Alirocumab

1 INDICATIONS AND USAGE PRALUENT ® is indicated: To reduce the risk of major adverse cardiovascular (CV) events (coronary heart disease death, myocardial infarction, stroke, or unstable angina requiring hospitalization) in adults at increased risk for these events . As an adjunct to diet and exercise to reduce low- density lipoprotein cholesterol (LDL-C) in: adults with hypercholesterolemia. adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). adults with homozygous familial hypercholesterolemia (HoFH). PRALUENT is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor indicated: To reduce the risk of major adverse cardiovascular (CV) events (coronary heart disease death, myocardial infarction, stroke, or unstable angina requiring hospitalization) in adults at increased risk for these events. ( 1 ) As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in : adults with hypercholesterolemia ( 1 ) adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). ( 1 ) adults with homozygous familial hypercholesterolemia (HoFH). ( 1 )

2 DOSAGE AND ADMINISTRATION In adults with hypercholesterolemia, including HeFH ( 2.1 ): The recommended starting dosage of PRALUENT is either 75 mg once every 2 weeks or 300 mg once every 4 weeks administered subcutaneously. For patients receiving PRALUENT 300 mg every 4 weeks, measure LDL-C just prior to the next scheduled dosage, because LDL-C can vary between dosages in some patients. If the LDL-C response is inadequate, the dosage may be adjusted 150 mg subcutaneously every 2 weeks. In adults with HeFH undergoing LDL apheresis or in adults with HoFH ( 2.1 ): The recommended dosage of PRALUENT is 150 mg once every 2 weeks administered subcutaneously. PRALUENT can be administered without regard to the timing of LDL apheresis. In pediatric patients with HeFH ( 2.2 ): The recommended dosage of PRALUENT for patients with a body weight less than 50 kg is 150 mg once every 4 weeks administered subcutaneously. The recommended dosage of PRALUENT for patients with a body weight of 50 kg or more is 300 mg once every 4 weeks administered subcutaneously. If the LDL-C response is inadequate, the dosage may be adjusted for patients with a body weight less than 50 kg to 75 mg subcutaneously once every 2 weeks or for patients with a body weight of 50 kg or more to 150 mg subcutaneously once every 2 weeks. Assess LDL-C when clinically appropriate. The LDL-lowering effect of PRALUENT may be measured as early as 4 weeks after initiation. ( 2.1 ) Administer PRALUENT subcutaneously into areas of the thigh, abdomen, or upper arm that are not tender, bruised, red, or indurated. Rotate injection sites for each administration. ( 2.4 ) To administer the 300 mg dosage, give two 150 mg PRALUENT injections consecutively at two different injection sites. ( 2.4 ) 2.1 Recommended Dosage in Adults Hypercholesterolemia, including HeFH: The recommended starting dosage of PRALUENT is either 75 mg once every 2 weeks or 300 mg once every 4 weeks administered subcutaneously [see Dosage and Administration (2.4) ] . For patients receiving PRALUENT 300 mg every 4 weeks, measure LDL-C just prior to the next scheduled dose, because LDL-C can vary between doses in some patients [see Clinical Studies (14) ] . If the LDL-C response is inadequate, the dosage may be adjusted to 150 mg subcutaneously every 2 weeks. HeFH undergoing LDL apheresis or with HoFH: The recommended dosage of PRALUENT is 150 mg once every 2 weeks administered subcutaneously [see Dosage and Administration (2.4) ] . PRALUENT can be administered without regard to the timing of LDL apheresis. Assess LDL-C when clinically appropriate. The LDL-lowering effect of PRALUENT may be measured as early as 4 weeks after initiation. 2.2 Recommended Dosage in Pediatric Patients Aged 8 years and Older With HeFH The recommended dosage of PRALUENT for patients with a body weight less than 50 kg is 150 mg once every 4 weeks administered subcutaneously [see Dosage and Administration (2.4) ] . If the LDL-C lowering response is inadequate, the dosage may be adjusted to 75 mg subcutaneously once every 2 weeks [see Dosage and Administration (2.4) ] . The recommended dosage of PRALUENT for patients with a body weight of 50 kg or more is 300 mg once every 4 weeks administered subcutaneously [see Dosage and Administration (2.4) ] . If the LDL-C lowering response is inadequate, the dosage may be adjusted to 150 mg subcutaneously once every 2 weeks [see Dosage and Administration (2.4) ] . Assess LDL-C when clinically appropriate. The LDL-lowering effect of PRALUENT may be measured as early as 4 weeks after initiation. 2.3 Missed Doses If a dose is missed: Within 7 days from the missed dose, instruct the patient to administer PRALUENT and resume the patient's original schedule. More than 7 days after the missed dose: For every 2-week dosage, instruct the patient to wait until the next dose on the original schedule. For every 4-week dosage, instruct the patient to administer the dose and start a new schedule based on this date. 2.4 Important Administration Instructions Train patients and/or caregivers on how to prepare and administer PRALUENT, according to the Instructions for Use and instruct them to read and follow the Instructions for Use each time they use PRALUENT. In children aged 12 to 17 years, it is recommended that PRALUENT be given by or under the supervision of an adult. In children aged 8 to 11 years, PRALUENT should be given by a caregiver. Prior to use, allow PRALUENT to warm to room temperature for 30 to 40 minutes if PRALUENT has been refrigerated [see How Supplied/Storage and Handling (16) ]. Visually inspect PRALUENT prior to administration. PRALUENT is a clear, colorless to pale yellow solution. Do not use if the solution is cloudy, discolored, or contains particles. Administer PRALUENT subcutaneously into areas of the thigh, abdomen, or upper arm that are not tender, bruised, red, or indurated. Rotate injection sites for each administration. It may take up to 20 seconds to inject PRALUENT. To administer the 300 mg dose, give two 150 mg PRALUENT injections consecutively at two different injection sites.

