REPATHA Solution for injection Ref.[8131] Active ingredients: Evolocumab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hepatic impairment

In patients with moderate hepatic impairment, a reduction in total evolocumab exposure was observed that may lead to a reduced effect on LDL-C reduction. Therefore, close monitoring may be warranted in these patients.

Patients with severe hepatic impairment (Child-Pugh class C) have not been studied (see section 5.2).

Evolocumab should be used with caution in patients with severe hepatic impairment.

Dry natural rubber

Repatha 140 mg solution for injection in pre-filled syringe

The needle cover of the glass pre-filled syringe is made from dry natural rubber (a derivative of latex), which may cause severe allergic reactions.

Repatha 140 mg solution for injection in pre-filled pen

The needle cover of the pre-filled pen is made from dry natural rubber (a derivative of latex), which may cause severe allergic reactions.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

No interaction studies have been performed.

The pharmacokinetic interaction between statins and evolocumab was evaluated in the clinical trials. An approximately 20% increase in the clearance of evolocumab was observed in patients co-administered statins. This increased clearance is in part mediated by statins increasing the concentration of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) which did not adversely impact the pharmacodynamic effect of evolocumab on lipids. No statin dose adjustments are necessary when used in combination with evolocumab.

No studies on pharmacokinetic and pharmacodynamics interaction between evolocumab and lipid- lowering medicinal products other than statins and ezetimibe have been conducted.

Pregnancy

There are no or limited amount of data from the use of Repatha in pregnant women.

Animal studies do not indicate direct or indirect effects with respect to reproductive toxicity (see section 5.3).

Repatha should not be used during pregnancy unless the clinical condition of the woman requires treatment with evolocumab.

Breast-feeding

It is unknown whether evolocumab is excreted in human milk.

A risk to breastfed newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or discontinue/abstain from Repatha therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No data on the effect of evolocumab on human fertility are available. Animal studies did not show any effects on fertility endpoints at area under the concentration time curve (AUC) exposure levels much higher than in patients receiving evolocumab at 420 mg once monthly (see section 5.3).

Repatha has no or negligible influence on the ability to drive and use machines.

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 hypercholesterolaemia population was consistent with that demonstrated in the primary hypercholesterolaemia and mixed dyslipidaemia 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:

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, haemorrhage, injection site pain, and swelling.

Paediatric population

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

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 neutralising antibodies and none of the patients tested positive for neutralising 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 paediatric patients treated with Repatha.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.