Summary of medicine characteristics - Praluent
1. NAME OF THE MEDICINAL PRODUCT
Praluent 75 mg solution for injection in pre-filled pen
Praluent 150 mg solution for injection in pre-filled pen
Praluent 75 mg solution for injection in pre-filled syringe
Praluent 150 mg solution for injection in pre-filled syringe
Praluent 300 mg solution for injection in pre-filled pen
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Praluent 75 mg solution for injection in pre-filled pen
Each single-use pre-filled pen contains 75 mg alirocumab in 1 ml solution.
Praluent 75 mg solution for injection in pre-filled syringe
Each single-use pre-filled syringe contains 75 mg alirocumab in 1 ml solution.
Praluent 150 mg solution for injection in pre-filled pen
Each single-use pre-filled pen contains 150 mg alirocumab in 1 ml solution.
Praluent 150 mg solution for injection in pre-filled syringe
Each single-use pre-filled syringe contains 150 mg alirocumab in 1 ml solution.
Praluent 300 mg solution for injection in pre-filled pen
Each single-use pre-filled pen contains 300 mg alirocumab in 2 ml solution.
Alirocumab is a human IgG1 monoclonal antibody produced in Chinese Hamster Ovary cells by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection)
Clear, colourless to pale yellow solution.
pH: 5.7 – 6.3
Osmolality:
Praluent 75 mg solution for injection
293 – 439 mOsm/kg
Praluent 150 mg solution for injection
383 – 434 mOsm/kg
Praluent 300 mg solution for injection
383 – 434 mOsm/kg
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Primary hypercholesterolaemia and mixed dyslipidaemia
Praluent is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:
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– 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,
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– 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:
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– in combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies or,
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– 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
Prior to initiating alirocumab secondary causes of hyperlipidaemia or mixed dyslipidaemia (e.g., nephrotic syndrome, hypothyroidism) should be excluded.
The usual starting dose for alirocumab is 75 mg administered subcutaneously once every 2 weeks. Patients requiring larger LDL-C reduction (>60%) may be started on 150 mg once every 2 weeks, or 300 mg once every 4 weeks (monthly), administered subcutaneously.
The dose of alirocumab can be individualised based on patient characteristics such as baseline LDL-C level, goal of therapy, and response. Lipid levels can be assessed 4 to 8 weeks after treatment initiation or titration, and dose adjusted accordingly (up-titration or down-titration). If additional LDL-C reduction is needed in patients treated with 75 mg once every 2 weeks or 300 mg once every 4 weeks (monthly), the dosage may be adjusted to the maximum dosage of 150 mg once every 2 weeks.
If a dose is missed, the patient should administer the injection as soon as possible and thereafter resume treatment 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 and adolescents less than 18 years of age have not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. Alirocumab has not been studied in paediatric patients less than 8 years of age.
Method of administration
Subcutaneous use.
Alirocumab is injected as a subcutaneous injection into the thigh, abdomen or upper arm.
Each pre-filled pen or pre-filled syringe 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.
The patient 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.
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).
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 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 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.
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 the national reporting system listed in
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.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: lipid modifying agents, other lipid modifying agents, ATC code: C10AX14.
Mechanism of action
Alirocumab is a fully human IgG1 monoclonal antibody that binds with high affinity and specificity to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.
The LDLR also binds triglyceride-rich VLDL remnant lipoproteins and intermediate-density lipoprotein (IDL). Therefore, alirocumab treatment can produce reductions in these remnant lipoproteins as evidenced by its reductions in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TG). Alirocumab also results in reductions in lipoprotein (a) [Lp(a)], which is a form of LDL that is bound to apolipoprotein (a). However, the LDLR has been shown to have a low affinity for Lp(a), therefore the exact mechanism by which alirocumab lowers Lp(a) is not fully understood.
In genetic studies in humans, PCSK9 variants with either loss-of-function or gain-of-function mutations have been identified. Individuals with single allele PCSK9 loss-of-function mutation have lower levels of LDL-C, which correlated with a significantly lower incidence of coronary heart disease. A few individuals have been reported, who carry PCSK9 loss-of-function mutations in two alleles and have profoundly low LDL-C levels, with HDL-C and TG levels in the normal range. Conversely, gain-of-function mutations in the PCSK9 gene have been identified in patients with increased LDL-C levels and a clinical diagnosis of familial hypercholesterolaemia.
