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 Praluent 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 3).
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". (See Table 3.)
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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 Precautions). 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, 1158 patients (34.7%) treated with Praluent were ≥65 years of age and 241 patients (7.2%) treated with Praluent were ≥75 years of age. In the cardiovascular outcomes controlled study, 2505 patients (26.5%) treated with Praluent were ≥65 years of age and 493 patients (5.2%) treated with Praluent were ≥75 years of age. There were no significant differences observed in safety and efficacy with increasing age.
Paediatric population: 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.
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 <25 mg/dL (<0.65 mmol/L): In all clinical studies background lipid lowering therapies could not be adjusted by trial design. The percentage of patients who reached LDL-C values <25 mg/dL (<0.65 mmol/L) 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 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 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 previously.
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.