PRODUCT MONOGRAPH. From the Publishers of

Transcription

1 PRODUCT MONOGRAPH From the Publishers of

2 IMPORTANT SAFETY INFORMATION Contraindication: Repatha (evolocumab) is contraindicated in patients with a history of a serious hypersensitivity reaction to Repatha. Allergic reactions: Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients treated with Repatha, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with Repatha, treat according to the standard of care, and monitor until signs and symptoms resolve. Adverse reactions: The most common adverse reactions (> 5% of Repatha -treated patients and more common than placebo) were: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. In a 52-week trial, adverse reactions led to discontinuation of treatment in 2.2% of Repatha -treated patients and 1% of placebotreated patients. The most common adverse reaction that led to Repatha treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for Repatha and placebo, respectively). Adverse reactions from a pool of the 52-week trial and seven 12-week trials: Local injection site reactions occurred in 3.2% and 3.0% of Repatha -treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in Repatha -treated patients and placebo-treated patients were 0.1% and 0%, respectively. Allergic reactions occurred in 5.1% and 4.7% of Repatha -treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for Repatha and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%). Neurocognitive events were reported in less than or equal to 0.2% in Repatha -treated and placebo-treated patients. In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1,988 patients treated with Repatha had at least one LDL C value < 25 mg/dl. Changes to background lipid-altering therapy were not made in response to low LDL-C values, and Repatha dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by Repatha are unknown. Musculoskeletal adverse reactions were reported in 14.3% of Repatha -treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for Repatha and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%). Homozygous familial hypercholesterolemia (HoFH): In 49 patients with HoFH studied in a 12-week, double-blind, randomized, placebo-controlled trial, 33 patients received 420 mg of Repatha subcutaneously once monthly. The adverse reactions that occurred in at least two (6.1%) Repatha -treated patients, and more frequently than in placebo-treated patients, included upper respiratory tract infection (9.1% versus 6.3%), influenza (9.1% versus 0%), gastroenteritis (6.1% versus 0%), and nasopharyngitis (6.1% versus 0%). Immunogenicity: Repatha is a human monoclonal antibody. As with all therapeutic proteins, there is a potential for immunogenicity with Repatha. 2 FEBRUARY

3 PUBLISHING STAFF EDITORIAL & PRODUCTION Managing Editor Davy James Assistant Editors Lauren Santye & Laurie Toich Contributing Editors Stacey Ness, PharmD, RPh, MSCS & Quintin Jessee, RPh, DPh Designer Gwendolyn Salas Senior Vice President of Operations and Clinical Affairs Jeff Prescott, PharmD, RPh Proofreaders Maggie Shaw & Griselda Demassey SALES & MARKETING Senior Account Director John Dykeman; Strategic Partnership Executive Colin Fishbein; Sales & Marketing Coordinator Nicole Reina Senior Project Manager Dawn Colon; OPERATIONS & FINANCE Director of Operations Michael Pico Group Director, Circulation and Production John Burke; Vice President of Finance Leah Babitz, CPA Accountant Kim Rotunno CORPORATE Chairman and CEO Mike Hennessy, Sr Vice Chairman Jack Lepping President Mike Hennessy, Jr Chief Financial Officer Neil Glasser, CPA/CFE Executive Vice President and General Manager John Maglione Chief Marketing Officer Warren Dardine Vice President of Editorial Services and Production Kerrie Keegan Chief Digital Strategy Officer Steve Ennen Vice President, Digital Media Jung Kim Chief Creative Officer Jeff Brown Human Resource Director Shari Lundenberg Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of Pharmacy & Healthcare Communications, LLC, the editorial staff, or any member of the editorial advisory board. Pharmacy & Healthcare Communications, LLC, is not responsible for accuracy of dosages given in articles printed herein. The appearance of advertisements in this journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. Pharmacy & Healthcare Communications, LLC, disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements. Specialty Pharmacy Times is published by Pharmacy & Healthcare Communications, LLC, 666 Plainsboro Road, Suite 300, Plainsboro, NJ All rights reserved. Editorial and advertising offices are at 666 Plainsboro Road, Suite 300, Plainsboro, NJ Phone: Fax: Contents may not be reproduced without permission of the publisher. PRODUCT MONOGRAPH table of contents This REPATHA Product Monograph was developed by Specialty Pharmacy Times, in conjunction with and sponsored by Amgen. ABOUT THIS MONOGRAPH 4 UNDERSTANDING CLINICAL ASCVD 4 UNDERSTANDING FH 4 TREATMENT GUIDELINES FOR LOW-DENSITY LIPOPROTEIN CHOLESTEROL MANAGEMENT IN PATIENTS WITH CLINICAL ASCVD AND FH 5 ABOUT REPATHA (EVOLOCUMAB) 5 THE REPATHA PUSHTRONEX SYSTEM (ON-BODY INFUSOR WITH PREFILLED CARTRIDGE) 12 THE REPATHA SURECLICK AUTOINJECTOR 12 PATIENT COUNSELING INFORMATION 13 THE ROLE OF THE SPECIALTY PHARMACIST 13 SUMMARY 13 INDICATION REPATHA is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C). REPATHA is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. The effect of REPATHA on cardiovascular morbidity and mortality has not been determined. The safety and effectiveness of REPATHA have not been established in pediatric patients with HoFH who are younger than 13 years old or in pediatric patients with primary hyperlipidemia or HeFH. FEBRUARY