In a multicenter, double-blind, placebo-controlled, 14 week study, 13 patients with heterozygous familial hypercholesterolaemia (heFH) due to gain-of-function mutations in the PCSK9 gene were randomised to receive either alirocumab 150 mg Q2W or placebo. Mean baseline LDL-C was 151.5 mg/dL (3.90 mmol/L). At week 2, the mean reduction from baseline in LDL-C was 62.5% in the alirocumab-treated patients as compared to 8.8% in the placebo patients. At week 8, the mean reduction in LDL-C from baseline with all patients treated with alirocumab was 72.4%.
Pharmacodynamic effects
In in vitro assays, alirocumab did not induce Fc-mediated effector function activity (antibody-dependent cell-mediated toxicity and complement-dependent cytotoxicity) either in the presence or absence of PCSK9 and no soluble immune complexes capable of binding complement proteins were observed for alirocumab when bound to PCSK9.
Clinical efficacy and safety in primary hypercholesterolaemia and mixed dyslipidaemia
Summary of the Phase 3 Clinical Trials Program – 75 mg and/or 150 mg every 2 weeks (Q2W) dosing regimen
The efficacy of alirocumab was investigated in ten phase 3 trials (five placebo-controlled and five ezetimibe-controlled studies), involving 5,296 randomised patients with hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, with 3,188 patients randomised to alirocumab. In the phase 3 studies, 31% of patients had type 2 diabetes mellitus, and 64% of patients had a history of coronary heart disease. Three of the ten studies were conducted exclusively in patients with heterozygous familial hypercholesterolaemia (heFH). The majority of patients in the phase 3 program were taking background lipid-modifying therapy consisting of a maximally tolerated dose of statin, with or without other lipid-modifying therapies, and were at high or very high cardiovascular (CV) risk. Two studies were conducted in patients who were not concomitantly treated with a statin, including one study in patients with documented statin intolerance.
Two studies (LONG TERM and HIGH FH ), involving a total of 2,416 patients, were performed with a 150 mg every 2 weeks (Q2W) dose only. Eight studies were performed with a dose of 75 mg Q2W, and criteria-based up-titration to 150 mg Q2W at week 12 in patients who did not achieve their pre-defined target LDL-C based on their level of CV risk at week 8.
The primary efficacy endpoint in all of the phase 3 studies was the mean percent reduction from baseline in LDL-C at week 24 as compared to placebo or ezetimibe. All of the studies met their primary endpoint. In general, administration of alirocumab also resulted in a statistically significant greater percent reduction in total cholesterol (Total-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (Apo B), and lipoprotein (a) [Lp(a)] as compared to placebo/ ezetimibe, whether or not patients were concomitantly being treated with a statin. Alirocumab also reduced triglycerides (TG), and increased high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (Apo A-1) as compared to placebo. For detailed results see Table 2 below. Reduction in LDL-C was seen across age, gender, body mass index (BMI), race, baseline LDL-C levels, patients with heFH and non-heFH, patients with mixed dyslipidaemia, and diabetic patients. Although similar efficacy was observed in patients over 75 years, data are limited in this age group. LDL-C reduction was consistent regardless of concomitantly used statins and doses. A significantly higher proportion of patients achieved an LDL-C of <70 mg/dL (<1.81 mmol/L) in the alirocumab group as compared to placebo or ezetimibe at week 12 and week 24. In studies using the criteria-based up-titration regimen, a majority of patients achieved the pre-defined target LDL-C (based on their level of CV risk) on the 75 mg Q2W dose, and a majority of patients maintained treatment on the 75 mg Q2W dose. The lipid-lowering effect of alirocumab was observed within 15 days after the first dose reaching maximum effect at approximately 4 weeks. With long-term treatment, efficacy was sustained over the duration of the studies (up to 2 years). Following discontinuation of alirocumab, no rebound in LDL-C was observed, and LDL-C levels gradually returned to baseline levels.
