4.1. Therapeutic indications

Primary hypercholesterolaemia and mixed dyslipidaemia

Praluent is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, and in paediatric patients 8 years of age and older with heterozygous familial hypercholesterolaemia (HeFH) 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.

Established atherosclerotic cardiovascular disease

Praluent is indicated in adults with established 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.

4.2. Posology and method of administration

Posology

Adults

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

The recommended alirocumab doses are 75 mg once every 2 weeks, 150 mg once every 2 weeks, 300 mg once every 4 weeks (monthly), administered subcutaneously. All doses may be used for initiation of treatment.

The dose of alirocumab can be individualised based on patient characteristics such as baseline LDL-C level, goal of therapy, and response to treatment. Lipid levels can be assessed 4 to 8 weeks after treatment initiation or titration, and dose adjusted accordingly (up-titration or down-titration). Intense LDL-C reduction is expected with alirocumab 150 mg once every 2 weeks and 300 mg once every 4 weeks (monthly), where 150 mg once every 2 weeks is the maximum dose (see section 5.1).

HeFH in paediatric patients 8 years of age and older

Body weight of patients

Recommended dose

Recommended dose if additional LDL-C reduction is needed*

Less than 50 kg

150 mg once every 4 weeks

75 mg once every 2 weeks

50 kg or more

300 mg once every 4 weeks

150 mg once every 2 weeks

* Lipid levels can be assessed 8 weeks after treatment initiation or titration and dose adjusted accordingly.

Missed dose

If a dose is missed, the dose should be administered as soon as possible and thereafter, dosing should be resumed on the original schedule.

Special populations

Elderly

No dose adjustment is needed for elderly patients.

Hepatic impairment

No dose adjustment is needed for patients with mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment (see section 5.2).

Renal impairment

No dose adjustment is needed for patients with mild or moderate renal impairment. Limited data are available in patients with severe renal impairment (see section 5.2).

Body weight

No dose adjustment is needed in patients based on weight.

Paediatric population

The safety and efficacy of Praluent in children less than 8 years of age have not been established. No data are available.

Method of administration

Subcutaneous use.

Alirocumab is injected as a subcutaneous injection into the thigh, abdomen or upper arm.

Each pre-filled pen is for single use only.

To administer the 300 mg dose, either one 300 mg injection or two 150 mg injections should be given consecutively at two different injection sites.

It is recommended to rotate the injection site with each injection.

Alirocumab should not be injected into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections.

Alirocumab must not be co-administered with other injectable medicinal products at the same injection site.

Precautions to be taken before handling or administering the medicinal product

The solution should be allowed to warm to room temperature prior to use (see section 6.6).

Paediatric patients 8 years of age and older

In adolescents 12 years of age and older, it is recommended that Praluent be administered by or under the supervision of an adult.

In children less than 12 years of age, Praluent must be given by a caregiver.

Adults

Adult patients may either self‑inject alirocumab, or a caregiver may administer alirocumab, after guidance has been provided by a healthcare professional on proper subcutaneous injection technique.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

Allergic reactions

General allergic reactions, including pruritus, as well as rare and sometimes serious allergic reactions such as hypersensitivity, nummular eczema, urticaria, and hypersensitivity vasculitis have been reported in clinical studies. Angioedema has been reported in the postmarketing setting (see section 4.8). If signs or symptoms of serious allergic reactions occur, treatment with alirocumab must be discontinued and appropriate symptomatic treatment initiated (see section 4.3).

Renal impairment

In clinical studies, there was limited representation of patients with severe renal impairment (defined as eGFR < 30 mL/min/1.73 m2) (see section 5.2). Alirocumab should be used with caution in patients with severe renal impairment.

Hepatic impairment

Patients with severe hepatic impairment (Child-Pugh C) have not been studied (see section 5.2). Alirocumab should be used with caution in patients with severe hepatic impairment.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of alirocumab on other medicinal products

Since alirocumab is a biological medicinal product, no pharmacokinetic effects of alirocumab on other medicinal products and no effect on cytochrome P450 enzymes are anticipated.

Effects of other medicinal products on alirocumab

Statins and other lipid‑modifying therapy are known to increase production of PCSK9, the protein targeted by alirocumab. This leads to the increased target-mediated clearance and reduced systemic exposure of alirocumab. Compared to alirocumab monotherapy, the exposure to alirocumab is about 40%, 15%, and 35% lower when used concomitantly with statins, ezetimibe, and fenofibrate, respectively. However, reduction of LDL-C is maintained during the dosing interval when alirocumab is administered every two weeks.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Praluent in pregnant women. Alirocumab is a recombinant IgG1 antibody, therefore it is expected to cross the placental barrier (see section 5.3).