4 REPATHA (evolocumab) Product Monograph ABOUT THIS MONOGRAPH This monograph presents information regarding REPATHA to enable specialty pharmacists to counsel patients regarding the product and its use. Information on the management of low-density lipoprotein cholesterol (LDL-C) in patients with clinical atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia (FH) is also included. UNDERSTANDING CLINICAL ASCVD A guideline for the management of blood cholesterol was developed by the American College of Cardiology/American Heart Association (ACC/AHA). In the context of this guideline, patients with any of the following conditions have clinical ASCVD: acute coronary syndrome, a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin. 1 Additional information regarding clinical ASCVD is shown in TABLE 1 2. TABLE 1. RISK FACTORS FOR ASCVD 2 Age Sex Total cholesterol LDL-C Systolic blood pressure Treatment for hypertension Diabetes Current smoking ASCVD = atherosclerotic cardiovascular disease. Epidemiology of Uncontrolled LDL-C in Patients with ASCVD In the United States, there are 11 million people with ASCVD and/ or FH, who have uncontrolled levels of LDL-C greater than 70 mg/ dl despite treatment with statins and/or other cholesterol-lowering therapies. 3,4 UNDERSTANDING FH FH is an autosomal dominant condition usually caused by a genetic mutation. 5,6 This inherited condition is associated with increased levels of LDL-C and can lead to cardiovascular disease at an early age. 7 There are 2 types of FH: heterozygous FH (HeFH) and homozygous FH (HoFH). Very high cholesterol levels are one of the hallmarks of FH. In patients with HeFH, LDL-C levels before treatment generally range from 190 mg/dl to 400 mg/dl, whereas patients with HoFH have LDL-C levels greater than 400 mg/dl. 8 Epidemiology of FH Of the subtypes of FH, HeFH is far more common, affecting 1 in 200 to 1 in 500 individuals. 9 By contrast, HoFH affects approximately 1 person per 160,000 to 1,000,000 in the general population. 10 In the United States, there are 1 million patients with FH (both HeFH and HoFH). 9,11 Diagnosis Signs of FH may include fatty skin deposits (xanthomas), cholesterol deposits located on the eyelids (xanthelasmas) or in the cornea (corneal arcus), or very high LDL-C levels. 7,12 Assessing each patient s family history of heart disease is also crucial in establishing the diagnosis. 12 Several patient factors are associated with an increased likelihood of FH, including an LDL-C level greater than 190 mg/dl (adults) or greater than 160 mg/dl (children/adolescents); a total cholesterol level greater than 310 mg/dl (adults) or greater than 230 mg/dl (children/adolescents); a history of premature coronary heart disease, xanthomas, xanthelasmas, or corneal arcus; and a family history of FH. 10 However, in considering these factors, it is important to recognize that very high cholesterol levels alone are not sufficient for a diagnosis of FH, as the cholesterol levels of patients with FH and patients in the general population overlap. As a result, relying on cholesterol levels alone can result in diagnostic error in 8% to 18% of cases. 13 Additionally, although genetic testing can confirm FH, it cannot exclude the diagnosis. Up to 20% of patients with clinically definite FH have no detectable mutation, likely because of as-yet-uncharacterized genetic forms of the disease. 14 To aid clinicians in establishing a diagnosis of FH, formal diagnostic criteria have been developed, including the MedPed criteria, the Simon Broome criteria, and the Dutch Lipid Clinic Network diagnostic algorithm. 13 These criteria differ in the cholesterol levels used for diagnosis, and place varying emphasis on family history and clinical characteristics. Other criteria, including those developed by the AHA, offer a simplified approach for raising the clinical suspicion of possible FH (TABLE 2). 8 It is important to recognize that FH is underdiagnosed. In the United States, it is estimated that fewer than 1% of individuals with FH have been diagnosed. 9 4 FEBRUARY

5 TABLE 2. KEY CONSIDERATIONS FOR FH SCREENING BASED ON AMERICAN HEART ASSOCIATION 8 Consider FH in: Patients with a family member who has confirmed FH Patients with a family history of early heart disease (eg, patient has a first-degree relative with heart disease before age 55 years in men and before age 65 years in women) Patients aged 20 years or older (adults) with an LDL-C level 190 mg/dl Patients aged <20 years (children) with an LDL-C level 160 mg/dl FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol. TREATMENT GUIDELINES FOR LOW-DENSITY LIPOPROTEIN CHOLESTEROL MANAGEMENT IN PATIENTS WITH CLINI- CAL ASCVD AND FH Guidelines developed by the ACC/AHA and the National Lipid Association (NLA) identify LDL-C as an important target. 1,15 Current strategies for reducing LDL-C levels include lifestyle change and appropriate pharmacotherapy. 15 Treatment options prioritized by the ACC/AHA guideline include high-intensity statin therapy to achieve LDL-C reductions of 50% or more and moderate-intensity statin therapy intended to reduce LDL-C levels by at least 30%. 1 Although the 2013 ACC/AHA guideline focused on statin therapies, in May 2016, the ACC/NLA released further guidance on the use of non-statin therapies. This consensus document highlights the role of the pharmacologic non-statin therapies ezetimibe, bile acid sequestrants, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors. The document outlines non-statin treatment options for several groups of patients, including those with clinical ASCVD with and without comorbidities (TABLE 3). 