14 1

88 94 72 56 40 39 47 29

81 80 39 52 4 9 8 <1

Blood bicarbonate decreased 31 <1 25 0 The denominator used to calculate the rate varied from 85 to 144 in the PBO+AZA arm and from 125 to 283 in the VEN+AZA arm based on the number of patients with at least one post-treatment value. VENCLEXTA in Combination with Azacitidine or Decitabine The safety of VENCLEXTA in combination with azacitidine (N=67) or decitabine (N=13) was evaluated in M14-358, a non-randomized trial of patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity . Patients received VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or decitabine (20 mg/m2 intravenously on Days 1-5 of each 28-day cycle). Azacitidine The median duration of exposure to VENCLEXTA when administered in combination with azacitidine was 6.5 months (range: 0.1 to 38.1 months). The safety of VENCLEXTA in combination with azacitidine in this trial is consistent with that of VIALE-A. Decitabine The median duration of exposure to VENCLEXTA when administered in combination with decitabine was 8.4 months (range: 0.5 to 39 months). Serious adverse reactions were reported in 85% of patients who received VENCLEXTA with decitabine, the most frequent (≥10%) being sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment. Permanent discontinuation of VENCLEXTA due to adverse reactions occurred in 38% of patients. The most frequent adverse reaction leading to permanent discontinuation (≥5%) was pneumonia (8%). Dosage reductions of VENCLEXTA due to adverse reactions occurred in 15% of patients. The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia (15%). Dosage interruptions of VENCLEXTA due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions leading to dose interruption (≥10%) were neutropenia (38%), febrile neutropenia (23%), leukopenia (15%), and pneumonia (15%). The most common adverse reactions (≥30%) were febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexia (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%), and vomiting (31%). The most common laboratory abnormalities (≥30%) were neutrophils decreased (100%), lymphocytes decreased (100%), white blood cells decreased (100%), platelets decreased (92%), calcium decreased (85%), hemoglobin decreased (69%), glucose increased (69%), magnesium decreased (54%), potassium decreased (46%), bilirubin increased (46%), albumin decreased (38%), alkaline phosphatase increased (38%), sodium decreased (38%), ALT increased (31%), creatinine increased (31%), and potassium increased (31%). VENCLEXTA in Combination with Low-Dose Cytarabine VIALE-C The safety of VENCLEXTA in combination with low-dose cytarabine (VEN+LDAC) (N=142) versus placebo with low-dose cytarabine (PBO+LDAC) (N=68) was evaluated in VIALE-C, a double-blind randomized trial in patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients were randomized to receive VENCLEXTA 600 mg orally once daily after completion of a 4-day ramp-up phase in combination with low-dose cytarabine (20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle) or placebo in combination with low-dose cytarabine. Among patients who received VEN+LDAC, the median duration of exposure to VENCLEXTA was 3.9 months (range: <0.1 to 17.1 months). Serious adverse reactions were reported in 65% of patients who received VEN+LDAC, with the most frequent (≥10%) being pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). Fatal adverse

Revista Puertorriqueña de Medicina y Salud Pública 58 20065599 Venclexta PB-7.5 x 10.5(3.5).indd 3

reactions occurred in 23% of patients who received VEN+LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%). Adverse reactions led to permanent discontinuation of VENCLEXTA in 25% of patients, dose reductions in 9%, and dose interruptions in 63%. The most frequent adverse reaction (>2%) which resulted in permanent discontinuation of VENCLEXTA was pneumonia (6%). Adverse reactions which required a dose reduction in ≥1% of patients were pneumonia (1%) and thrombocytopenia (1%), and the adverse reactions which required a dose interruption in ≥5% of patients included neutropenia (20%), thrombocytopenia (15%), pneumonia (8%), febrile neutropenia (6%), and sepsis (excluding fungal; 6%). Among patients who achieved bone marrow clearance of leukemia, 32% underwent dose interruptions for ANC <500/microliter. Table 9 presents adverse reactions identified in VIALE-C. Table 9. Adverse Reactions (≥10%) in Patients with AML Who Received VEN+LDAC with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Compared with PBO+LDAC in VIALE-C

Adverse Reaction

VENCLEXTA + Low-Dose Cytarabine (N = 142)

Placebo + Low-Dose Cytarabine (N = 68)

All Grade All Grade Grades 3 or 4 Grades 3 or 4 (%) (%) (%) (%) Gastrointestinal disorders

Table 10. New or Worsening Laboratory Abnormalities (≥10%) in Patients with AML Who Received VEN+LDAC with Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+LDAC in VIALE-C

Laboratory Abnormality

VENCLEXTA + Low-Dose Cytarabine

Placebo + Low-Dose Cytarabine

All Grade All Grade Grades 3 or 4 Grades 3 or 4 (%) (%) (%) (%)

Hematology Platelets decreased

Neutrophils decreased

Lymphocytes decreased

Hemoglobin decreased

Bilirubin increased

Albumin decreased

Potassium decreased

Calcium decreased

Glucose increased

Chemistry

Nausea

AST increased

Diarrhea

Alkaline phosphatase increased

Vomiting

ALT increased

Abdominal paina

Sodium increased

Stomatitisb

Hemorrhaged

Hypotensione

Blood and lymphatic system disorders Febrile neutropenia Infections and infestations c

