Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Marketing Authorisation Holder: sanofi-aventis groupe, 54, rue La Boétie, F – 75008 Paris, France
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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).
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.
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.
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.
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.
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-fetal 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.
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.
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.
Praluent has no or negligible influence on the ability to drive and use machines.
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.
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 events is qualified as “not known”.
Table 1. Adverse Reactions:
Rare: Hypersensitivity, hypersensitivity vasculitis
Common: Upper respiratory tract signs and symptoms*
Common: Pruritus
Rare: Urticaria, eczema nummular
Not Known: Angioedema
Common: Injection site reactions**
Not Known: Flu-like illness
* including mainly oropharyngeal pain, rhinorrhea, sneezing
** including erythema/redness, itching, swelling, pain/tenderness
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 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.
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.
The experience of alirocumab in paediatric patients is limited to 18 patients aged 8 to 17 years with homozygous familial hypercholesterolaemia (HoFH). No new safety finding was observed compared to the known adult safety profile.
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.
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 not <70 mg/dL or < 100 mg/dL (1.81 mmol/L or 2.59 mmol/L), 29.3% of patients with baseline LDL-C <100 mg/dL and 5.0% of patients with baseline LDL-C ≥100 mg/dL treated with alirocumab had two consecutive values of LDL-C <25 mg/dL (<0.65 mmol/L). 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 <50 mg/dL (1.29 mmol/L), 54.8% of patients with baseline LDL-C <100 mg/dL and 24.2% of patients with baseline LDL-C ≥100 mg/dL treated with alirocumab had two consecutive values of LDL-C <25 mg/dL (<0.65 mmol/L).
Although adverse consequences of very low LDL-C were not identified in alirocumab trials, the long-term effects of very low levels of LDL-C are unknown. In published genetic studies as well as clinical and observational trials with lipid lowering therapies an increased risk of new onset of diabetes has been associated with lower levels of LDL-C.
No adverse reaction was identified related to these LDL-C values.
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.
Immunogenicity data are highly dependent on the sensitivity and specificity of the ADA assay.
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.
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