16 Based on the 2016 ACC/NLA guidance, non-statin treatment options in combination with maximally tolerated statins are limited to ezetimibe and bile acid sequestrants for patients without ASCVD. However, in patients with ASCVD without comorbidities and persistent less than 50% LDL-C reduction or LDL-C 100 mg/ dl or higher or in patients with ASCVD with comorbidities, less than 50% LDL-C reduction or LDL-C 70 mg/dl or higher, treatment options also include PCSK9 inhibitors. In addition, PCSK9 inhibitors are also recommended for patients with ASCVD and baseline LDL-C levels of 190 mg/dl or higher not due to secondary causes and persistent less than 50% LDL-C reduction, or LDL-C 70 mg/dl or higher; or in patients without ASCVD and baseline LDL-C levels of 190 mg/dl or higher not due to secondary causes, less than 50% LDL-C reduction, or LDL-C 100 mg/dl or higher. Guidelines note the importance of recognizing high baseline LDL-C levels of 190 mg/dl or higher not due to secondary causes as a factor in raising clinical suspicion of genetic forms of hypercholesterolemia, which may warrant further investigation, including referral to a lipidologist. 16 Intensification of drug therapy should be strongly considered if 50% reduction in LDL-C is not achieved with maximally tolerated statin therapy. 14 Depending on the patient history and clinician-patient discussion, non-statin medication such as ezetimibe, bile acid sequestrants, and/or PCSK9 inhibitors are a consideration (TABLE 3). 16 Another guideline for the management of FH published by the NLA recommends lifestyle change and pharmacotherapy in patients with HeFH, with a general target of a 50% or greater LDL-C reduction. Greater reductions may be required in patients with other risk factors. 14 HoFH is treated with many of the same modalities as HeFH, although the level of intensity of treatment, monitoring techniques, and intensity of monitoring differ. Although statins are the mainstay of therapy, because their efficacy largely depends on intact hepatic LDLRs, and because many patients with HoFH have absent or greatly reduced LDLR function, HoFH more often requires additional, non-statin therapies, including LDL apheresis used in conjunction with other medications. 10 These medications may include mipomersen, an antisense oligonucleotide that targets apolipoprotein B encoding messenger RNA, and lomitapide, an inhibitor of microsomal triglyceride transfer protein. These 2 medications are indicated for use only in patients with HoFH. 15,17,18 ABOUT REPATHA (EVOLOCUMAB) In 2015 the FDA approved REPATHA injection as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical ASCVD who require additional lowering of LDL-C. REPATHA may be used with other LDL-C lowering therapies such as statins, ezetimibe, or LDL apheresis in patients with HoFH who require additional lowering of LDL-C. The effect of REPATHA on cardiovascular morbidity and mortality has not been determined. The safety and effectiveness of REPATHA have not been established in pediatric patients with HoFH who are younger than 13 years old or in pediatric patients with primary hyperlipidemia or HeFH. Use of REPATHA is contraindicated in patients with a history of serious hypersensitivity reaction to REPATHA. 19 See additional Important Safety Information on the inside cover of this monograph. Composition and Mechanism of Action REPATHA is a 144-kDa human monoclonal immunoglobulin G2 (IgG2) antibody that is produced using genetically engineered mammalian cells sourced from Chinese hamster ovaries. REPATHA is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous administration. 19 REPATHA binds to PCSK9, thereby inhibiting circulating PCSK9 from binding to low-density lipoprotein receptors (LDLRs). By binding to PCSK9, REPATHA prevents FEBRUARY

6 TABLE 3. NON-STATIN TREATMENT APPROACH IN SELECT PATIENT GROUPS 16 PATIENT POPULATION GOAL NON-STATIN PHARMACOLOGIC OPTIONS a Patients with stable clinical ASCVD without comorbidities who are on maximally tolerated statin therapy for secondary prevention Patients with clinical ASCVD with comorbidities who are on maximally tolerated statin therapy for secondary prevention Patients with clinical ASCVD with baseline LDL-C levels 190 mg/dl who are on maximally tolerated statin therapy for secondary prevention Patients without clinical ASCVD but with baseline LDL-C levels 190 mg/dl not due to secondary causes who are on maximally tolerated statin therapy for primary prevention 50% reduction in LDL-C or, optionally, an LDL-C level <100 mg/dl (provided that the patient is on a maximally tolerated statin) 50% reduction in LDL-C or, optionally, an LDL-C level <70 mg/dl or non HDL-C level <100 mg/dl (provided that the patient is on a maximally tolerated statin) 50% reduction in LDL-C or, optionally, an LDL-C level <70 mg/dl (provided that the patient is on a maximally tolerated statin) 50% reduction in LDL-C or, optionally, an LDL-C level <100 mg/dl (provided the patient is on a maximally tolerated statin) Ezetimibe (first), b PCSK9 inhibitor (added to ezetimibe or to replace ezetimibe after insufficient response) Ezetimibe (first), b PCSK9 inhibitor (added to ezetimibe or to replace ezetimibe after insufficient response) PCSK9 inhibitor or ezetimibe b PCSK9 inhibitor or ezetimibe b ASCVD = atherosclerotic cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin kexin 9. a Note that these pharmacologic options are a consideration after addressing statin adherence, intensifying lifestyle therapy, evaluating response and tolerability to statin therapy, control of other risk factors, a clinician-patient discussion regarding addition of non-statin therapies, and in some cases, referral to a lipidologist. b Consider a bile acid sequestrant as a second-line alternative to ezetimibe in ezetimibe-intolerant patients with triglyceride levels <300 mg/dl. PCSK9-mediated LDLR degradation, which increases the availability of LDLRs on the surface of liver cells. Because LDLRs help clear LDL-C from the blood, with more LDLRs available, more LDL-C is cleared from the blood and LDL-C levels are reduced. 