Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions at the recommended doses are nasopharyngitis (7.4%), upper respiratory tract infection (4.6%), back pain (4.4%), arthralgia (3.9%), influenza (3.2%), and injection site reactions (2.2%). The safety profile in the homozygous familial hypercholesterolemia population was consistent with that demonstrated in the primary hypercholesterolemia and mixed dyslipidemia population.

Tabulated list of adverse reactions

Adverse reactions reported in pivotal, controlled clinical studies, and spontaneous reporting, are displayed by system organ class and frequency in table 1 below using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000).

Table 1. Adverse reactions

MedDRA system organ class (SOC)              Adverse reactions            Frequency category Infections and infestations                  Influenza                    Common Nasopharyngitis              Common
Upper respiratory tract      Common infection
Immune system disorders                      Hypersensitivity             Common Rash                         Common
Urticaria                    Uncommon
Nervous system disorders                     Headache                     Common Gastrointestinal disorders                   Nausea                       Common Skin and subcutaneous tissue                 Angioedema                   Rare disorders
Musculoskeletal and connective               Back pain                    Common tissue disorders                             Arthralgia                   Common Myalgia                      Common
General disorders and administration         Injection site reactions1    Common site conditions                              Influenza-like illness       Uncommon 1
See section Description of selected adverse reactions.

The safety profile was consistent between subjects with post-baseline LDL-C < 25 mg/dL (0.65 mmol/L) or < 40 mg/dL(1.03 mmol/L) compared to subjects with higher post-baseline LDL-C (≥ 40 mg/dL[1.03 mmol/L]), with median (Q1, Q3) Repatha exposure of 84.2 (78.1, 89.8) months in subjects who continued on Repatha and 59.8 (52.8, 60.3) months in subjects on placebo who switched to Repatha in an open-label extension study.

Description of selected adverse reactions

Injection site reactions
The most frequent injection site reactions were injection site bruising, erythema, hemorrhage, injection site pain, and swelling.

Pediatric population

The safety and effectiveness of Repatha have been established in pediatric patients with heterozygous and homozygous familial hypercholesterolemia. A clinical study to evaluate the effects of Repatha was conducted in 158 pediatric patients aged ≥ 10 to < 18 years old with heterozygous familial hypercholesterolemia. No new safety concerns were identified and the safety data in this pediatric population was consistent with the known safety profile of the product in adults with heterozygous familial hypercholesterolemia. Twenty-six pediatric patients with homozygous familial hypercholesterolemia have been treated with Repatha in clinical studies conducted in patients aged ≥ 10 to < 18 years. No difference in safety was observed between pediatric and adult patients with homozygous familial hypercholesterolemia.

Elderly population

Of the 18,546 patients treated with evolocumab in double-blind clinical studies 7,656 (41.3%) were ≥ 65 years old, while 1,500 (8.1%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients.

Immunogenicity

In clinical studies, 0.3% of patients (48 out of 17,992 patients) treated with at least one dose of evolocumab tested positive for binding antibody development. The patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies and none of the patients tested positive for 
neutralizing antibodies. The presence of anti-evolocumab binding antibodies did not impact the pharmacokinetic profile, clinical response, or safety of evolocumab.

The development of anti-evolocumab antibodies was not detected in clinical trials of pediatric patients treated with Repatha.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/