Pneumonia

Vascular Disorders

Musculoskeletal and connective tissue disorders Musculoskeletal painf

General Disorders and Administration Site Conditions Fatigueg

Nervous System Disorders Headache aIncludes

abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. bIncludes stomatitis, mouth ulceration, aphthous ulcer, glossitis, mucosal inflammation, and tongue ulceration. cIncludes pneumonia, lung infection, lower respiratory tract infection, pneumonia fungal, lower respiratory tract infection fungal, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia cytomegaloviral, and pneumonia pseudomonal. dIncludes epistaxis, conjunctival hemorrhage, hemoptysis, gastrointestinal hemorrhage, gingival bleeding, mouth hemorrhage, upper gastrointestinal hemorrhage, hematuria, retinal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, gastric hemorrhage, gastritis hemorrhagic, hemorrhage intracranial, hemorrhage subcutaneous, lip hemorrhage, mucosal hemorrhage, pharyngeal hemorrhage, post procedural hemorrhage, pulmonary alveolar hemorrhage, pulmonary hemorrhage, tooth pulp hemorrhage, uterine hemorrhage, and vascular access site hemorrhage. eIncludes hypotension and orthostatic hypotension. fIncludes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, arthritis, bone pain, musculoskeletal chest pain, and spinal pain. gIncludes fatigue and asthenia. Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 9 or <10% are presented below: Hepatobiliary disorders: cholecystitis/cholelithiasisa (1%) Infections and infestations: sepsisb (excluding fungal; 15%), urinary tract infectionc (8%) Metabolism and nutrition disorders: decreased appetite (19%), tumor lysis syndrome (6%) Nervous system disorders: dizzinessd (9%) Respiratory, thoracic, and mediastinal disorders: dyspneae (10%) Investigations: weight decreased (9%). aIncludes cholecystitis and cholecystitis acute. bIncludes sepsis, bacteremia, septic shock, neutropenic sepsis, staphylococcal bacteremia, streptococcal bacteremia, bacterial sepsis, Escherichia bacteremia, pseudomonal bacteremia, and staphylococcal sepsis. cIncludes urinary tract infection and escherichia urinary tract infection. dIncludes dizziness and vertigo. eIncludes dyspnea and dyspnea exertional. Table 10 describes laboratory abnormalities identified in VIALE-C.

The denominator used to calculate the rate varied from 38 to 68 in the PBO+LDAC arm and from 65 to 142 in the VEN+LDAC arm based on the number of patients with at least one post-treatment value. M14-387 The safety of VENCLEXTA in combination with low-dose cytarabine (N=61) was evaluated in M14-387, a non-randomized, open- label trial of patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients received VENCLEXTA 600 mg orally once daily after completion of the ramp-up phase in combination with low-dose cytarabine (20mg/m2 subcutaneously on Days 1-10 of each 28-day cycle). The safety of VENCLEXTA in combination with low-dose cytarabine is consistent with that of VIALE-C. DRUG INTERACTIONS Effects of Other Drugs on VENCLEXTA Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax Cmax and AUC0-INF, which may increase VENCLEXTA toxicities, including the risk of TLS [see Warnings and Precautions]. Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated [see Contraindications]. In patients with CLL/SLL taking a steady daily dosage (after ramp-up phase), consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions. In patients with AML, adjust VENCLEXTA dosage and monitor more frequently for adverse reactions. Resume the VENCLEXTA dosage that was used prior to concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A. Strong or Moderate CYP3A Inducers Concomitant use with a strong CYP3A inducer decreases venetoclax Cmax and AUC0-INF, which may decrease VENCLEXTA efficacy. Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers. Effect of VENCLEXTA on Other Drugs Warfarin Concomitant use of VENCLEXTA increases warfarin Cmax and AUC0-INF, which may increase the risk of bleeding. Monitor international normalized ratio (INR) more frequently in patients using warfarin concomitantly with VENCLEXTA. P-gp Substrates Concomitant use of VENCLEXTA increases Cmax and AUC0-INF of P-gp substrates, which may increase toxicities of these substrates. Avoid concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VENCLEXTA use in pregnant women to inform a drug-associated risk. Administration of venetoclax to pregnant mice during the period of organogenesis was fetotoxic at exposures 1.2 times the human exposure at the recommended dose of 400 mg daily based on AUC. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

/21/Dec2020 2:56 PM

DO NOT RE-SIZE US-VENA-200310

Data Animal data In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human exposure at the recommended dose of 400 mg once daily). No teratogenicity was observed in either the mouse or the rabbit. Lactation Risk Summary There are no data on the presence of VENCLEXTA in human milk or the effects on the breastfed child or milk production. Venetoclax was present in the milk when administered to lactating rats (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose. Data Animal Data Venetoclax was administered (single dose; 150 mg/kg oral) to lactating rats 8 to 10 days post-parturition. Venetoclax in milk was 1.6 times lower than in plasma. Parent drug (venetoclax) represented the majority of the total drug-related material in milk, with trace levels of three metabolites. Females and Males of Reproductive Potential VENCLEXTA may cause fetal harm when administered to pregnant women [see Use in Specific Populations]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating VENCLEXTA. Contraception Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose. Infertility Based on findings in animals, VENCLEXTA may impair male fertility. Pediatric Use The safety and effectiveness of VENCLEXTA have not been established in pediatric patients. Juvenile Animal Toxicity Data In a juvenile toxicology study, mice were administered venetoclax at 10, 30, or 100 mg/kg/day by oral gavage from 7 to 60 days of age. Clinical signs of toxicity included decreased activity, dehydration, skin pallor, and hunched posture at ≥30 mg/kg/day. In addition, mortality and body weight effects occurred at 100 mg/kg/day. Other venetoclax-related effects were

20065599 Venclexta PB-7.5 x 10.5(3.5).indd 4

reversible decreases in lymphocytes at ≥10 mg/kg/day; a dose of 10 mg/kg/day is approximately 0.06 times the clinical dose of 400 mg on a mg/m2 basis for a 20 kg child. Geriatric Use Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Of the 352 patients with previously treated CLL/SLL evaluated for safety from 3 open-label trials of VENCLEXTA monotherapy, 57% (201/352) were ≥65 years of age and 18% (62/352) were ≥75 years of age. No clinically meaningful differences in safety and effectiveness were observed between older and younger patients in the combination and monotherapy studies. Acute Myeloid Leukemia Of the 283 patients who received VENCLEXTA with azacitidine in VIALE-A, 96% were ≥65 years of age and 60% were ≥75 years of age. Of the 13 patients who received VENCLEXTA in combination with decitabine in M14-358, 100% were ≥65 years of age and 62% were ≥75 years of age. Of the 142 patients who received VENCLEXTA in combination with low-dose cytarabine in VIALE-C, 92% were ≥65 years of age and 57% were ≥75 years of age. Clinical studies of VENCLEXTA in patients with AML did not include sufficient numbers of younger adults to determine if patients 65 years of age and older respond differently from younger adults. Renal Impairment Due to the increased risk of TLS, patients with reduced renal function (CLcr <80 mL/min, calculated by Cockcroft-Gault formula) require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA [Warnings and Precautions]. No dose adjustment is recommended for patients with mild, moderate or severe renal impairment (CLcr ≥15 mL/min). Hepatic Impairment No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions. OVERDOSAGE There is no specific antidote for VENCLEXTA. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities. Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.

