Low LDL-C Levels
In a pool of placebo- and active-controlled trials, as well as open-label extension
studies that followed them, a total of 1988 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 Events
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%).
Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia
In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with
HoFH (Study 4), 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
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, 0.1% of patients treated
with at least one dose of REPATHA tested positive for binding antibody development.
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 longterm consequences of continuing REPATHA treatment in the presence of anti-drug
binding antibodies are unknown.
The detection of antibody formation is highly dependent on the sensitivity and
specificity of the assay. Additionally, the observed incidence of 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
with the incidence of antibodies to other products may be misleading.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data available on use of REPATHA in pregnant women to inform a drugassociated 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 con 6V