Animal studies do not indicate direct or indirect harmful effects with respect to maintenance of pregnancy or embryo-foetal development; maternal toxicity was noted in rats, but not in monkeys at doses in excess of the human dose, and a weaker secondary immune response to antigen challenge was observed in the offspring of monkeys (see section 5.3).

The use of Praluent is not recommended during pregnancy unless the clinical condition of the woman requires treatment with alirocumab.

Breast‑feeding

It is not known whether alirocumab is excreted in human milk. Human immunoglobulin G (IgG) is excreted in human milk, in particular in colostrum; the use of Praluent is not recommended in breast-feeding women during this period. For the remaining duration of breast-feeding, exposure is expected to be low.

Since the effects of alirocumab on the breast-fed infant are unknown, a decision should be made whether to discontinue nursing or to discontinue Praluent during this period.

Fertility

In animal studies, there were no adverse effects on surrogate markers of fertility (see section 5.3). There are no data on adverse effects on fertility in humans.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions, at recommended doses, are local injection site reactions (6.1%), upper respiratory tract signs and symptoms (2.0%), and pruritus (1.1%). Most common adverse reactions leading to treatment discontinuation in patients treated with alirocumab were local injection site reactions.

The safety profile in ODYSSEY OUTCOMES was consistent with the overall safety profile described in the Phase 3 controlled trials.

No difference in the safety profile was observed between the two doses (75 mg and 150 mg) used in the Phase 3 program.

Tabulated list of adverse reactions

The following adverse reactions were reported in patients treated with alirocumab in pooled controlled studies and/or post-marketing use (see Table 1).

Frequencies for all adverse reactions identified from clinical trials have been calculated based on their incidence in pooled Phase 3 clinical trials. Adverse reactions are presented by system organ class. Frequency categories are defined as: 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); very rare (<1/10,000) and not known (cannot be estimated from the available data).

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as "not known".

Table 1 – Adverse reactions

System organ class

Common

Rare

Not known

Immune system disorders

Hypersensitivity,

hypersensitivity vasculitis

Respiratory, thoracic and mediastinal disorders

Upper respiratory tract signs and symptoms*

Skin and subcutaneous tissue disorders

Pruritus

Urticaria,

eczema nummular

Angioedema

General disorders and administration site conditions

Injection site reactions**

Flu-like illness

* including mainly oropharyngeal pain, rhinorrhea, sneezing

** including erythema/redness, itching, swelling, pain/tenderness

Description of selected adverse reactions

Local injection site reactions

Local injection site reactions, including erythema/redness, itching, swelling, and pain/tenderness, were reported in 6.1% of patients treated with alirocumab versus 4.1% in the control group (receiving placebo injections). Most injection site reactions were transient and of mild intensity. The discontinuation rate due to local injection site reactions was comparable between the two groups (0.2% in the alirocumab group versus 0.3% in the control group). In the cardiovascular outcomes study (ODYSSEY OUTCOMES), injection site reactions also occurred more frequently in alirocumab-treated patients than in placebo-treated patients (3.8% alirocumab versus 2.1% placebo).

General allergic reactions

General allergic reactions were reported more frequently in the alirocumab group (8.1% of patients) than in the control group (7.0% of patients), mainly due to a difference in the incidence of pruritus. The observed cases of pruritus were typically mild and transient. In addition, rare and sometimes serious allergic reactions such as hypersensitivity, nummular eczema, urticaria, and hypersensitivity vasculitis have been reported in controlled clinical studies (see section 4.4). In the cardiovascular outcomes study (ODYSSEY OUTCOMES), general allergic reactions were similar in alirocumab-treated patients and placebo-treated patients (7.9% alirocumab, 7.8% placebo). No difference was seen in the incidence of pruritus.

Special populations

Elderly

Although no safety issues were observed in patients over 75 years of age, data are limited in this age group.

In the Phase 3 primary hypercholesterolemia and mixed dyslipidaemia controlled studies, 1,158 patients (34.7%) treated with alirocumab were ≥65 years of age and 241 patients (7.2%) treated with alirocumab were ≥75 years of age. In the cardiovascular outcomes controlled study, 2,505 patients (26.5%) treated with alirocumab were ≥65 years of age and 493 patients (5.2%) treated with alirocumab were ≥75 years of age. There were no significant differences observed in safety and efficacy with increasing age.