Manufactured and Marketed by: AbbVie Inc. North Chicago, IL 60064 and Marketed by: Genentech USA, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 © 2016-2020 AbbVie Inc. © 2016-2020 Genentech, Inc. 20065599 November 2020 Ref: 20065599 Revised: November 2020 LAB-4394 MASTER

US-VENA-200310

Revista Puertorriqueña de Medicina y Salud Pública

/21/Dec2020 2:56 PM

OSTEOARTRITIS, UNA CONDICIÓN METABÓLICA QUE REQUIERE ATENCIÓN TEMPRANA PARA NO LLEGAR A SER LIMITANTE

RESUMEN En entrevista con la Revista Medicina y Salud Pública, el Dr. Efraín Carrasquillo, reumatólogo y pasado presidente de la Asociación de Reumatólogos de Puerto Rico explicó cuál es la sintomatología que puede ayudar al paciente a detectar la condición de osteoartritis, una condición progresiva que requiere atención temprana. La osteoartritis, del grupo de las artritis, es la afección más común en seres humanos, siendo el envejecimiento el factor número uno para padecerla.

PALABRAS CLAVE osteoartritis KEYWORDS osteoarthritis Rayo X posterior de la cadera anterior que muestra osteoartritis avanzada de la cadera izquierda que necesita artroplastia

Revista Puertorriqueña de Medicina y Salud Pública

ABSTRACT In an interview with the "Revista Medicina y Salud Pública", Dr. Efraín Carrasquillo, rheumatologist and past president of the Association of Rheumatologists of Puerto Rico, explained the symptoms that can help the patient detect the condition of osteoarthritis, a progressive condition that requires early attention. Osteoarthritis, of the group of arthritis, is the most common condition in human beings, aging being the number one factor in suffering from it.

DR. EFRAÍN CARRASQUILLO Dr. Efraín Carrasquillo, reumatólogo y pasado presidente de la Asociación de Reumatólogos de Puerto Rico

SÍNTOMAS Rigidez en la mañana que alivia según la persona se va moviendo y va calentando, la necesidad de tomar tabletas para sentir alivio y la urgencia de ajustar estilo de vida a dichas condiciones son los síntomas más comunes de esta condición médica. En personas jóvenes, lo que la precipita son las lesiones como los traumas y golpes cerca de una coyuntura, que pueden empezar a cambiar a una edad temprana y no en la edad común. La obesidad, además hace que las coyunturas sostengan demasiado peso, generando dificultad en espalda baja, caderas, pies y tobillos, afectando la vida del paciente. "Si me preguntan qué es el miedo de un paciente, es el miedo de perder independencia, más que el dolor, si le damos herramientas para el dolor el paciente siempre tiene en la mira poder lograrlo", recalcó el reumatólogo. El cambio degenerativo va modificando la vida del paciente, limitándolo en su movimiento y volviéndolo dependiente de alguien, por eso, la meta es trabajar para lograr que el paciente pueda defenderse por sí solo, favoreciendo así no solo su vida sino la de todo el núcleo familiar. OSTEOPOROSIS LIGADA A LA OSTEOARTRITIS Siendo una condición metabólica también, su sintomatología suele ser más común en mujeres especialmente durante los primeros 8 años después de la menopausia, teniendo factores que las limitan. "M ujeres que inician su

menopausia a los 40 años ya a los 48 años tendrían la posibilidad de tener un esqueleto envejecido... condiciones que las limitan y las lastiman", expresó el especialista. Además, recalcó la importancia de un acompañamiento completo en el campo de la salud, en donde el ginecólogo debe estar preparado para entender cuando la mujer este iniciando este cambio, para que sepan identificar el problema y se acerquen a tiempo a un profesional. El acompañamiento debe ser desde el reumatólogo que entiende las relaciones de hueso con los sistemas, pasando por el fisiatra, hasta el ortopeda que evalúa los cambios en la estructura y brinda alternativas para las coyunturas afectadas. TRATAMIENTOS El paciente con osteoartritis requiere un control multidisciplinario especialmente por la necesidad de cuidar enfermedades crónicas como la diabetes y la obesidad. En muchos casos, es indispensable alterar los estilos de vida que se manejan hoy, el estrés, el sedentarismo, la alimentación, la falta de actividad física, esto es tan indispensable como la medicina. Los analgésicos son una alternativa para pacientes que se puede utilizar solo en momentos de malestar y no los hace dependientes a medicamentos siendo el más común el acetaminofén. Con los antiinflamatorios, el paciente tiene opción de hacer un tratamiento por corto tiempo y existe la opción de inyectar las coyunturas, pero no todos los pacientes son candidatos para todos los métodos, por eso

es indispensable la adecuada evaluación y el diagnostico de diferentes especialistas. En caso de requerirlo, el fisiatra también puede brindar alternativas de acuerdo a las necesidades de cada paciente, con el fin de facilitar la forma en la que realiza sus acciones evitando accidentes y limitaciones. Cuando el paciente llega a casos de remplazo, se debe a una afectación completa de la articulación, sin embargo, en la mayoría de los casos, el paciente aún es muy funcional. Se deben evaluar además las demás condiciones, por ejemplo, un diabético con insulina, no es candidato para cirugía de reemplazo, y la diabetes es una condición que es muy común en Puerto Rico. ¿ES POSIBLE REGENERAR ARTICULACIONES? Los ortopedas usan la glucosamina y otros suplementos que son proteínas y que, por ejemplo, los cartílagos cuando están jóvenes la tienen en altas cantidades, pero con el paso de los años se va perdiendo. Ante esto, se ha evidenciado que al brindársele al paciente de forma temprana tienen una desaceleración en el proceso. "A veces estamos contemplando solamente que medicamento le puedo dar para aliviarlo, pero no estás pensando en cómo lo puedo rehabilitar y cómo se puede fortalecer, así que la acción no descansaría solamente en los medicamentos, sino en la rehabilitación para mantener al paciente fuerte", señaló el Dr. Carrasquillo. Revista Puertorriqueña de Medicina y Salud Pública

USO CONCURRENTE DE OPIOIDES Y BENZODIACEPINAS: EL VERDADERO DESAFÍO

ALGUNAS RECOMENDACIONES SON:

Utilizar terapias no farmacológicas y/o terapias farmacológicas no opioides.

Establecer metas realistas y educar al paciente sobre los opioides.

Utilizar opioides de acción inmediata en lugar de acción prolongada.

Evaluar frecuentemente los beneficios y riesgos de la terapia con opioides.

Evitar recetar opioides y benzodiacepinas simultáneamente.

Revista Puertorriqueña de Medicina y Salud Pública

DRA. CAROLYN RODRÍGUEZ RIVERA, PHARMD Vicepresidenta Ejecutiva de Farmacia de MCS

Existen alternativas terapéuticas que pueden ser consideradas para remplazar el uso de opioides y benzodiacepinas1, 4

RESUMEN n los últimos años han aumentado significativamente las muertes por sobredosis de opioides. Se estima que 1 de cada 3 de estas muertes involucra una benzodiacepina. En Puerto Rico existe sobreutilización de ambos medicamentos, pues, tan solo en el 2018, se registraron casi 500 mil recetas de opioides y más de un millón de recetas de benzodiacepinas.

ABSTRACT Opioid overdose deaths have increased significantly in recent years. An estimated 1 in 3 of these deaths involves a benzodiazepine. In Puerto Rico there is overuse of both drugs, since, in 2018 alone, almost 500 thousand opioid prescriptions and more than one million benzodiazepine prescriptions were registered.

PALABRAS CLAVE opioides, sobredosis KEYWORDS opioids, overdose

El uso concurrente de opioides y benzodiacepinas puede provocar serias complicaciones de salud. Estas incluyen deterioro cognitivo, somnolencia extrema, depresión respiratoria, caídas, estado de coma e incluso la muerte, y son más comunes en pacientes de 65 años o más. Esta población, comúnmente, utiliza múltiples medicamentos recetados por varios proveedores, lo que dificulta la identificación de sobreutilización y efectos adversos1. Las benzodiacepinas, incluso cuando se toman en las dosis recomendadas, pueden provocar abuso y adicción. Por ello, la Administración de Alimentos y Medicamentos (FDA, por sus siglas en inglés) requirió que se le añadiera una alerta (boxed warning) para promover su uso seguro2. Asimismo, el Centro para el Control y la Prevención de Enfermedades (CDC, por sus siglas en inglés) publicó una guía para evitar la sobreutilización de opioides y, por ende, reducir su uso simultáneo con benzodiacepinas3.

Revista Puertorriqueña de Medicina y Salud Pública

TERAPIA FARMACOLÓGICA

ALTERNATIVA TERAPÉUTICA

OPIOIDES

• Medicamentos analgésicos (OTC): acetaminofén, ibuprofen, naproxen • Inhibidores de recaptación de serotonina-norepinefrina • SSRI: sertralina, escitalopram, fluoxetina. SNRI: venlafaxina, duloxetina, milnacipran • Medicamentos tópicos: Diclofenac (gel) • Inyecciones localizadas • Estimulación nerviosa eléctrica transcutánea

BENZODIACEPINAS

• Medicamentos inhibidores selectivos de la recaptación de serotonina (SSRI, SNRI) • Buspirona

Los Centros de Servicios de Medicare y Medicaid (CMS, por sus siglas en inglés) han implementado programas para revisar la utilización de opioides y benzodiacepinas5. Estos pueden ayudar a identificar pacientes a riesgo y manejar adecuadamente su terapia. Así, cumplimos como profesionales de la salud con brindar un tratamiento seguro y eficaz a nuestros pacientes. Las guías clínicas recomiendan limitar la dosis y duración de las benzodiacepinas, ya sean solas o en combinación, al mínimo necesario para lograr el efecto clínico deseado. Se debe disminuir gradualmente la dosis de uno, o ambos, para minimizar los síntomas de retirada6. Para reducir la ansiedad asociada al proceso, se

recomienda disminuir paulatinamente los opioides antes que las benzodiacepinas6. Es importante dialogar con los pacientes sobre los medicamentos controlados que utilizan, especialmente cuando estos son recetados por diferentes proveedores. Además, se debe reevaluar el progreso del tratamiento, considerar alternativas seguras y descontinuar medicamentos innecesarios. Estas prácticas clínicas ayudan a controlar el uso de estas terapias para evitar su sobreutilización y efectos adversos, contribuyendo a mantener a los pacientes seguros. REFERENCIAS by

1. Reduce Risk of Opioid Overdose Deaths Avoiding and Reducing Co -Prescribing

Benzodiazepines, 2019. https://www.cms.gov/ Outreach-and-Education/Medicare-Learning-Net work- MLN/MLNMat tersArticles/Downloads/ SE19011.pdf 2.Concurrent Use of Opioids with Other Central Nervous System-Active Medications Among Older Adults. Population Health Management 2020; 23(4): 286-296. 3.CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. JAMA. 2016 April 19; 315(15): 1624–1645. 4.Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ 2017;356: j760. 5.Concurrent Use of Opioids and Benzodiazepines (COB-AD). Measure Details, cmit.cms.gov/CMIT_ public/ViewMeasure?MeasureId=5887. 6.Opioids and Benzodiazepines Just Don't Mix. Timely Information for Providers in South Carolina, South Caroline Healthy Connections, cme-opioids-benzodiazepines-dont-mix, 2018. https://msp.scdhhs. gov/tipsc/sites/default/files/tipsc_mailer_v3_23%20 final%204-13-18%20(003).pdf

AFILIADO DE MCS CLASSICARE

Nadie puede contra TO' LOS POWERS de MCS Classicare

MCS Classicare es un producto suscrito por MCS Advantage, Inc. MCS Classicare es un plan OSS con un contrato Medicare. La afiliación en MCS Classicare de la renovación dely Salud contrato. Revista Puertorriqueña de Medicina Pública Ciertas restricciones aplican. H5577_1317S0121_M 64 depende

www.mcsclassicare.com

@MCSPuertoRico

CENTRO MÉDICO EPISCOPAL SAN LUCAS CONCEDE GRADOS A 46 NUEVOS MÉDICOS ESPECIALISTAS

Luego de más de un año de inesperadas experiencias, un grupo de 46 galenos de Educación Médica Graduada en el Centro Médico Episcopal San Lucas (CMESL) completó una jornada en el camino profesional convirtiéndose en nuevos especialistas que aportarán al cuidado de la salud de los puertorriqueños. Entre los nuevos galenos se encuentran especialistas en medicina interna (8), pediatría (6), medicina de emergencia (7), obstetricia y ginecología (4), cirugía (3), preliminar de cirugía (3) y subespecialidad de cardiología (2). Además, completaron su año transicional 13 médicos.

“Nuestras metas se han logrado, preservar el legado, continuarlo con estándares altos y creando nuevos programas de residencia para ayudar a nuestro país en la retención de médicos en diferentes especialidades. Como galenos que somos sigamos trabajando con el altruismo que nos caracteriza y dando nuestro mejor esfuerzo a cada paciente que necesite nuestro cuidado”, mencionó la Dra. María Valentín Mari, Directora de Educación Médica Graduada. El Dr. Gabriel José Ramos González fue reconocido por su compromiso y liderazgo durante sus años de residencia en Educación Médica Graduada y, además, recibió el premio especial Dr.

Raúl Armstrong de Cirugía General, concedido por primera vez en la historia del Centro Médico Episcopal San Lucas. El Programa de Educación Médica, está acreditado por el Accreditation Council for Graduate Medical Education (ACGME), organismo que rige las residencias médicas en Estados Unidos y es parte de un consorcio educativo con la Ponce Health Sciences University. Para información sobre el Centro Médico Episcopal San Lucas Ponce y otros servicios puede visitar su página web www.sanlucaspr.org, seguirles a través de Facebook, Instagram, LinkedIn y YouTube o comunicarse al 787-844-2080. Revista Puertorriqueña de Medicina y Salud Pública

CENTRO MÉDICO EPISCOPAL SAN LUCAS INAUGURA MODERNA UNIDAD DE SALUD CONDUCTUAL CON SERVICIOS ESPECIALIZADOS

El proyecto cuenta con sala estabilizadora y una moderna unidad aguda

Con el propósito de brindar atención médica especializada y atender las necesidades de los pacientes de salud conductual en todo Puerto Rico, el Centro Médico Episcopal San Lucas inauguró el Centro de Salud Conductual San Lucas, un programa holístico que combina lo físico, mental y espiritual. Esta moderna unidad, construida con una inversión de $5.2 millones, ha generado más de 50 empleos directos en la región Sur de la Isla. El proyecto cuenta con una sala estabilizadora de emergencias psiquiátricas disponible los siete días, con médicos y enfermeros capacitados para estabilizar al paciente. La misma atenderá situaciones como crisis psicótica aguda, ideas suicidas, 66

Revista Puertorriqueña de Medicina y Salud Pública

intoxicación a medicamentos o sustancias ilegales, autoagresiones y otros eventos de riesgo. Del mismo modo, contará con una unidad de tratamiento agudo, con 30 camas distribuidas en habitaciones privadas y semi privadas, y tratamiento psiquiátrico a pacientes mayores de 18 años. Para obtener orientación puede llamar al 787-625-1430 y coordinación de servicios 787-813-1111. Para información sobre el Centro Médico Episcopal San Lucas Ponce y otros servicios puede visitar su página web: www.sanlucaspr.org, seguirles a través de Facebook, Instagram, LinkedIn, Twitter y YouTube/CentroMedicoEpiscopalSanLucas o comunicarse al 787-844-2080.

NUEVO Y MODERNO MRI EN EL HOSPITAL METROPOLITANO El Hospital Metropolitano adquirió recientemente nueva tecnología de servicio de imagen por resonancia magnética (MRI) que le asegura al paciente una atmósfera agradable, relajante y cómoda. Se trata del equipo conocido como opción InBore Experience, único en Puerto Rico, el Ingenia Ambition S, adquirido a un costo de $1.6 millones. El nuevo MRI forma parte de los servicios especializados que ofrece el Hospital Metropolitano, explicó Talavera. El hospital cuenta con un centro de imágenes con alta tecnología para diversos estudios y procedimientos tales como Tomografía Computarizada (CT Scan), Sonografía Digital, Radiología Convencional, Medicina Nuclear, entre otros. También cuenta con D’Mujer Health and Prevention Center, que es un centro comprensivo especializado en el campo de las imágenes al cuidado del bienestar y la salud de la mujer. El “Metro MRI” se encuentra en el primer piso de la Torre Médica del Hospital Metropolitano, ubicado en la Carr. 21 #1785 Ave. Las Lomas #21, San Juan (entre las estaciones del tren de Martínez Nadal y Las Lomas). Para información adicional o para coordinar una cita puede comunicarse al 787-782-9999 ext. 7777, 1133 o 5352. Revista Puertorriqueña de Medicina y Salud Pública

PUERTO RICO SE UNE A LOS PAÍSES QUE REALIZAN EL ESTUDIO DE VACUNAS EXPERIMENTALES PARA LA PREVENCIÓN DEL VIH

El Proyecto GAMMA en unión al Proyecto ACTU del Recinto de Ciencias Médicas (RCM) de la Universidad de Puerto Rico (UPR), anunciaron hoy que han sido seleccionados para participar del estudio MOSAICO. El histórico estudio, el cual aborda dos vacunas experimentales para la prevención del VIH, estará a cargo de la Dra Irma L. Febo, Investigadora Principal, y el Dr. Jorge L. Santana. MOSAICO inició en noviembre de 2019, desde entonces se han seguido incluyendo participantes en 2020 y 2021 en países como: Argentina, Brasil,

México, Perú, Italia, Polonia, España, y Estados Unidos. Y se espera que 3,800 participantes participen en el mismo. Para participar en la investigación, el voluntario debe ser un hombre cisgénero o una persona transgénero que tenga relaciones sexuales con hombres cisgénero y/o con personas transgénero. Debe tener entre 18 y 60 años de edad, no estar infectado con el VIH y haber decidido no usar profilaxis previa a la exposición (PrEP) para prevenir la infección por VIH. También existen otros criterios que se deben cumplir.

