Alirocumab

6 ADVERSE REACTIONS The following adverse reactions are also discussed in the other sections of the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Common (>5% of patients treated with PRALUENT and more frequently than placebo) adverse reactions in adults with: Primary hypercholesterolemia : injection site reactions, and influenza. ( 6 ) Established CV disease: myalgia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-844-734-6643 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults with Hypercholesterolemia The data in Table 1 are derived from 9 primary hypercholesterolemia placebo-controlled trials that included 2,476 adult patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks, including 2,135 exposed for 6 months and 1,999 exposed for more than 1 year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were female, 90% were White, 4% were Black or African American, 3% were Asian, and 3% other races; 6% identified as Hispanic or Latino ethnicity. Adverse reactions reported in at least 2% of PRALUENT-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1. Table 1: Adverse Reactions Occurring in >2% of PRALUENT-Treated Adult Patients and ≥1% More Frequently Than with Placebo Adverse Reactions Placebo (N=1,276) % PRALUENT 75 mg every 2 weeks and 150 mg every 2 weeks combined (N=2,476) % Injection site reactions Includes erythema/redness, itching, swelling, pain/tenderness 5 7 Influenza 5 6 Diarrhea 4 5 Myalgia 3 4 Muscle spasms 2 3 Contusion 1 2 Adverse reactions led to discontinuation of treatment in 5.3% of patients treated with PRALUENT and 5.1% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with PRALUENT were allergic reactions (0.6% versus 0.2% for PRALUENT and placebo, respectively) and elevated liver enzymes (0.3% versus <0.1%). In an analysis of ezetimibe-controlled trials in which 864 patients were exposed to PRALUENT for a median of 27 weeks and 618 patients were exposed to ezetimibe for a median of 24 weeks, the types and frequencies of common adverse reactions were similar to those listed above. Adverse Reactions in a Cardiovascular Outcomes Trial in Adults In a CV outcomes trial in which 9,451 patients were exposed to PRALUENT for a median of 31 months and 9,443 patients were exposed to placebo for a median of 32 months, common adverse reactions (greater than 5% of patients treated with PRALUENT and occurring more frequently than placebo) included myalgia (6% PRALUENT, 5% placebo). Adverse Reactions in Pediatric Patients with HeFH In a 24-week placebo-controlled clinical trial in which 101 pediatric patients aged 8 to 17 years with HeFH were exposed to PRALUENT and 52 pediatric patients with HeFH were exposed to placebo [see Clinical Studies (14.3) ], the safety profile of PRALUENT observed in this population was consistent with the safety profile observed in adults with HeFH. Other Adverse Reactions Local Injection Site Reactions In a pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every 2 weeks in adults, local injection site reactions including erythema/redness, itching, swelling, and pain/tenderness were reported more frequently in patients treated with PRALUENT (7.2% versus 5.1% for PRALUENT and placebo, respectively). Few patients discontinued treatment because of these reactions (0.2% versus 0.4% for PRALUENT and placebo, respectively), but patients receiving PRALUENT had a greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo. In a 48-week placebo-controlled trial evaluating PRALUENT 300 mg every 4 weeks and 75 mg every 2 weeks in adults, in which all patients received an injection of drug or placebo every 2 weeks, local injection site reactions were reported more frequently in patients treated with PRALUENT 300 mg every 4 weeks as compared to those receiving PRALUENT 75 mg every 2 weeks or placebo (16.6%, 9.6%, and 7.9%, respectively). Three patients (0.7%) treated with PRALUENT 300 mg every 4 weeks discontinued treatment due to local injection site reactions versus no patients (0%) in the other 2 treatment groups. In a CV outcomes trial in adults, local injection site reactions were reported in 3.8% of patients treated with PRALUENT versus 2.1% patients treated with placebo, and led to permanent discontinuation in 26 patients (0.3%) versus 3 patients (<0.1%), respectively. In the trial of pediatric patients with HeFH, local injection site reactions were reported in 5% of patients treated with PRALUENT versus 0% patients treated with placebo; no patients discontinued treatment due to injection site reactions. Hypersensitivity Reactions in Adults Hypersensitivity reactions were reported more frequently in adult patients treated with PRALUENT than in those treated with placebo (8.6% versus 7.8%). The most common hypersensitivity reaction was pruritus (1.1% versus 0.4% for PRALUENT and placebo, respectively). The proportion of patients who discontinued treatment due to allergic reactions was higher among those treated with PRALUENT (0.6% versus 0.2%). Serious allergic reactions, such as hypersensitivity, nummular eczema, and hypersensitivity vasculitis were reported in patients using PRALUENT in controlled clinical trials. Liver Enzyme Abnormalities in Adults In the hypercholesterolemia trials in adults, liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of patients treated with PRALUENT and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with PRALUENT and 1.4% of patients treated with placebo. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of PRALUENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions: Angioedema Influenza-like illness