Paediatric population

The safety and efficacy of Praluent have been established in children and adolescents with heterozygous familial hypercholesterolaemia (HeFH). A clinical study to evaluate the effects of Praluent was conducted in 153 patients, 8 to 17 years of age with HeFH. No new safety findings were identified and the safety data in this population were consistent with the known safety profile of the product in adults with HeFH.

The experience of alirocumab in paediatric patients with homozygous familial hypercholesterolaemia (HoFH) is limited to 18 patients aged 8 to 17 years. No new safety finding was observed compared to the known adult safety profile.

Every 4 week dosing study

The safety profile in patients treated with a 300 mg once every 4 week (monthly) dosing regimen was similar to the safety profile as described for the clinical studies program using a 2 week dosing regimen, except for a higher rate of local injection site reactions. Local injection site reactions were reported overall at a frequency of 16.6% in the 300 mg once every 4 weeks treatment group and 7.9% in the placebo group. Patients in the alirocumab 300 mg every 4 weeks treatment group received alternating placebo injections to maintain blinding in regard to injection frequency. Excluding injection site reactions (ISRs) that occurred after these placebo injections, the frequency of ISRs was 11.8%. The discontinuation rate due to injection site reactions was 0.7% in the 300 mg once every 4 weeks treatment group and 0% in the placebo group.

LDL‑C values <0.65 mmol/L (<25 mg/dL)

In all clinical studies background lipid lowering therapies could not be adjusted by trial design. The percentage of patients who reached LDL-C values <0.65 mmol/L (<25 mg/dL) depended both on the baseline LDL-C and the dose of alirocumab.

In a pool of controlled studies using a 75 mg every 2 week (Q2W) starting dose and in which the dose was increased to 150 mg Q2W if the patient's LDL-C was <1.81 mmol/L or <2.59 mmol/L (<70 mg/dL or <100mg/dL), 29.3% of patients with baseline LDL-C <2.59 mmol/L (<100 mg/dL) and 5.0% of patients with baseline LDL-C >2.59 mmol/L (≥100 mg/dL) treated with alirocumab had two consecutive values of LDL-C <0.65 mmol/L (<25 mg/dL). In the ODYSSEY OUTCOMES study, in which the starting alirocumab dose was 75 mg Q2W and the dose was increased to 150 mg Q2W if the patient's LDL-C was not <1.29 mmol/L (<50 mg/dL), 54.8% of patients with baseline LDL-C <2.59 mmol/L (<100 mg/dL) and 24.2% of patients with baseline LDL-C ≥2.59 mmol/L (≥100 mg/dL) treated with alirocumab had two consecutive values of LDL-C <0.65 mmol/L (<25 mg/dL).

Although adverse consequences of very low LDL-C were not identified in alirocumab trials, the long-term effects of sustained very low levels of LDL-C are unknown.

Immunogenicity/ Anti-drug-antibodies (ADA)

In the ODYSSEY OUTCOMES trial, 5.5% of patients treated with alirocumab 75 mg and/or 150 mg every 2 weeks (Q2W) had anti-drug antibodies (ADA) detected after initiating treatment compared with 1.6% of patients treated with placebo, most of these were transient responses. Persistent ADA responses were observed in 0.7% of patients treated with alirocumab and 0.4% of patients treated with placebo. Neutralising antibody (NAb) responses were observed in 0.5% of patients treated with alirocumab and in <0.1% of patients treated with placebo.

Anti-drug antibody responses, including NAb, were low titer and did not appear to have a clinically meaningful impact on the efficacy or safety of alirocumab, except for a higher rate of injection site reactions in patients with treatment emergent ADA compared to patients who were ADA negative (7.5% vs 3.6%). The long-term consequences of continuing alirocumab treatment in the presence of ADA are unknown. In a pool of ten placebo-controlled and active-controlled trials of patients treated with alirocumab 75 mg and/or 150 mg Q2W as well as in a separate clinical study of patients treated with alirocumab 75 mg Q2W or 300 mg every 4 weeks (including some patients with dose adjustment to 150 mg Q2W), the incidence of detecting ADA and NAb was similar to the results from the ODYSSEY OUTCOMES trial described above.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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