Revista Puertorriqueña de Medicina y Salud Pública

Los investigadores explicaron que la vacuna de proteínas está compuesta por proteínas artificiales que son similares a una proteína que se encuentra en la superficie del VIH. Se espera que el estudio dure alrededor de cuatro años. MOSAICO es par te de una colaboración entre las organizaciones: Janssen Vaccines & Prevention B.V., el Instituto Nacional de Alergias y Enfermedades infecciosas (NIAID por sus siglas en inglés) y la Red de Ensayos de Vacunas contra el VIH (HVTN por sus siglas en inglés).

LILLY REVELA LAS BARRERAS CRÍTICAS PARA LA ATENCIÓN ÓPTIMA DE LA MIGRAÑA

Y LOS CONOCIMIENTOS DE LA NUEVA EVIDENCIA CLÍNICA Y DEL MUNDO REAL CENTRADA EN EL PACIENTE, QUE RESPALDA LA CARTERA DE TRATAMIENTOS PREVENTIVOS Y AGUDOS DE LILLY EN AHS 2021

Para mejorar la comprensión y avanzar en el tratamiento de la migraña, Eli Lilly and Company (NYSE: LLY) presentó datos sobre las necesidades insatisfechas en la migraña del estudio OVERCOME (EE. UU.) Y sobre su cartera de medicamentos para la migraña durante la American Headache Society (AHS) 2021. Reunión científica anual virtual, 3-6 de junio. Los nuevos hallazgos de OVERCOME (EE. UU.) Revelaron las seis razones principales por las que las personas dudan en buscar atención para la migraña.Los datos del mundo real revelaron una mayor adherencia y persistencia para Emgality® (galcanezumabgnlm), un anticuerpo monoclonal peptídico relacionado con el gen de la calcitonina (CGRP) mAb), en comparación con los tratamientos de atención oral estándar (mAb no CGRP) preventivos para la migraña en un estudio de reclamos de atención médica y una mayor probabilidad de que el paciente prefiera el perfil autoinyector Emgality en comparación con el dispositivo Aimovig® (erenumab) y AJOVY® (fremanezumab) características en una encuesta.En el primer metanálisis en red de comparación por pares (NMA) para el tratamiento agudo de la migraña, que incluye la totalidad de la literatura disponible hasta la

fecha, las personas que toman dosis de 100 mg y 200 mg de REYVOW® (lasmiditan) CV tuvo mayores probabilidades de un inicio temprano de la eficacia en comparación con los que tomaron Nurtec® (rimegepant) o UBRELVY® (ubrogepant). "Las personas con migraña quieren y necesitan una liberación rápida y completa de la migraña. Es importante que encuentren opciones de tratamiento que les funcionen para que puedan seguir utilizándolas, en lugar de estar insatisfechas o, lo que es peor, perder la esperanza y ni siquiera buscar tratamiento. Estos nuevos conocimientos revelan barreras para una atención óptima y refuerzan los perfiles sólidos de Emgality y REYVOW como medicamentos preventivos y para la migraña aguda, respectivamente", dijo Ilya Yuffa, vicepresidente senior y presidente de Lilly Bio-Medicines. "Esperamos inspirar a las personas con migraña y a los proveedores de atención médica a hablar sobre el impacto que esta debilitante enfermedad neurológica tiene en la vida diaria. Las personas deben esperar más y obtener más de sus tratamientos en el camino hacia la liberación del dolor debilitante de la migraña". Revista Puertorriqueña de Medicina y Salud Pública

FDA APRUEBA OPDIVO® (NIVOLUMAB) COMO TRATAMIENTO ADYUVANTE PARA EL CÁNCER ESOFÁGICO

Opdivo es la primera y única inmunoterapia aprobada para esta población de pacientes En CheckMate 577, Opdivo duplicó la mediana de supervivencia libre de enfermedad frente al placebo en el caso de estos pacientes La aprobación expande el rol de Opdivo en los estadios más tempranos de la enfermedad y tiene dos indicaciones en el entorno de adyuvantes en tres tipos de cáncer

Bristol Myers Squibb (NYSE: BMY) anunció que la Administración de Alimentos y Medicamentos (FDA, por sus siglas en inglés) de los EE. UU. aprobó el uso de Opdivo® (nivolumab, inyección para uso intravenoso) como tratamiento adyuvante contra el cáncer esofágico completamente resecado o de la unión gastroesofágica (GEJ, por sus siglas en inglés) con enfermedad patológica residual en pacientes que han recibido quimiorradioterapia (CRT, por sus siglas en inglés) neoadyuvante. La aprobación se basa en los resultados del ensayo de fase 3 CheckMate 577 que evaluó Opdivo (n=532) en comparación con el placebo (n=262) en pacientes con cáncer esofágico o de la GEJ con enfermedad patológica residual después de la CRT neoadyuvante y la resección completa. En el ensayo, entre los pacientes que recibieron Opdivo, la mediana de supervivencia libre de enfermedad (DFS, por sus siglas en inglés) fue dos veces mayor que en aquellos que recibieron el placebo (22.4

Revista Puertorriqueña de Medicina y Salud Pública

meses [intervalo de confianza [IC, por sus siglas en inglés] del 95%: 16.6 a 34.0] en comparación con 11.0 meses [IC del 95%: 8.3 a 14.3]).Opdivo redujo el riesgo de recurrencia de la enfermedad o de muerte en un 31% en comparación con el placebo (cociente de riesgo [CR, por sus siglas en inglés] de 0.69; IC del 95%: 0.56 a 0.85; P=0.0003). “Los tipos de cáncer esofágico y de la unión gastroesofágica localmente avanzados son tipos de tumores agresivos que suelen requerir múltiples enfoques para abordar la enfermedad, incluida la quimioterapia, la radiación y la cirugía”, indicó Ronan J. Kelly, M.D., MBA, director, Centro para el Cáncer Baylor Scott & White Charles A. Sammons y W.W. Caruth Jr. Cátedra Patrocinada de Inmunología en el Centro Médico de la Universidad de Baylor. “Incluso después de la CRT neoadyuvante seguida de una cirugía, puede haber un riesgo de recurrencia para los pacientes que no alcanzaron una respuesta patológica completa.