19 Dosage Forms REPATHA is available in 3 dosage forms: a solution of 140 mg/ ml supplied in a single-use prefilled syringe, a solution of 140 mg/ ml in a single-use prefilled SureClick autoinjector, and a solution of 420 mg/3.5 ml in a single-use Pushtronex system (on-body infusor with prefilled cartridge). 19 Recommended Dosage In patients with HeFH or primary hyperlipidemia with established clinical ASCVD, REPATHA should be subcutaneously administered as 140 mg every 2 weeks or 420 mg once monthly. In patients who are switching from the every-2-week regimen to the once-monthly regimen, administer the first dose of the new regimen on the next scheduled date of the prior regimen. 19 In patients with HoFH, REPATHA should be administered subcutaneously once monthly at the 420-mg dose. After starting REPATHA, patients with HoFH should be assessed for LDL-C levels 4 to 8 weeks after starting therapy because the response to REPATHA depends on the degree of LDLR function. 19 Patients who missed a dose of REPATHA should administer the next dose as soon as possible as long as doses are separated by more than 7 days. Alternatively, patients may skip the missed dose and administer the next dose according to the original dosing schedule of the medication. 19 Administering REPATHA Patients and caregivers should be instructed on how to prepare and administer REPATHA prior to use, including proper aseptic technique, and should follow the Instructions for Use with each administration of REPATHA. Administering a 420-mg dose on a monthly basis can be done either using the Pushtronex system over a 9-minute administration through the on-body infusor with prefilled cartridge or through 3 injections of REPATHA 140 mg (single-use prefilled autoinjector or single-use prefilled syringe) administered subcutaneously within a 30-minute time frame. 19 REPATHA may be stored in a refrigerator (at a temperature of 36 F to 46 F [2 C to 8 C]) but prior to use should be allowed to warm to room temperature for a minimum of 30 minutes for the single-use prefilled autoinjector or single-use prefilled syringe and for at least 45 minutes for the Pushtronex system. Instruct patients not to warm REPATHA using any method other than allowing a previously refrigerated dose to warm gradually in a room-temperature environment. For patients who do not want to keep REPATHA refrigerated, REPATHA may be kept at room temperature at 68 F to 77 F (20 C to 25 C) if the medication is kept in the original carton and the medication is used within 30 days. 19 Prior to administration of REPATHA, patients or caregivers 6 FEBRUARY

7 should visually inspect the solution for particles and discoloration. REPATHA is a clear to opalescent, colorless to pale yellow solution and should not be used if the solution appears cloudy or discolored or contains particles. 19 REPATHA may be administered using a single-use prefilled syringe, single-use prefilled autoinjector, or through the Pushtronex system. REPATHA may be administered subcutaneously into the abdomen, thigh, or upper arm, provided the area where the injection is administered is not tender, bruised, red, or indurated. Instruct patients not to administer REPATHA at the same injection site as other medications and to rotate the injection site with each administration. 19 Contraindication REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to REPATHA. 19 Warnings and Precautions In patients receiving REPATHA, hypersensitivity reactions such as rash and urticaria have been reported, including some that have led to treatment discontinuation. Patients experiencing signs or symptoms of a serious allergic reaction should discontinue treatment with REPATHA, should receive standard-of-care therapy for allergic reactions, and should be monitored until associated signs and symptoms resolve. 19 Adverse Reactions-Clinical Trials Experience In 8 placebo-controlled trials in patients with primary hyperlipidemia and in patients with heterozygous FH, a total of 2651 patients received REPATHA. A total of 557 patients received 6 months of treatment and 515 patients received 1 year of treatment. In all trials combined, the mean duration of exposure was 20 weeks and the median duration of exposure was 12 weeks. 19 Patients receiving REPATHA across these 8 placebo-controlled trials had a mean age of 57 years, and 49% of patients receiving treatment were women. Although the majority of patients (85%) receiving REPATHA were white, 6% of patients were black, 8% of patients were of Asian ancestry, and 2% of patients were of other ethnic backgrounds. 19 In a 52-week, double-blind, randomized, placebo-controlled trial, a total of 599 patients received monthly doses of REPATHA 420 mg. Patients receiving therapy in this trial had a mean age of 56 years, ranging from 22 years to 75 years. A total of 2.2% of patients receiving REPATHA discontinued treatment because of adverse reactions versus 1% of patients receiving placebo. The most common adverse reaction leading to discontinuation of REPATHA and occurring at a rate greater than placebo was myalgia, which occurred in 0.3% of patients receiving REPATHA versus 0% of patients receiving placebo. Adverse reactions reported in at least 3% of patients receiving REPATHA that occurred more TABLE 4. ADVERSE REACTIONS OCCURRING IN GREATER THAN OR EQUAL TO 3% OF REPATHA- TREATED PATIENTS AND MORE FREQUENTLY THAN WITH PLACEBO IN STUDY 2 19 Placebo (N = 302) % REPATHA (N = 599) % Nasopharyngitis Upper respiratory tract infection Influenza Back pain Injection-site reactions a Cough Urinary tract infection Sinusitis Headache Myalgia Dizziness Musculoskeletal pain Hypertension Diarrhea Gastroenteritis a Reactions include erythema, pain, and bruising. frequently than in patients receiving placebo over the 52-week trial are reported in TABLE In a total of seven 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received REPATHA every 2 weeks, and 1059 patients received REPATHA monthly. Patients had a mean age of 57 years, ranging from 18 years to 80 years. Approximately half (49%) of patients participating in these trials were women. Adverse reactions that were reported in at least 1% of patients receiving REPATHA and more often than in placebo-treated patients are reported in TABLE In 8 pooled controlled trials (seven 12-week trials and one 52- week trial), adverse reactions included local injection-site reactions, allergic reactions, neurocognitive events, low LDL-C levels, and musculoskeletal events. 