In pre-specified analyses before possible up-titration at week 12 in the 8 studies in which patients started with the 75 mg every 2 weeks dosing regimen, mean reductions in LDL-C ranging from 44.5% to 49.2% were achieved. In the 2 studies in which patients were started and maintained on 150 mg every 2 weeks, the achieved mean reduction of LDL-C at week 12 was 62.6%. In analyses of pooled phase 3 studies that allowed up-titration, among the subgroup of patients up-titrated, an increase from 75 mg Q2W to 150 mg Q2W alirocumab at week 12 resulted in an additional 14% mean reduction in LDL-C in patients on a background statin. In patients not on a background statin, up-titration of alirocumab resulted in an additional 3% mean reduction in LDL-C, with the majority of the effect seen in approximately 25% of patients who achieved at least an additional 10% LDL-C lowering after up-titration. Patients up-titrated to 150 mg Q2W had a higher mean baseline LDL-C.
Evaluation of cardiovascular (CV) events
In pre-specified analyses of pooled phase 3 studies, treatment-emergent CV events confirmed by adjudication, consisting of coronary heart disease (CHD) death, myocardial infarction, ischemic stroke, unstable angina requiring hospitalisation, congestive heart failure hospitalisation, and revascularisation, were reported in 110 (3.5%) patients in the alirocumab group and 53 (3.0%) patients in the control group (placebo or active control) with HR=1.08 (95% CI, 0.78 to 1.50). Major adverse cardiovascular events (“MACEplus”, i.e.: CHD death, myocardial infarction, ischemic stroke, and unstable angina requiring hospitalisation) confirmed by adjudication were reported in 52 of 3,182 (1.6%) patients in the alirocumab group and 33 of 1,792 (1.8%) patients in the control group (placebo or active control); HR=0.81 (95% CI, 0.52 to 1.25).
In pre-specified final analyses of the LONG TERM study, treatment-emergent CV events confirmed by adjudication occurred in 72 of 1,550 (4.6%) patients in the alirocumab group and in 40 of 788 (5.1%) patients in the placebo group; MACE-plus confirmed by adjudication were reported in 27 of 1,550 (1.7%) patients in the alirocumab group and 26 of 788 (3.3%) patients in the placebo group. Hazard ratios were calculated post-hoc; for all CV events, HR=0.91 (95% CI, 0.62 to 1.34); for MACE-plus, HR=0.52 (95% CI, 0.31 to 0.90).
All-cause mortality
All-cause mortality in phase 3 studies was 0.6% (20 of 3,182 patients) in the alirocumab group and 0.9% (17 of 1,792 patients) in the control group. The primary cause of death in the majority of these patients was CV events.
Combination therapy with a statin
Placebo-controlled phase 3 studies (on background statin) in patients with primary hypercholesterolaemia or mixed dyslipidaemia
LONG TERM study
This multicenter, double-blind, placebo-controlled, 18-month study included 2,310 patients with primary hypercholesterolaemia at high or very high CV risk and on a maximally tolerated dose of statin, with or without other lipid-modifying therapy. Patients received either alirocumab at a dose of 150 mg Q2W or placebo in addition to their existing lipid-modifying therapy. The LONG TERM study included 17.7% heFH patients, 34.6% with type 2 diabetes mellitus, and 68.6% with a history of coronary heart disease. At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was –61.9% (95% CI: –64.3%, –59.4%; p-value: <0.0001). For detailed results see Table 2. At week 12, 82.1% of patients in the alirocumab group reached an LDL-C <70 mg/dL (<1.81 mmol/L) compared to 7.2% of patients in the placebo group. Difference versus placebo was statistically significant at week 24 for all lipids/lipoproteins.
