Data from FDA - Curated by EPG Health - Last updated 18 December 2019

Indication(s)

1 INDICATIONS AND USAGE REPATHA is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody indicated: to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease. (1.1) as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce low-density lipoprotein cholesterol (LDL-C). (1.2) as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. (1.3) 1.1 Prevention of Cardiovascular Events In adults with established cardiovascular disease, REPATHA® is indicated to reduce the risk of myocardial infarction, stroke, and coronary revascularization. 1.2 Primary Hyperlipidemia (Including Heterozygous Familial Hypercholesterolemia) REPATHA is indicated as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C). 1.3 Homozygous Familial Hypercholesterolemia 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to REPATHA. Serious hypersensitivity reactions including angioedema have occurred in patients treated with REPATHA [ s ee Warnings and Precautions ( 5.1 )] . Patients with a history of a serious hypersensitivity reaction to REPATHA. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the label: Allergic Reactions [ s ee Warnings and Precautions ( 5.1 ) ] Common adverse reactions in clinical trials in primary hyperlipidemia (including heterozygous familial hypercholesterolemia) (> 5% of patients treated with REPATHA and occurring more frequently than placebo): nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. (6) Common adverse reactions in the cardiovascular outcomes trial (> 5% of patients treated with REPATHA and occurring more frequently than placebo): diabetes mellitus, nasopharyngitis and upper respiratory tract infection. (6) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults with Primary Hyperlipidemia (including Heterozygous Familial Hypercholesterolemia ) The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks). The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races. Adverse Reactions in a 52-Week Controlled Trial In a 52-week, double-blind, randomized, placebo-controlled trial (Study 3 [DESCARTES, NCT01516879]), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies ( 14.2 )] . The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian; 6% identified as Hispanic ethnicity. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients in DESCARTES, are shown in Table 1. Adverse reactions led to discontinuation of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated 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). Table 1. Adverse Reactions Occurring in Greater than or Equal to 3% of REPATHA-treated Patients and More Frequently than with Placebo in DESCARTES Placebo (N = 302) % REPATHA (N = 599) % Nasopharyngitis 9.6 10.5 Upper respiratory tract infection 6.3 9.3 Influenza 6.3 7.5 Back pain 5.6 6.2 Injection site reactions † 5.0 5.7 Cough 3.6 4.5 Urinary tract infection 3.6 4.5 Sinusitis 3.0 4.2 Headache 3.6 4.0 Myalgia 3.0 4.0 Dizziness 2.6 3.7 Musculoskeletal pain 3.0 3.3 Hypertension 2.3 3.2 Diarrhea 2.6 3.0 Gastroenteritis 2.0 3.0 † includes erythema, pain, bruising Adverse Reactions in Seven Pooled 12-Week Controlled Trials In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly. The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian; 5% identified as Hispanic ethnicity. Adverse reactions reported in at least 1% of REPATHA-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2. Table 2. Adverse Reactions Occurring in Greater than 1% of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Trials Placebo (N = 1224) % REPATHA † (N = 2052) % Nasopharyngitis 3.9 4.0 Back pain 2.2 2.3 Upper respiratory tract infection 2.0 2.1 Arthralgia 1.6 1.8 Nausea 1.2 1.8 Fatigue 1.0 1.6 Muscle spasms 1.2 1.3 Urinary tract infection 1.2 1.3 Cough 0.7 1.2 Influenza 1.1 1.2 Contusion 0.5 1.0 † 140 mg every 2 weeks and 420 mg once monthly combined Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial ) The adverse reactions described below are from a pool of the 52-week trial (DESCARTES) and seven 12-week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively. Local Injection Site Reactions 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 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%). Adverse Reactions in the Cardiovascular Outcomes Trial In a double-blind, randomized, placebo-controlled cardiovascular outcomes trial (Study 1 [REPATHA Cardiovascular Outcomes Trial, FOURIER, NCT01764633]), 27,525 patients received at least one dose of REPATHA or placebo [see Clinical Studies ( 14.1 )]. The mean age was 62.5 years (range: 40 to 86 years), 45% were 65 years or older, 9% were 75 years or older, 25% women, 85% White, 2% Black and 10% Asian; 8% identified as Hispanic ethnicity. Patients were exposed to REPATHA or placebo for a median of 24.8 months; 91% of patients were exposed for ≥ 12 months, 54% were exposed for ≥ 24 months and 5% were exposed for ≥ 36 months. The safety profile of REPATHA in this trial was generally consistent with the safety profile described above in the 12- and 52-week controlled trials involving patients with primary hyperlipidemia (including HeFH). Serious adverse events occurred in 24.8% and 24.7% of REPATHA-treated and placebo-treated patients, respectively. Adverse events led to discontinuation of study treatment in 4.4% of patients assigned to REPATHA and 4.2% assigned to placebo. Common adverse reactions (> 5% of patients treated with REPATHA and occurring more frequently than placebo) included diabetes mellitus (8.8% REPATHA, 8.2% placebo), nasopharyngitis (7.8% REPATHA, 7.4% placebo), and upper respiratory tract infection (5.1% REPATHA, 4.8% placebo). Among the 16,676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the trial was 8.1% in patients assigned to REPATHA compared with 7.7% in those assigned to placebo. Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 6 [TESLA, NCT01588496]), 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies ( 14.3 )] . The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other. 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%) Nasopharyngitis (6.1% versus 0%) 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to REPATHA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In a pool of placebo- and active-controlled clinical trials, 0.3% (48 out of 17,992) of patients treated with at least one dose of REPATHA tested positive for the development of binding antibodies. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies. There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA, but the long-term consequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown. 6.3 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of REPATHA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic reactions: Angioedema Influenza-like illness