19 Local injection-site reactions occurred in 3.2% of patients receiving REPATHA and 3.0% of patients receiving placebo. Common symptoms of injection-site reactions reported in these trials included erythema, pain, and bruising. 19 Allergic reactions occurred in 5.1% of patients receiving REPATHA versus 4.7% of patients receiving placebo. Rash, eczema, erythema, and urticaria were the most common types of allergic reactions observed FEBRUARY

8 TABLE 5. ADVERSE REACTIONS OCCURRING IN GREATER THAN 1% OF REPATHA-TREATED PATIENTS AND MORE FREQUENTLY THAN WITH PLACEBO IN POOLED 12-WEEK STUDIES 19 Placebo (N = 1224) % REPATHA a (N = 2052) % Nasopharyngitis Back pain Upper respiratory tract infection Arthralgia Nausea Fatigue Muscle spasms Urinary tract infection Cough Influenza Contusion a 140 mg every 2 weeks and 420 mg once monthly combined. Neurocognitive events occurred in 0.2% or fewer of patients receiving REPATHA and patients receiving placebo. 19 In placebo-controlled, active-controlled, and open-label extension studies, a total of 1988 patients receiving REPATHA had an LDL-C level less than 25 mg/dl on at least 1 occasion. These very low levels of LDL-C did not result in any change to background lipid-lowering therapy, REPATHA dosing changes, interruption of REPATHA therapy, or adverse consequences. However, it is important to note that the long-term effects of very low levels of LDL-C are unknown. 19 Musculoskeletal events occurred in 14.3% of patients receiving REPATHA versus 12.8% of patients receiving placebo. Back pain, arthralgia, and myalgia were the most common manifestations of musculoskeletal events, with each of these manifestations occurring at a rate greater than that observed in patients receiving placebo. 19 REPATHA was studied in a 12-week trial of 49 patients with HoFH in which 33 patients received REPATHA 420 mg subcutaneously each month. In this trial, the mean age of participants was 31 years, ranging from 13 to 57 years, and approximately half (49%) of patients were women. In terms of ethnic background, 90% of patients were white, 4% were of Asian background, and 6% of patients were classified as members of other ethnicities. Adverse reactions occurring in at least 2 (6.1%) patients receiving REPATHA and more frequently than in patients receiving placebo included upper respiratory tract infection (9.1% vs 6.3%), influenza (9.1% vs 0%), gastroenteritis (6.1% vs 0%), and nasopharyngitis (6.1% vs 0%). 19 Adverse Reactions Immunogenicity REPATHA was tested for immunogenicity using an electrochemiluminescent bridging screening immunoassay for anti-drug antibodies. Patients who showed signs of anti-drug antibodies were further evaluated using an in vitro biological assay to detect neutralizing antibodies. A total of 0.1% of patients receiving at least 1 dose of REPATHA had a positive test result for the presence of anti-drug antibodies across placebo-controlled and active-controlled clinical trials, with no patients testing positive for neutralizing antibodies. There was no evidence that anti-drug antibodies affected pharmacokinetic parameters, clinical response, or the safety of REPATHA. However, the long-term consequences of continuing treatment in the presence of anti-drug antibodies remain unknown. 19 It is important to recognize that antibody detection is highly dependent on the sensitivity and specificity of the assay used, as well as the methodology of the anti-drug antibody assay. Several factors such as how the sample is handled, the timing of the sample collection, the concomitant medications that patients use, and each patient s underlying disease processes may affect the results of an anti-drug assay. As a result of these factors, comparison of the incidence of antibodies to REPATHA with the incidence of antibodies to other products may be misleading. 19 Use in Specific Populations There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk. REPATHA has been studied in animal reproduction studies. In these animal reproduction studies, no effect on pregnancy or neonatal or infant development was found in monkeys when REPATHA was administered subcutaneously at dose exposures up to 12 times that of the maximum recommended human dose of 420 mg every month. 19 Results of studies with another medication in the PCSK9 inhibitor class showed humoral immune suppression in infant monkeys who had received the medication in utero, and it occurred at a rate greater than would be expected in infant monkeys not exposed to the medication. No assessment for immune suppression was conducted with evolocumab in infant monkeys. Infant monkeys exposed to REPATHA showed serum concentrations of the medication similar to those observed in the serum of mothers. This result indicates that, like other IgG antibodies, REPATHA crosses the placental barrier. 19 FDA experience with monoclonal antibodies indicates that they are unlikely to cross the placental barrier in humans during the first trimester of pregnancy, but are likely to cross the placenta in increasing amounts during the second and third trimesters. Healthcare professionals should assess the potential risks to the fetus and the 8 FEBRUARY

9 benefits of treatment to the mother before administering REPATHA to a pregnant woman. 19 With regard to lactation, there is no available information on the presence of REPATHA in human milk, the effect on the breastfed infant, or the effects on milk production. As a result, healthcare professionals should assess the health benefits of breast-feeding along with the mother s clinical need for REPATHA and any potential adverse effects on the breastfed infant from REPATHA or from the underlying maternal condition. Although human IgG is present in human milk, data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. 19 The safety and effectiveness of REPATHA in combination with diet and other LDL-C-lowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebo-controlled trial that included 10 adolescents (ages 13 to 17 years old) with HoFH. In these 10 adolescents, 7 received REPATHA at the 420-mg subcutaneous monthly dose (the remaining 3 adolescents received placebo). REPATHA reduced LDL-C levels to a degree similar to that observed in adult patients with HoFH. Including experience from open-label, uncontrolled studies, 14 adolescents with HoFH have received REPATHA, with a median exposure of 9 months, confirming a safety profile in adolescents similar to that observed in adults with HoFH. Safety and effectiveness, however, have not been established in patients with HoFH younger than 13 years of age or in pediatric patients with primary hyperlipidemia or HeFH. 19 A total of 1420 patients receiving REPATHA in controlled studies were aged 65 years or older, and 171 patients enrolled in controlled studies were aged 75 years or older. Compared with younger patients, no overall differences in safety, effectiveness, or response were found. However, greater sensitivity to medication in some older individuals cannot be ruled out. 19 No dose adjustment with REPATHA is required in patients with mild to moderate renal impairment or in patients with mild to moderate hepatic impairment. However, data are not available in patients with severe renal impairment or in patients with severe hepatic impairment. Following a single 140-mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20% to 30% lower mean C max and 40% to 50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients. 19 Pharmacokinetics and Pharmacodynamics A single dose of REPATHA 140 mg or 420 mg results in maximum suppression of circulating unbound PCSK9 levels within 4 hours of administration, and unbound PCSK9 levels gradually recover after the active ingredient in REPATHA is slowly metabolized. 19 With the 420-mg monthly dose of REPATHA administered to healthy volunteers, the average maximum concentration and area under the curve were 59.0 mcg/ml and 924 days mcg/ml, respectively. Corresponding averages with the 140-mg dose administered every 2 weeks were 18.6 mcg/ml and 188 days mcg/ml. With repeat dosing, 2- to 3-fold accumulation in serum concentration was observed with both the 420-mg dose administered monthly and the 140-mg dose administered every 2 weeks. Serum trough concentrations approached steady state by 12 weeks of dosing. 19 With respect to absorption characteristics, peak serum concentrations of REPATHA are reached within 3 to 4 days, and absolute bioavailability is estimated at 72%. The volume of distribution is estimated at 3.3 L at steady state after receipt of a single 420-mg intravenous dose. Systemic clearance of the 420-mg dose occurs at a rate of approximately 12 ml/h. However, as REPATHA shows nonlinear kinetics, 2 elimination phases are observed: 1 at low concentrations of medication, in which elimination occurs through saturable binding to PCSK9, and another that occurs at high concentrations, in which REPATHA is eliminated through a nonsaturable proteolytic pathway. The estimated elimination half-life of REPATHA is 11 to 17 days. 19 Clinical Studies In patients with primary hyperlipidemia and clinical ASCVD, investigators performed a multicenter, double-blind, randomized, controlled trial in which patients initially received open-label treatment with a statin-based regimen for 4 weeks. Following this open-label period, patients were randomized to receive REPATHA 140 mg every 2 weeks (n = 105), REPATHA 420 mg monthly (n = 105), or placebo (n = 86) over a 12-week study period. In this trial, a total of 296 patients received REPATHA or placebo in combination with 1 of 3 statin regimens (daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg). Patients had a mean baseline age of 63 years, with an age range of 32 years to 80 years. 19 Following the 4-week statin therapy period, the baseline LDL-C averaged 108 mg/dl. By week 12, patients receiving REPATHA 140 mg every 2 weeks experienced a 71% greater reduction in LDL-C versus placebo (95% CI, 61%-81%; P <.0001), and patients receiving REPATHA 420 mg monthly experienced a 63% greater reduction in LDL-C versus placebo (95% CI, 50%-76%; P <.0001). See TABLE 6 19 for the effect of REPATHA on lipid parameters in this study and FIGURE 1 19 for the LDL-C reductions observed with each of the 3 statin regimens used in the study. 19 In a second study of patients with primary hyperlipidemia and ASCVD, investigators performed a 52-week, double-blind, randomized, controlled trial in 139 patients receiving protocol-determined background therapy with atorvastatin 80 mg with or without ezetimibe 10 mg daily. Patients stable on the background lipid-lowering regimen were randomized to receive placebo or REPATHA 420 mg monthly. Patients had a mean baseline age of 59 years, with an age range of 35 years to 75 years FEBRUARY