COMBO I study
A multicenter, double-blind, placebo-controlled, 52 week study included 311 patients categorised as very high CV risk and not at their pre-defined target LDL-C on a maximally tolerated dose of statin, with or without other lipid-modifying therapy. Patients received either 75 mg alirocumab Q2W or placebo in addition to their existing lipid-modifying therapy. Dose up-titration of alirocumab to 150 mg Q2W occurred at week 12 in patients with LDL-C >70 mg/dL (>1.81 mmol/L). At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was –45.9% (95% CI: –52.5%, –39.3%; p-value: <0.0001). For detailed results see Table 4. At week 12 (before up-titration), 76.0% of patients in the alirocumab group reached an LDL-C of <70 mg/dL (< 1.81 mmol/L) as compared to 11.3% in the placebo group. The dose was up-titrated to 150 mg Q2W in 32 (16.8%) patients treated beyond 12 weeks. Among the subgroup of patients up-titrated at week 12, an additional 22.8% mean reduction in LDL-C was achieved at week 24. The difference versus placebo was statistically significant at week 24 for all lipids/ lipoproteins except TG and Apo A-1.
Placebo-controlled phase 3 studies (on background statin) in patients with heterozygous familial hypercholesterolaemia (heFH)
FHI and FHII studies
Two multicenter, placebo-controlled, double-blind 18-month studies included 732 patients with heFH receiving a maximally tolerated dose of statin, with or without other lipid-modifying therapy. Patients received either alirocumab 75 mg Q2W or placebo in addition to their existing lipid-modifying therapy. Dose up-titration of alirocumab to 150 mg Q2W occurred at week 12 in patients with LDL-C
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> 70 mg/dL (>1.81 mmol/L). At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was –55.8% (95% CI: –60.0%, –51.6%; p-value: < 0.0001). For detailed results see Table 2. At week 12 (before up-titration), 50.2% of patients reached an LDL-C of
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< 70 mg/dL (<1.81 mmol/L) as compared to 0.6% in the placebo group. Among the subgroup of patients up-titrated at week 12, an additional 15.7% mean reduction in LDL-C was achieved at week 24. Difference versus placebo was statistically significant at week 24 for all lipids/ lipoproteins.
HIGH FH study
A third multicenter, double-blind, placebo-controlled 18-month study included 106 heFH patients on a maximally tolerated dose of statin, with or without other lipid-modifying therapies, and a baseline LDL-C >160 mg/dL (>4.14 mmol/L). Patients received either alirocumab at a dose of 150 mg Q2W or placebo in addition to their existing lipid-modifying therapy. At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was –39.1% (95% CI: –51.1%, –27.1%; p-value: <0.0001). For detailed results see Table 2. Mean changes for all other lipids/ lipoproteins were similar to the FH I and FH II studies, however statistical significance was not reached for TG, HDL-C and Apo A-1.
Ezetimibe-controlled phase 3 study (on background statin) in patients with primary hypercholesterolaemia or mixed dyslipidaemia
COMBO II study
A multicenter, double-blind, ezetimibe-controlled 2 year study included 707 patients categorised as very high CV risk and not at their pre-defined target LDL-C on a maximally tolerated dose of statin. Patients received either alirocumab 75 mg Q2W or ezetimibe 10 mg once daily in addition to their existing statin therapy. Dose up-titration of alirocumab to 150 mg Q2W occurred at week 12 in patients with LDL-C
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> 70 mg/dL (>1.81 mmol/L). At week 24, the mean treatment difference from ezetimibe in LDL-C percent change from baseline was –29.8% (95% CI: –34.4%, –25.3%; p-value: <0.0001). For detailed results see Table 2. At week 12 (before up-titration), 77.2% of patients reached an LDL-C of
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< 70 mg/dL (<1.81 mmol/L) as compared to 46.2% in the ezetimibe group. Among the subgroup of patients up-titrated at week 12, an additional 10.5% mean reduction in LDL-C was achieved at week 24. Difference versus ezetimibe was statistically significant at week 24 for all lipids/ lipoproteins except for TG, and Apo A-1.