AGENDA MÉDICA 2021 EVENTOS Y CONVENCIONES Puerto Rico

www.medicinaysaludpublica.com

Fecha

Actividad

Lugar

Contacto

TIPO DE EVENTO

mayo 2021

Convención Semi anual SPED

Ponce Hilton Hotel

Educational Partners & Coaching 787-646-0780 perez.vilma@gmail.com

Convención

28-30 de mayo de 2021

Sociedad Radiológica de Puerto Rico

Sheraton Puerto Rico Hotel

info@socrad.com info@serrayserra.com 787 406-4571/787 640-5776

Convención

4 al 6 de junio de 2021

Asociación de Reumatólogos de Puerto Rico

Virtual

reumatologospr@serrayserra.com 787 406-4571/ 787 640-5776

Convención

11 al 13 de junio de 2021

11 ma Convención Anual de la Academia de Médicos Generalistas y Primarios de PR

Hyatt Regency Grand Reserve PR Río Grande, PR

SR Consultants & Events 939-292-4115 / 787-649-2367 srconsultants&events@gmail.com

Simposio

25-26 de junio de 2021

Asociación Puertorriqueña de Medicina Física y Rehabilitación

Caribe Hilton Hotel

asocfisiatraspr@serrayserra.com 787 406-4571 / 787 640-5776

Convención

13 al 15 de agosto de 2021

24 th Convención anual de la Sociedad Radiológica de Puerto Rico

Sheraton Convention Center Hotel San Juan, PR

info@socrad.com info@serrayserra.com 787 406-4571/787 640-5776

Convención

7 al 21 de agosto de 2021

Compulsory Courses Regarding

Virtual

High Education Health 787-964-6394 heh@hehpr.com/www.hehpr.com

Curso

19 al 22 de agosto de 2021

Convención anual del Colegio de Farmacéuticos de PR

Wyndham Grand Rio Mar Río Grande, PR

Colegio de Farmacéuticos de PR 787-753-7157

Convención

27 al 29 de agosto 2021

Congreso anual Coalición de Asma de PR

Sheraton Convention Center Hotel San Juan, PR

IC Planners ivettecolon@icplannerspr.com 787-504-3655

Congreso

8 al 11 de octubre de 2021

Convención anual de la Asociación de Hematología y Oncología Médica de PR (AHOMPR)

Ponce Hilton Hotel & Casino Ponce, PR

Germaine Quiñones caribegyn2015@gmail.com 787-608-1477

Convención

Revista Puertorriqueña de Medicina y Salud Pública

Fecha

Actividad

Lugar

Contacto

TIPO DE EVENTO

Sábado 9 de octubre de 2021

Sociedad Radiológica de Puerto Rico Breast Imaging Annual Summit

Sheraton Puerto Rico Hotel

info@socrad.com info@serrayserra.com 787 406-4571/787 640-5776

Seminario

13 al 15 de octubre de 2021

Convención anual de la Asociación de Hospitales de PR

Distrito de Convenciones San Juan, PR

AHPR 787-764-0290 www.hospitalepr.com

Convención

14 al 17 de octubre de 2021

Convención anual Sociedad Puertorriqueña de Cardiología

Virtual

Sociedad Puertorriqueña de Cardiología 787-620-2228 socprcardio@gmail.com

Convención

21 al 24 de octubre de 2021

Convención Caribe Gyn 2021

Ponce Hilton Hotel & Casino Ponce, PR

Germaine Quiñones caribegyn2015@gmail.com 787-608-1477

Convención

Octubre de 2021

Convención anual Puerto Rico Urological Association

Por confirmar**

Aixa Vélez genteinc@gmail.com 787-649-7681

Convención

5 al 7 de noviembre de 2021

Convención anual PR HIV Treaters Association

Virtual

Educational Partners & Coaching 787-646-0780 perez.vilma@gmail.com

Convención

Noviembre de 2021

Convención anual American College of Cardiology, PR Chapter

Por confirmar**

Aixa Vélez genteinc@gmail.com 787-649-7681

Convención

10 al 12 de diciembre de 2021

Convención Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED)

Hotel San Juan San Juan, PR

Educational Partners & Coaching 787-646-0780 perez.vilma@gmail.com

Convención

Revista Puertorriqueña de Medicina y Salud Pública

LOS VOLUNTARIOS DE ABBVIE APOYAN LOS ESFUERZOS DE ENTRADA DE DATOS DE VACUNACIÓN DE LA ORGANIZACIÓN DIRECT RELIEF

Demostrando el compromiso con los puertorriqueños, AbbVie se unió a la organización sin fines de lucro y socio de mucho tiempo Direct Relief en sus esfuerzos de entrada de datos relacionados con las actividades de vacunación COVID-19 en la Isla. La compañía farmacéutica, como parte de su programa de voluntariado proveyó cerca de 80 empleados parar dos días de trabajo cuyas funciones se destacaban la entrada de datos al sistema de rastreo y en apoyo al cumplimiento del proceso de vacunación. Direct Relief, organización que trabaja con mejorar con mejorar la salud y la vida de las personas afectadas por la pobreza o las emergencias como la pandemia del COVID-19, está apoyando activamente a la organización que lidera los esfuerzos de vacunación en Puerto Rico y ha creado un centro de datos para tener los registros de vacunación de las personas lo más actualizados posible.

“Para todos los que trabajamos en AbbVie, estamos comprometidos a brindar apoyo a nuestras comunidades locales, y eso incluye brindar ayuda en los esfuerzos de vacunación de Puerto Rico. Tener datos precisos es fundamental en el proceso de vacunación y, junto con nuestro socio Direct Relief, nuestros empleados están dando un paso al frente para ayudar a estas organizaciones en su objetivo de lograr una comunidad completamente vacunada”, Alejandro Drevón, gerente general de AbbVie Puerto Rico.