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

12.3 Pharmacokinetics Absorption After subcutaneous administration of 75 mg to 300 mg alirocumab, median times to maximum serum concentrations (t max ) 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 pharmacokinetics analysis. A slightly greater than dose proportional increase was observed, with a 2.1-fold to 2.7-fold increase in total alirocumab concentrations for a 2-fold increase in dose from 75 mg every 2 weeks to 150 mg every 2 weeks. Monthly dose normalized exposure with 300 mg every 4 weeks treatment was similar to that of 150 mg every 2 weeks. 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. Elimination Specific metabolism studies were not conducted, because alirocumab is a protein. Alirocumab is expected to degrade to small peptides and individual amino acids. In clinical studies where alirocumab was administered in combination with atorvastatin or rosuvastatin, no relevant changes in statin concentrations were observed in the presence of repeated administration of alirocumab, indicating that cytochrome P450 enzymes (mainly CYP3A4 and CYP2C9) and transporter proteins such as P-gp and OATP were not affected by alirocumab. 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 at subcutaneous doses of 75 mg every 2 weeks or 150 mg every 2 weeks. Specific Populations A population pharmacokinetic analysis was conducted on data from 2799 patients. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence alirocumab pharmacokinetics. Pediatric Patients The pharmacokinetics of alirocumab were evaluated in 140 pediatric patients aged 8 to 17 years with HeFH. Steady-state concentrations were reached at or before week 8 (first PK sampling during repeated dosing) with recommended dosing regimen [see Dosage and Administration (2.2) ] . 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. No data are available in patients with severe renal impairment. Hepatic Impairment Following administration of a single 75 mg SC dose, alirocumab pharmacokinetic profiles in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function. No data are available in patients with severe hepatic impairment. Drug-Drug Interactions The median apparent half-life of alirocumab is reduced to 12 days when administered with a statin; however, this difference is not clinically meaningful.