10 TABLE 6. EFFECT OF REPATHA ON LIPID PARAMETERS IN PATIENTS WITH ATHEROSCLEROTIC CARDIOVASCULAR DISEASE ON ATORVASTATIN 80 MG, ROSUVASTATIN 40 MG, OR SIMVASTATIN 40 MG (MEAN % CHANGE FROM BASELINE TO WEEK 12 IN STUDY 1) 19,a TREATMENT GROUP LDL-C NON HDL-C APO B TOTAL CHOLESTEROL Placebo every 2 weeks (n = 42) REPATHA 140 mg every 2 weeks a (n = 105) Mean difference from placebo (95% CI) 71 ( 81 to 61) 58 ( 67 to 49) 55 ( 62 to 47) 42 ( 48 to 36) Placebo once monthly (n = 44) REPATHA 420 mg once monthly b (n = 105) Mean difference from placebo (95% CI) 63 ( 76 to 50) 52 ( 63 to 41) Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. a Estimates based on a multiple imputation model that accounts for treatment adherence. b 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C. 49 ( 58 to 39) 36 ( 43 to 28) FIGURE 1. EFFECT OF REPATHA ON LDL-C IN PATIENTS WITH ATHEROSCLEROTIC CARDIOVASCULAR DISEASE WHEN COMBINED WITH STATINS (MEAN % CHANGE FROM BASELINE TO WEEK 12 IN STUDY 1) 19 Mean Percent Change in LDL-C Compared to Placebo Pooled Statins LDL-C = low-density lipoprotein cholesterol. Atorvastatin 80 mg QD REPATHA 140 mg every 2 weeks Rosuvastatin 40 mg QD REPATHA 420 mg once monthly Simvastatin 40 mg QD Following the stabilization period, the baseline LDL-C averaged 105 mg/dl. By week 52, patients receiving REPATHA 420 mg monthly experienced a 54% greater percentage change in LDL-C versus placebo (95% CI, 42%-65%; P <.0001). See TABLE 7 19 for the effect of REPATHA on lipid parameters in this study and FIGURE 2 19 for the LDL-C reductions observed with each of the regimens used in the study at weeks 12, 24, 36, and In a study of 329 patients with HeFH using statins with or without additional lipid-lowering therapies, investigators performed a multicenter, double-blind, randomized, placebo-controlled trial 10 FEBRUARY

11 TABLE 7. EFFECT OF REPATHA ON LIPID PARAMETERS IN PATIENTS WITH ATHEROSCLEROTIC CARDIOVASCULAR DISEASE ON ATORVASTATIN 80 MG WITH OR WITHOUT EZETIMIBE 10 MG DAILY (MEAN % CHANGE FROM BASELINE TO WEEK 52 IN STUDY 2) 19,a TREATMENT GROUP LDL-C NON HDL-C APO B TOTAL CHOLESTEROL Placebo once monthly (n = 44) REPATHA 420 mg once monthly (n = 95) Mean difference from placebo (95% CI) 54 ( 65 to 42) 44 ( 56 to 32) Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. a Estimates based on a multiple imputation model that accounts for treatment adherence. 40 ( 50 to 30) 31 ( 39 to 24) FIGURE 2. EFFECT OF REPATHA 420 MG ONCE MONTHLY ON LOW-DENSITY LIPOPROTEIN CHOLESTEROL IN PATIENTS WITH ATHEROSCLEROTIC CARDIOVASCULAR DISEASE ON ATORVASTATIN 80 MG WITH OR WITHOUT EZETIMIBE 10 MG DAILY 19 Percent Change from Baseline Observed n: Observed n: Baseline Week 12 Week 24 Week 36 Week 52 Placebo once monthly REPATHA 420 mg once monthly over 12 weeks. All patients in this study had received a previous diagnosis of HeFH based on the Simon Broome criteria and were randomized to receive REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo. Patients had a mean baseline age of 51 years, with an age range of 19 years to 79 years. More than one-third (38%) of patients enrolled in this trial had clinical ASCVD, and more than three-fourths (76%) of patients were on high-intensity statin therapy. 19 The average baseline LDL-C level was 156 mg/dl, and by week 12, patients receiving REPATHA 140 mg every 2 weeks experienced a 61% greater percent reduction in LDL-C versus placebo (95% CI, 55%-67%; P <.0001). Patients receiving REPATHA 420 mg monthly experienced a 60% greater reduction in LDL-C versus placebo (95% CI, 52%-68%; P <.0001). See TABLE 8 19 for details on the effect of REPATHA on lipid parameters in this study. 19 In a study of 49 patients with HoFH not on lipid apheresis therapy, investigators performed a multicenter, double-blind, randomized, placebo-controlled trial over 12 weeks. A total of 33 patients in the trial received REPATHA 420 mg monthly. The remaining 16 patients received a placebo injection in addition to background lipid-lowering therapies. Patients had a mean baseline age of 31 years and a mean LDL-C level of 349 mg/dl, with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis (untreated LDL-C greater than 500 mg/dl with xanthoma before 10 years or evidence of HeFH in both parents). Patients FEBRUARY

12 TABLE 8. EFFECT OF REPATHA ON LIPID PARAMETERS IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (MEAN % CHANGE FROM BASELINE TO WEEK 12 IN STUDY 3) 19,a TREATMENT GROUP LDL-C NON HDL-C APO B TOTAL CHOLESTEROL Placebo every 2 weeks (n = 54) REPATHA 140 mg every 2 weeks a (n = 110) Mean difference from placebo (95% CI) 61 ( 67 to 55) 54 ( 60 to 49) 49 ( 54 to 43) 40 ( 45 to 36) Placebo once monthly (n = 55) REPATHA 420 mg once monthly b (n = 110) Mean difference from placebo (95% CI) 60 ( 68 to 52) 53 ( 60 to 46) Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. a Estimates based on a multiple imputation model that accounts for treatment adherence. b 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C. 48 ( 55 to 41) 39 ( 45 to 33) TABLE 9. EFFECT OF REPATHA ON LIPID PARAMETERS IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (MEAN % CHANGE FROM BASELINE TO WEEK 12 IN STUDY 4) 19,a TREATMENT GROUP LDL-C NON HDL-C APO B TOTAL CHOLESTEROL Placebo once monthly (n = 16) REPATHA 420 mg once monthly (n = 33) Mean difference from placebo (95% CI) 31 ( 44 to 18) 28 ( 41 to 16) Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. a Estimates based on a multiple imputation model that accounts for treatment adherence. 21 ( 33 to 9) 25 ( 36 to 14) receiving REPATHA 420 mg monthly experienced a 31% greater reduction in LDL-C versus placebo (95% CI, 18%-44%; P <.0001) at Week 12. See TABLE 9 19 for the effect of REPATHA on lipid parameters in this study. Patients known to have 2 LDL-receptor negative alleles (little to no residual function) did not respond to REPATHA. 19 THE REPATHA PUSHTRONEX SYSTEM (ON-BODY INFU- SOR WITH PREFILLED CARTRIDGE) The REPATHA Pushtronex system consists of a prefilled cartridge and an on-body infusor. Before using the REPATHA onbody infusor with prefilled cartridge, it is important for patients and/or caregivers to receive training from their healthcare provider. Patients should be aware of instructions for storage of the system and instructions for using the system. Patients may use the on-body infusor with prefilled cartridge while performing moderate physical activities, such as walking, reaching, or bending. 