Usage information

Dosing and administration
2 DOSAGE AND ADMINIST R ATION Administer subcutaneously. (2.1) Adults with established cardiovascular disease or primary hyperlipidemia (including heterozygous familial hypercholesterolemia): 140 mg every 2 weeks or 420 mg once monthly in abdomen, thigh, or upper arm. (2.1) HoFH: 420 mg once monthly. (2.1) The 420 mg dose of REPATHA can be administered: over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector or single-use prefilled syringe. (2.2) See Dosage and Administration for important administration instructions. (2.2) 2.1 Recommended Dosage The recommended subcutaneous dosage of REPATHA in adults with established cardiovascular disease or in adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) is either 140 mg every 2 weeks OR 420 mg once monthly, based on patient preference for dosing frequency and injection volume. When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. The recommended subcutaneous dosage of REPATHA in patients with HoFH is 420 mg once monthly. In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function. When monitoring LDL-C for patients receiving REPATHA 420 mg once monthly, note that LDL-C can vary considerably during the dosing interval in some patients [ see Clinical Studies ( 14 ) ]. If a dose is missed, instruct the patient to administer REPATHA within 7 days from the missed dose and resume the patient’s original schedule. If an every-2-week dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule. If a once-monthly dose is not administered within 7 days, instruct the patient to administer the dose and start a new schedule based on this date. 2.2 Important Administration Instructions The 420 mg dose of REPATHA can be administered: Provide proper training to patients and/or caregivers on how to prepare and administer REPATHA prior to use, according to the Instructions for Use, including aseptic technique. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use REPATHA. Keep REPATHA in the refrigerator. Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes for the single-use prefilled autoinjector or single-use prefilled syringe and for at least 45 minutes for the single-use on-body infusor with prefilled cartridge. Do not warm in any other way. Alternatively, for patients and caregivers, REPATHA can be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton. However, under these conditions, REPATHA must be used within 30 days [see How Supplied/Storage and Handling ( 16 )]. Visually inspect REPATHA for particles and discoloration prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy or discolored or contains particles. Administer REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use prefilled syringe, single-use prefilled autoinjector, or single-use on-body infusor with prefilled cartridge. Do not co-administer REPATHA with other injectable drugs at the same administration site. Rotate the site of each subcutaneous administration. over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector or single-use prefilled syringe.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REPATHA during pregnancy. Please contact 1-877-311-8972 or https://mothertobaby.org/ongoing-study/repatha/ to enroll in or to obtain information about the registry. Risk Summary There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month. In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses. The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically. No assessment for immune suppression was conducted with evolocumab in infant monkeys. Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier. FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester. Consider the benefits and risks of REPATHA and possible risks to the fetus before prescribing REPATHA to pregnant women. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. No test of humoral immunity in infant monkeys was conducted with evolocumab. 8.2 Lactation Risk Summary There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered 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. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. 8.4 Pediatric Use 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 [see Clinical Studies ( 14.3 )]. In this trial, 7 adolescents received REPATHA 420 mg subcutaneously once monthly and 3 adolescents received placebo. The effect of REPATHA on LDL-C was generally similar to that observed among adult patients with HoFH. Including experience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with REPATHA, with a median exposure duration of 9 months. The safety profile of REPATHA in these adolescents was similar to that described for adult patients with HoFH. The safety and effectiveness of REPATHA have not been established in pediatric patients with HoFH who are younger than 13 years old. The safety and effectiveness of REPATHA have not been established in pediatric patients with primary hyperlipidemia or HeFH. 8.5 Geriatric Use In controlled trials, 7656 (41%) patients treated with REPATHA were ≥ 65 years old and 1500 (8%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dose adjustment is needed in patients with renal impairment [see Clinical Pharmacology ( 12.3 )]. 8.7 Hepatic Impairment No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment [ see Clinical Pharmacology ( 12.3 )].

More information

Category Value
Authorisation number BLA125522
Agency product number LKC0U3A8NJ
Orphan designation No
Product NDC 55513-770,55513-760,55513-750
Date Last Revised 06-02-2019
Type HUMAN PRESCRIPTION DRUG
RXCUI 1665895
Marketing authorisation holder Amgen Inc