5.2 Pharmacokinetic properties
Absorption
After subcutaneous administration of 50 mg to 300 mg alirocumab, median times to maximum serum concentration (tmax) were 3–7 days. The pharmacokinetics of alirocumab after single subcutaneous administration of 75 mg into the abdomen, upper arm or thigh were similar. The absolute bioavailability of alirocumab after subcutaneous administration was about 85% as determined by population pharmacokinetic analysis. Monthly exposure with 300 mg every 4 weeks treatment was similar to that of 150 mg every 2 weeks. The fluctuations between Cmax and Ctrough were higher for the every 4 weeks dosage regimen. Steady state was reached after 2 to 3 doses with an accumulation ratio up to a maximum of about 2-fold.
Distribution
Following intravenous administration, the volume of distribution was about 0.04 to 0.05 L/kg indicating that alirocumab is distributed primarily in the circulatory system.
Biotransformation
Specific metabolism studies were not conducted, because alirocumab is a protein. Alirocumab is expected to degrade to small peptides and individual amino acids.
Elimination
Two elimination phases were observed for alirocumab. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of alirocumab is largely through a non-saturable proteolytic pathway.
Based on a population pharmacokinetic analysis, the median apparent half-life of alirocumab at steady state was 17 to 20 days in patients receiving alirocumab as monotherapy at subcutaneous doses of either 75 mg Q2W or 150 mg Q2W. When co-administered with a statin, the median apparent half-life of alirocumab was 12 days.
Linearity/non-linearity
A slightly greater than dose proportional increase was observed, with a 2.1– to 2.7-fold increase in total alirocumab concentrations for a 2-fold increase in dose from 75 mg to 150 mg Q2W.
Special populations
Elderly
Based on a population pharmacokinetic analysis, age was associated with a small difference in alirocumab exposure at steady state, with no impact on efficacy or safety.
Gender
Based on a population pharmacokinetic analysis, gender has no impact on alirocumab pharmacokinetics.
Race
Based on a population pharmacokinetic analysis, race had no impact on alirocumab pharmacokinetics. Following single-dose subcutaneous administration of 100 mg to 300 mg alirocumab, there was no meaningful difference in exposure between Japanese and Caucasian healthy subjects.
Body weight
Body weight was identified as one significant covariate in the final population PK model impacting alirocumab pharmacokinetics. Alirocumab exposure (AUC0–14d) at steady state at both the 75 and 150 mg
Q2W dosing regimen was decreased by 29% and 36% in patients weighing more than 100 kg as compared to patients weighing between 50 kg and 100 kg. This did not translate into a clinically meaningful difference in LDL-C lowering.
Hepatic impairment
In a phase 1 study, after administration of a single 75 mg subcutaneous dose, alirocumab pharmacokinetic profiles in subjects with mild and moderate hepatic impairment were similar as compared to subjects with normal hepatic function. No data are available in patients with severe hepatic impairment.
Renal impairment
Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of alirocumab. Population pharmacokinetic analyses showed that alirocumab exposure (AUC0–14d) at steady state at both the 75 and 150 mg Q2W dosing regimen was increased by 22%-35%, and 49%-50% in patients with mild and moderate renal impairment, respectively, compared to patients with normal renal function. The distribution of body weight and age, two covariates impacting alirocumab exposure, were different among renal function categories and most likely explain the observed pharmacokinetic differences. Limited data are available in patients with severe renal impairment; in these patients the exposure to alirocumab was approximately 2-fold higher compared with subjects with normal renal function.
Paediatric population
Limited pharmacokinetic data are available in 18 paediatric patients (8 to 17 years of age) with HoFH. The steady-state mean Ctrough alirocumab concentrations was reached at or before Week 12 in both alirocumab 75 mg Q2W and 150 mg Q2W groups. No studies with alirocumab have been performed in paediatric patients less than 8 years of age (see section 5.1).
Pharmacokinetic/pharmacodynamic relationship(s)
The pharmacodynamic effect of alirocumab in lowering LDL-C is indirect, and mediated through the binding to PCSK9. A concentration-dependent reduction in free PCSK9 and LDL-C is observed until target saturation is achieved. Upon saturation of PCSK9 binding, further increases in alirocumab concentrations do not result in a further LDL-C reduction, however an extended duration of the LDL-C lowering effect is observed.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
Reproductive toxicology studies in rats and monkeys indicated that alirocumab, like other IgG antibodies, crosses the placental barrier.