19 The on-body infusor and prefilled cartridge should be kept in their original carton to protect them from light or physical damage. Both the on-body infusor and the prefilled cartridge must be kept in the refrigerator at a temperature of 36 F to 46 F (2 C to 8 C). If the infusor and prefilled cartridge are removed from refrigerator storage, ensure that patients keep the on-body infusor with prefilled cartridge in the original carton at room temperature, between 68 F and 77 F (20 C and 25 C), and instruct them that it must be used within 30 days. Instruct patients not to store the on-body infusor with prefilled cartridge at temperatures higher than 77 F (25 C) and not to freeze either component of the system. 19 Please refer to the complete Instructions for Use accompanying this monograph. THE REPATHA SURECLICK AUTOINJECTOR Before using the REPATHA SureClick autoinjector, it is important that patients understand they should not give themselves or anyone else the injection unless they have received training from their healthcare provider. Additionally, before using the autoinjector, patients should be aware that the orange cap of the REPATHA Sure- Click autoinjector contains a needle cover located inside the cap that contains dry natural rubber, a derivative of latex. Patients with a latex allergy should be aware of this component. 19 The REPATHA SureClick autoinjector should be kept in the original carton to protect from light during storage. The REPATHA 12 FEBRUARY

13 Cartridge bottom Front view Medicine Cartridge door (Do not close without cartridge) Prefilled Cartridge White plunger On-Body Infusor Cartridge top (Do not rotate) Cartridge label Skin Status Start button adhesive light (Do not press until ready to inject) Back view Needle cover Adhesive paper Battery Strip Left pull tab Important: Needle is inside. Medicine window Pull tabs Needle inside (under cover) Right pull tab SureClick autoinjector should be kept in the refrigerator between 36 F to 46 F (2 C to 8 C). If removed from the refrigerator, the REPATHA SureClick autoinjector should be kept at room temperature at 68 F to 77 F (20 C to 25 C) in the original carton and must be used within 30 days. The REPATHA SureClick autoinjector should not be placed in the freezer, and a REPATHA SureClick autoinjector that has been frozen should not be used. 19 Please refer to the complete Instructions for Use accompanying this monograph. PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use) before the patient starts using REPATHA, and each time the patient gets a refill as there may be new information they need to know. Provide guidance to patients and caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-use prefilled autoinjector, single-use prefilled syringe, or single-use on-body infusor with prefilled cartridge correctly (see Instructions for Use leaflet). Inform patients that it may take up to 15 seconds to administer REPATHA using the single-use prefilled autoinjector or single-use prefilled syringe and about 9 minutes to administer REPATHA using the single-use on-body infusor with prefilled cartridge. 19 Latex-sensitive patients should be advised that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the glass single-use prefilled syringe and the single-use prefilled autoinjector. The single-use on-body infusor with prefilled cartridge is not made with natural rubber latex. 19 THE ROLE OF THE SPECIALTY PHARMACIST Specialty pharmacists have an important role in counseling patients on the appropriate use and risks of a variety of specialty medications, including REPATHA. Key points to reinforce with patients include: Educating patients regarding medications, including risks Highlighting the importance of continued adherence with cholesterol-lowering therapy Providing administration instructions specific to the form of REPATHA each patient is using, including the REPATHA Pushtronex System Ensuring that patients understand and recognize the potential for hypersensitivity reactions and can identify hypersensitivity reactions when they occur Referring patients to further information sources to support their continued use of medication SUMMARY High levels of circulating LDL-C levels are an important factor in the pathogenesis of cardiovascular disease. To optimize hyperlipidemia management, healthcare providers must consider LDL-C levels in the context of each patient. In addition, with an awareness of the genetic component of hyperlipidemia, healthcare professionals can work to identify more of the individuals in the United States with HeFH. For patients with HeFH and patients with clinical ASCVD on maximally tolerated statin therapy as an adjunct to diet who require additional reduction in LDL-C, therapies such as REPATHA help augment LDL-C reduction. REFERENCES 1. Stone NJ, Robinson JG, Lichtenstein AH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B): doi: /j.jacc Goff DC Jr, Lloyd-Jones DM, Bennett G, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S49-S73. doi: /01. cir Centers for Disease Control and Prevention. Vital signs: prevalence, treatment, and control of high levels of low-density lipoprotein cholesterol--united States, and MMWR Morb Mortal Wkly Rep. 2011;60(4): Data on File, Amgen; Onorato A, Sturm AC. Heterozygous familial hypercholesterolemia. Circulation. 2016;133(14):e587-e589. doi: /CIRCULATIONAHA Wiegman A, Gidding SS, Watts GF, et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36): doi: /eurheartj/ehv Primary Panel: Genest J, Hegele RA, Bergeron J, et al. Canadian Cardiovascular Society position FEBRUARY