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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 as follows 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 (DESCARTES, NCT01516879), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. 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 10. 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). (See Table 10.)
Click on icon to see table/diagram/imageAdverse 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 11. (See Table 11.)
Click on icon to see table/diagram/imageAdverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial): The adverse reactions described as follows 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.
Hypersensitivity Reactions: Hypersensitivity 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 (REPATHA Cardiovascular Outcomes Trial, FOURIER, NCT01764633), 27,525 patients received at least one dose of REPATHA or placebo [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. 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 previously in the 12- and 52-week controlled trials involving patients with primary hyperlipidemia. 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 treated with REPATHA compared with 7.7% in patients that received placebo.
Adverse Reactions in Pediatric Patients with HeFH: In a 24-week, randomized, placebo-controlled, double-blind trial of 157 pediatric patients with HeFH, 104 patients received 420 mg REPATHA subcutaneously once monthly [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The mean age was 13.7 years (range: 10 to 17 years), 56% were female, 85% White, 1% Black, 1% Asian, and 13% other; 8% identified as Hispanic ethnicity. Common adverse reactions (>5% of patients treated with REPATHA and occurring more frequently than placebo) included: Nasopharyngitis (12% versus 11%); Headache (11% versus 2%); Oropharyngeal pain (7% versus 0%); Influenza (6% versus 4%); Upper respiratory tract infection (6% versus 2%).
Adverse Reactions in Adult and Pediatric Patients with HoFH: In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (TESLA, NCT01588496), 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. 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%).
In a multicenter, open-label 5-year extension study, 106 patients with HoFH, including 14 pediatric patients, received 420 mg of REPATHA subcutaneously once monthly or every 2 weeks [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The mean age was 34 years (range: 13 to 68 years), 51% were women, 80% White, 12% Asian, 1% Native American, and 7% other; 5% identified as Hispanic ethnicity. No new adverse reactions were observed during the open-label extension study.
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 as follows 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 adult 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.
The development of anti-evolocumab antibodies was not detected in clinical trials of pediatric patients treated with REPATHA.
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.
Postmarketing Experience: The following additional adverse reactions have been identified during postapproval 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.
Hypersensitivity reactions: Angioedema.
Influenza-like illness.
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