There were no adverse effects on surrogate markers of fertility (e.g. estrous cyclicity, testicular volume, ejaculate volume, sperm motility, or total sperm count per ejaculate) in monkeys, and no alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in any rat or monkey toxicology study.
There were no adverse effects on foetal growth or development in rats or monkeys. Maternal toxicity was not evident in pregnant monkeys at systemic exposures that were 81 times the human exposure at the 150 mg Q2W dose. However, maternal toxicity was noted in pregnant rats at systemic exposures estimated to be approximately 5.3 times greater than the human exposure at the 150 mg Q2W dose (based on exposure measured in non-pregnant rats during a 5-week toxicology study).
The offspring of monkeys that received high doses of alirocumab weekly throughout pregnancy had a weaker secondary immune response to antigen challenge than did the offspring of control animals. There was no other evidence of alirocumab-related immune dysfunction in the offspring.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Histidine
Sucrose
Polysorbate 20
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
Praluent 75 mg solution for injection in pre-filled pen
3 years.
Praluent 75 mg solution for injection in pre-filled syringe
3 years.
Praluent 150 mg solution for injection in pre-filled pen
2 years.
Praluent 150 mg solution for injection in pre-filled syringe
2 years.
Praluent 300 mg solution for injection in pre-filled pen
2 years.
6.4 Special precautions for storage
Store in a refrigerator (2°C to 8°C). Do not freeze.
Praluent can be stored outside the refrigerator (below 25 °C) protected from light for a single period not exceeding 30 days. After removal from the refrigerator, the medicinal product must be used within 30 days or discarded.
Keep the pen or syringe in the outer carton in order to protect from light.
6.5 Nature and contents of container
1 ml or 2 ml solution in a siliconised Type 1 clear glass syringe, equipped with a stainless steel staked needle, a styrene-butadiene rubber soft needle shield, and an ethylene tetrafluoroethylene -coated bromobutyl rubber plunger stopper.
75 mg solution for injection in pre-filled pen
The syringe components are assembled into a single-use pre-filled pen with a blue cap and a light green activation button.
Pack size:
1, 2 or 6 pre-filled pens.
Or
The syringe components are assembled into a single-use pre-filled pen with a blue cap and without activation button.
Pack size:
1, 2 or 6 pre-filled pens without activation button.
150 mg solution for injection in pre-filled pen
The syringe components are assembled into a single-use pre-filled pen with a blue cap and a dark grey activation button.
Pack size:
1, 2 or 6 pre-filled pens.
Or
The syringe components are assembled into a single-use pre-filled pen with a blue cap and without activation button.
Pack size:
1, 2 or 6 pre-filled pens without activation button.
300 mg solution for injection in pre-filled pen
The syringe components are assembled into a single-use pre-filled pen with a blue cap and without activation button.
Pack size:
1 or 3 pre-filled pens without activation button.
75 mg solution for injection in pre-filled syringe
The syringe is equipped with a light green polypropylene plunger rod.
Pack size:
1, 2 or 6 pre-filled syringes.
150 mg solution for injection in pre-filled syringe
The syringe is equipped with a dark grey polypropylene plunger rod.
Pack size:
1, 2 or 6 pre-filled syringes.
Not all presentations and pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
After use, the pre-filled pen/ pre-filled syringe should be placed into a puncture resistant container. The container should not be recycled.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
sanofi-aventis groupe
54, rue La Boétie
F – 75008 Paris
France
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/15/1031/001
EU/1/15/1031/002
EU/1/15/1031/003
EU/1/15/1031/004
EU/1/15/1031/005
EU/1/15/1031/006
EU/1/15/1031/007
EU/1/15/1031/008
EU/1/15/1031/009
EU/1/15/1031/010
EU/1/15/1031/011
EU/1/15/1031/012
EU/1/15/1031/013
EU/1/15/1031/014
EU/1/15/1031/015
EU/1/15/1031/016
EU/1/15/1031/017
EU/1/15/1031/018
EU/1/15/1031/019
EU/1/15/1031/020
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 23 September 2015
Date of latest renewal: 2 June 2020