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from clinical trials and postmarketing reports on PRALUENT use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. In monkeys, suppression of the humoral immune response was observed in infant monkeys when alirocumab was dosed during organogenesis to parturition at dose exposures 13-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. No additional effects on pregnancy or neonatal/infant development were observed at dose exposures up to 81-fold the maximum recommended human dose of 150 mg every two weeks. Measurable alirocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that alirocumab, like other IgG antibodies, crosses the placental barrier. Monoclonal antibodies are transported across the placenta in increasing amounts especially near term; therefore, alirocumab has the potential to be transmitted from the mother to the developing fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. There is a pregnancy safety study for PRALUENT. If PRALUENT is administered during pregnancy, healthcare providers should report PRALUENT exposure by contacting Regeneron at 1-844-734-6643. Data Animal data In Sprague Dawley rats, no effects on embryo-fetal development were observed when alirocumab was dosed at up to 75 mg/kg/dose by the subcutaneous route on gestation days 6 and 12 at exposures 12-fold the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. In cynomolgus monkeys, suppression of the humoral immune response to keyhole limpet hemocyanin (KLH) antigen was observed in infant monkeys at 4 to 6 months of age when alirocumab was dosed during organogenesis to parturition at 15 mg/kg/week and 75 mg/kg/week by the subcutaneous route, corresponding to 13-fold and 81-fold the human exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. The lowest dose tested in the monkey resulted in humoral immune suppression; therefore, it is unknown if this effect would be observed at clinical exposure. No study designed to challenge the immune system of infant monkeys was conducted. No additional embryo-fetal, prenatal or postnatal effects were observed in infant monkeys, and no maternal effects were observed, when alirocumab was dosed at up to 75 mg/kg/week by the subcutaneous route, corresponding to maternal exposure of 81-fold the exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. 8.2 Lactation Risk Summary There is no information regarding the presence of alirocumab in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRALUENT and any potential adverse effects on the breastfed infant from PRALUENT or from the underlying maternal condition. Human IgG is present in human milk, but published data suggest that breast milk IgG antibodies do not enter the neonatal and infant circulation in substantial amounts. 8.4 Pediatric Use The safety and effectiveness of PRALUENT as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HeFH have been established in pediatric patients aged 8 years and older. Use of PRALUENT for this indication is based on data from a 24-week, randomized, placebo-controlled, double-blind trial in pediatric patients with HeFH. In the trial, 101 patients received PRALUENT and 52 patients received placebo; 26 patients (17%) were 8 to 9 years of age. This indication is supported by evidence from controlled trials in adults [see Adverse Reactions (6.1) and Clinical Studies (14.3) ]. The safety and effectiveness of PRALUENT have not been established in pediatric patients with HeFH who are younger than 8 years of age or in pediatric patients with other types of hypercholesterolemia. 8.5 Geriatric Use In controlled trials, 3663 patients treated with PRALUENT were ≥65 years of age and 734 patients treated with PRALUENT were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dose adjustment is needed for patients with mild or moderately impaired renal function. No data are available in patients with severe renal impairment [see Clinical Pharmacology (12.3) ] . 8.7 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 Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Available data from clinical trials and postmarketing reports on PRALUENT use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. In monkeys, suppression of the humoral immune response was observed in infant monkeys when alirocumab was dosed during organogenesis to parturition at dose exposures 13-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. No additional effects on pregnancy or neonatal/infant development were observed at dose exposures up to 81-fold the maximum recommended human dose of 150 mg every two weeks. Measurable alirocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that alirocumab, like other IgG antibodies, crosses the placental barrier. Monoclonal antibodies are transported across the placenta in increasing amounts especially near term; therefore, alirocumab has the potential to be transmitted from the mother to the developing fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. There is a pregnancy safety study for PRALUENT. If PRALUENT is administered during pregnancy, healthcare providers should report PRALUENT exposure by contacting Regeneron at 1-844-734-6643. Data Animal data In Sprague Dawley rats, no effects on embryo-fetal development were observed when alirocumab was dosed at up to 75 mg/kg/dose by the subcutaneous route on gestation days 6 and 12 at exposures 12-fold the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. In cynomolgus monkeys, suppression of the humoral immune response to keyhole limpet hemocyanin (KLH) antigen was observed in infant monkeys at 4 to 6 months of age when alirocumab was dosed during organogenesis to parturition at 15 mg/kg/week and 75 mg/kg/week by the subcutaneous route, corresponding to 13-fold and 81-fold the human exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. The lowest dose tested in the monkey resulted in humoral immune suppression; therefore, it is unknown if this effect would be observed at clinical exposure. No study designed to challenge the immune system of infant monkeys was conducted. No additional embryo-fetal, prenatal or postnatal effects were observed in infant monkeys, and no maternal effects were observed, when alirocumab was dosed at up to 75 mg/kg/week by the subcutaneous route, corresponding to maternal exposure of 81-fold the exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC.