evolocumab: prescribing information – dosing, contraindications, interactions, side effects

Hypercholesterolaemia and mixed dyslipidaemia

Repatha is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, and in paediatric patients aged 10 years and over with heterozygous familial hypercholesterolaemia, as an adjunct to diet:
- in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
- alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

Homozygous familial hypercholesterolaemia

Repatha is indicated in adults and paediatric patients aged 10 years and over with homozygous familial hypercholesterolaemia in combination with other lipid-lowering therapies.

Atherosclerotic cardiovascular disease

Repatha is indicated in adults with established or at high risk for atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors:
- in combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies or,
- alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

For study results with respect to effects on LDL-C, cardiovascular events and populations studied see section 5.1.

Prior to initiating evolocumab, secondary causes of hyperlipidaemia or mixed dyslipidaemia (e.g., nephrotic syndrome, hypothyroidism) should be excluded.

Posology

Primary hypercholesterolaemia and mixed dyslipidaemia (including heterozygous familial hypercholesterolaemia)

Adults and paediatric patients (aged 10 years and over)
The recommended dose of evolocumab is either 140 mg every two weeks or 420 mg once monthly;
both doses are clinically equivalent.

Homozygous familial hypercholesterolaemia in adults and paediatric patients aged 10 years and over The initial recommended dose is 420 mg once monthly. After 12 weeks of treatment, dose frequency can be up-titrated to 420 mg once every 2 weeks if a clinically meaningful response is not achieved.
Patients on apheresis may initiate treatment with 420 mg every two weeks to correspond with their apheresis schedule.

Atherosclerotic cardiovascular disease in adults
The recommended dose of evolocumab is either 140 mg every two weeks or 420 mg once monthly;
both doses are clinically equivalent.

Special populations

Elderly patients (age ≥ 65 years)
No dose adjustment is necessary in elderly patients.

Patients with renal impairment
No dose adjustment is necessary in patients with renal impairment (see section 5.2).

Patients with hepatic impairment
No dose adjustment is necessary in patients with mild hepatic impairment, see section 4.4 for patients with moderate and severe hepatic impairment.

Paediatric population
The safety and effectiveness of Repatha have not been established in paediatric patients with heterozygous familial hypercholesterolaemia (HeFH) or homozygous familial hypercholesterolaemia (HoFH) who are younger than 10 years old or in paediatric patients with other types of hyperlipidaemia.

Method of administration

Subcutaneous use.

Evolocumab is for subcutaneous injection into the abdomen, thigh or upper arm region. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red, or hard.

Evolocumab must not be administered intravenously or intramuscularly.

Repatha 140 mg solution for injection in pre-filled syringe
The 140 mg dose should be delivered using a single pre-filled syringe.
The 420 mg dose should be delivered using three pre-filled syringes administered consecutively within 30 minutes.

Repatha 140 mg solution for injection in pre-filled pen
The 140 mg dose should be delivered using a single pre-filled pen.
The 420 mg dose should be delivered using three pre-filled pens administered consecutively within 30 minutes.

Repatha 420 mg solution for injection in cartridge
The 420 mg dose should be delivered using a single cartridge with the automated mini-doser.

Repatha is intended for patient self-administration after proper training. Administration of evolocumab can also be performed by an individual who has been trained to administer the product.

For single use only.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

MedDRA system organ class
(SOC)
Adverse reactions
Frequency category
Infections and infestations
Influenza
Common
Nasopharyngitis
Common
Upper respiratory tract infection
Common
Immune system disorders
Hypersensitivity
Common
Rash
Common
Urticaria
Uncommon
Nervous system disorders
Headache
Common
Gastrointestinal disorders
Nausea
Common
Skin and subcutaneous tissue disorders
Angioedema
Rare
Musculoskeletal and connective tissue disorders
Back pain
Common
Arthralgia
Common
Myalgia
Common
General disorders and administration site conditions
Injection site reactions1
Common
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, 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 24 671 patients treated with evolocumab in double-blind clinical studies 11 126 (45.1%) were ≥ 65 years old, while 2 132 (8.6%) 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.

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.

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.

No adverse effects were observed in animal studies at exposures up to 300-fold higher than those in patients treated with 420 mg evolocumab once monthly.