Revista Puertorriqueña de Medicina y Salud Pública

GRADUACIONES 2021

VÍCTOR J. SERRANO MORALES SALUD PÚBLICA

SALUD PÚBLICA

RAHISA DELUCA SALUD PÚBLICA

DRA. JOSMARIE ORTIZ COTTO ENFERMERÍA

CIENCIAS BIOMÉDICAS

DRA. STEPHANIE BELTRÁN ROSARIO ESCUELA DE FARMACIA

DRA.AMBAR RAMIREZ RODRIGUEZ MEDICINA

DR. FRANCISCO MORAN RIVERA MEDICINA DENTAL

DRA. NATTALÍ RODRÍGUEZ VEGA MEDICINA DENTAL

Revista Puertorriqueña de Medicina y Salud Pública

GRADUACIONES 2021

LA PRESIDENTA DE LA UCC WALESKA CRESPO SE DIRIGE A LOS ESTUDIANTES Y SUS FAMILIARES Y LA FACULTAD DE LA INSTITUCIÓN.

CHRISTIAN MALPICA,MIENTRAS SE LE IMPONE LA ESCLAVINA DEL GRADO DE DOCTORADO EN BIOLOGÍA CELULAR MOLECULAR

LA PRESIDENTA DE LA UCC WALESKA CRESPO SE DIRIGE A LOS ESTUDIANTES Y SUS FAMILIARES Y LA FACULTAD DE LA INSTITUCIÓN.

LA ESTUDIANTE DE MEDICINA, EMILY GARDNER, QUE FUE EL PROMEDIO MÁS ALTO DE TODOS LOS PROGRAMAS DE LA UCC.

ESTUDIANTE RAFAEL RIVERA CON SU MADRE LA DRA. VANESSA SEPÚLVEDA.

FLAVIA TEJEDA BAYRÓN, MIENTRAS SE LE IMPONE LA ESCLAVINA DEL GRADO DE DOCTORADO EN BIOLOGÍA CELULAR MOLECULAR

CHRISTIAN MALPICA,MIENTRAS SE LE IMPONE LA ESCLAVINA DEL GRADO DE DOCTORADO EN BIOLOGÍA CELULAR MOLECULAR

ESTUDIANTE HACIENDO EL JURAMENTO DE HIPÓCRATES

Revista Puertorriqueña de Medicina y Salud Pública

GRADUACIONES 2021

PRESIDENTE – DR. DAVID LENIHAN

DE IZQUIERDA A DERECHA: DR. JOSÉ A. TORRES RUIZ, RECTOR, DRA. CAROLINE PALAVACCINO MAGGIO, FACULTAD DE NEUROBIOLOGÍA DE LA ESCUELA DE MEDICINA DE HARVARD UNIVERSITY DR. DAVID LENIHAN, PRESIDENTE Y CEO DE PHSU

FOTOS DE GRADUANDOS

Graduandos 2021

299 estudiantes completaron grados en diferentes campos de la salud en la Cuadragésima Primera Colación de Grados de Ponce Health Sciences University (PHSU). Esta es la cantidad de graduados más alta de la universidad. De estos, 88 obtuvieron el grado de Doctor en Medicina. También se otorgaron grados en maestría en Ciencias Médicas, doctorado en Ciencias Biomédicas, doctorados en Salud Pública, maestría en Salud Pública, doctorado en Psicología Clínica, maestría en Pscicología Clínica y bachillerato en Enfermería. PRESIDENTE – DR. DAVID LENIHAN

Revista Puertorriqueña de Medicina y Salud Pública

GRADUACIONES 2021

DRA. YOCASTA BRUGAL - PRESIDENTA & DECANA DE LA EMSJB

YARITZA DÍAZ - DECANA ASOCIADA DEL PROGRAMA DE MPH DE EMSJB

DRA. YOLANDA MIRANDA - DECANA DE ASUNTOS ESTUDIANTILES EMSJB

DR. CHARLES CASTRO - REPRESENTANTE DE CLASE MEDICINA 2021 EMSJB

DARAISHKA PÉREZ CARABALLO PREMIO MAGNA CUM LAUDE CLASE ENFERMERÍA 2021 & DRA. ELIZABETH PADILLA DECANA ASOCIADA PROGRAMA DE ENFERMERÍA EMSJB - DEDICATORIA DE GRADUACIÓN ENFERMERÍA A LA DRA. PADILLA

DRA. MIRIAM RAMOS - DECANA ASOCIADA EN CIENCIAS CLÍNICAS EMSJB

DR. ANDREW R. BLUNDELL ALEMÁN - PREMIO LCDO. JUAN A. CHAVES ABREU QUE OTORGA LA JUNTA DE SÍNDICOS DE EMSJB

DRA. XIONMARA S. MOLINIA PÉREZ - PREMIO DE PSIQUIATRÍA & PREMIO DE MEDICINA DE FAMILIA

VALERIE MOLINA PÉREZ & ANGELIE MARTÍNEZ CARTAGENA - PREMIO DE EXCELENCIA ACADEMIA ENFERMERÍA

Revista Puertorriqueña de Medicina y Salud Pública

A CIENCIA CIERTA LA MAGIA DE LA GRADUACIÓN NO SE BORRA EN TIEMPOS PANDEMIA La Facultad, la toga y el birrete, y hasta abrazar a compañeros de carrera durante un emotivo acto de graduación, fue para algunos, hechos que no pudieron disfrutar de lleno durante la entrega de su título. Sin embargo, estos factores no incidieron para que estudiantes de diversas carreras aliadas a la salud cerraran un ciclo de su vida académica recibiendo de manera especial su título profesional.

Revista Puertorriqueña de Medicina y Salud Pública

Las condiciones generadas por la pandemia del Covid-19, impulsaron desarrollar alternativas para este momento tan especial en la vida de todo estudiante mediante una serie de protocolos que permitió que nuestras cuatro escuelas de medicina celebraran La Colación de Grados 2021.

Revista Puertorriqueña de Medicina y Salud Pública