There is no specific treatment for evolocumab overdose. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: lipid modifying agents, other lipid modifying agents. ATC code:
C10AX13

Mechanism of action

Evolocumab binds selectively to PCSK9 and prevents circulating PCSK9 from binding to the low density lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation. Increasing liver LDLR levels results in associated reductions in serum LDL-cholesterol (LDL-C).

Pharmacodynamic effects

In clinical trials, evolocumab reduced unbound PCSK9, LDL-C, TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a), and increased HDL-C and ApoA1 in patients with primary hypercholesterolaemia and mixed dyslipidaemia.

A single subcutaneous administration of 140 mg or 420 mg evolocumab resulted in maximum suppression of circulating unbound PCSK9 by 4 hours followed by a reduction in LDL-C reaching a mean nadir in response by 14 and 21 days, respectively. Changes in unbound PCSK9 and serum lipoproteins were reversible upon discontinuation of evolocumab. No increase in unbound PCSK9 or

LDL-C above baseline was observed during the washout of evolocumab suggesting that compensatory mechanisms to increase production of PCSK9 and LDL-C do not occur during treatment.

Subcutaneous regimens of 140 mg every 2 weeks and 420 mg once monthly were equivalent in average LDL-C lowering (mean of weeks 10 and 12) resulting in -72% to -57% from baseline compared with placebo. Treatment with evolocumab resulted in a similar reduction of LDL-C when used alone or in combination with other lipid-lowering therapies.

Clinical efficacy in primary hypercholesterolaemia and mixed dyslipidaemia

LDL-C reduction of approximately 55% to 75% was achieved with evolocumab as early as week 1 and maintained during long-term therapy. Maximal response was generally achieved within 1 to 2 weeks after dosing with 140 mg every 2 weeks and 420 mg once monthly. Evolocumab was effective in all subgroups relative to placebo and ezetimibe, with no notable differences observed between subgroups, such as age, race, gender, region, body-mass index, National Cholesterol Education Program risk, current smoking status, baseline coronary heart disease (CHD) risk factors, family history of premature CHD, glucose tolerance status, (i.e. diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, statin dose and intensity, unbound baseline PCSK9, baseline LDL-C and baseline TG.

In 80-85% of all primary hyperlipidaemia patients treated with either dose, evolocumab demonstrated a ≥ 50% reduction in LDL-C at the mean of weeks 10 and 12. Up to 99% of patients treated with either dose of evolocumab achieved an LDL-C of < 2.6 mmol/L and up to 95% achieved an LDL-C < 1.8 mmol/L at the mean of weeks 10 and 12.

Combination with a statin and statin with other lipid-lowering therapies

Absorption and distribution

Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days. Administration of single subcutaneous dose of 140 mg resulted in a Cmax mean (SD) of 13.0 (10.4) μg/mL and AUClast mean (SD) of 96.5 (78.7) day•μg/mL. Administration of single subcutaneous dose 420 mg resulted in a Cmax mean (SD) of 46.0 (17.2) μg/mL and AUClast mean (SD) of 842 (333) day•μg/mL. Three subcutaneous 140 mg doses were bioequivalent to a single subcutaneous 420 mg dose. The absolute bioavailability after SC dosing was determined to be 72% from pharmacokinetic models.

Following a single 420 mg evolocumab intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L, suggesting evolocumab has limited tissue distribution.

Biotransformation

Evolocumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Elimination

Evolocumab was estimated to have an effective half-life of 11 to 17 days.

In patients with primary hypercholesterolaemia or mixed dyslipidaemia on high dose statin, the systemic exposure of evolocumab was slightly lower than in subjects on low-to-moderate dose statin (the ratio of AUClast 0.74 [90% CI 0.29; 1.9]). An approximately 20% increase in the clearance is in part mediated by statins increasing the concentration of PCSK9 which did not adversely impact the pharmacodynamic effect of evolocumab on lipids. Population pharmacokinetic analysis indicated no appreciable differences in evolocumab serum concentrations in hypercholesterolaemic patients (non- familial hypercholesterolaemia or familial hypercholesterolaemia) taking concomitant statins.