MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Alirocumab is human monoclonal antibody that binds to proprotein convertase subtilisin kexin type (PCSK9). PCSK9 binds to the low-density lipoprotein (LDL) receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.

ADVERSE REACTIONS SECTION.

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)] 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 hyperlipidemia: nasopharyngitis, injection site reactions, and influenza. (6) Established cardiovascular disease: non-cardiac chest pain, nasopharyngitis, and 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data in Table are derived from primary hyperlipidemia placebo-controlled trials that included 2476 patients treated with PRALUENT 75 mg and/or 150 mg every weeks, including 2135 exposed for months and 1999 exposed for more than year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were women, 90% were White, 4% were Black or African American, and 3% were Asian.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 Patients and More Frequently Than with PlaceboAdverse ReactionsPlacebo (N=1276)%PRALUENT75 mg every weeks and 150 mg every weeks combined (N=2476)%Nasopharyngitis11.111.3Injection site reactionsIncludes erythema/redness, itching, swelling, pain/tenderness 5.17.2Influenza4.65.7Urinary tract infection4.64.8Diarrhea4.44.7Bronchitis3.84.3Myalgia3.44.2Muscle spasms2.43.1Sinusitis2.73.0Cough2.32.5Contusion1.32.1Musculoskeletal pain1.62.1Adverse 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 median of 27 weeks and 618 patients were exposed to ezetimibe for median of 24 weeks, the types and frequencies of common adverse reactions were similar to those listed above.In cardiovascular outcomes trial in which 9451 patients were exposed to PRALUENT for median of 31 months and 9443 patients were exposed to placebo for median of 32 months, common adverse reactions (greater than 5% of patients treated with PRALUENT and occurring more frequently than placebo) included non-cardiac chest pain (7.0% PRALUENT, 6.8% placebo), nasopharyngitis (6.0% PRALUENT, 5.6% placebo), and myalgia (5.6% PRALUENT, 5.3% placebo).In the HoFH placebo-controlled trial in which 45 patients were exposed to PRALUENT for median of 12 weeks and 24 patients were exposed to placebo for median of 12 weeks, no additional adverse reactions were identified.. Local Injection Site ReactionsIn pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every weeks, 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 greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo.In 48-week placebo-controlled trial evaluating PRALUENT 300 mg every weeks and 75 mg every weeks, in which all patients received an injection of drug or placebo every weeks, local injection site reactions were reported more frequently in patients treated with PRALUENT 300 mg every weeks as compared to those receiving PRALUENT 75 mg every weeks or placebo (16.6%, 9.6%, and 7.9%, respectively). Three patients (0.7%) treated with PRALUENT 300 mg every weeks discontinued treatment due to local injection site reactions versus no patients (0%) in the other treatment groups.In cardiovascular outcomes trial, 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 patients (<0.1%), respectively.. Hypersensitivity ReactionsHypersensitivity reactions were reported more frequently in 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 AbnormalitiesIn the primary hyperlipidemia trials, 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 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 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity with PRALUENT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PRALUENT in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In cardiovascular outcomes trial, 5.5% (504/9091) of patients treated with PRALUENT 75 mg and/or 150 mg every weeks had anti-drug antibodies (ADA) detected after initiating treatment compared with 1.6% (149/9097) of patients treated with placebo. Persistent ADA responses, defined as at least consecutive post-baseline samples with positive ADA separated by at least 16-week period, were observed in 0.7% of patients treated with PRALUENT and 0.4% of patients treated with placebo. Neutralizing antibody (NAb) responses were observed in 0.5% of patients treated with PRALUENT and in <0.1% of patients treated with placebo. Efficacy based on reductions in LDL-C was mostly similar in patients with or without ADA. However, some patients treated with PRALUENT with persistent or neutralizing antibodies experienced attenuation in LDL-C efficacy.A higher incidence of injection site reactions were observed in patients with treatment-emergent ADA compared to patients who were ADA negative (7.5% vs 3.6%). In pool of ten placebo-controlled and active-controlled trials of patients treated with PRALUENT 75 mg and/or 150 mg every weeks as well as in separate clinical study of patients treated with PRALUENT 75 mg every weeks or 300 mg every weeks (including some patients with dose adjustment to 150 mg every weeks), the incidence of detecting ADA and NAb was similar to the results from the trial described above.The long-term consequences of continuing PRALUENT treatment in the presence of ADA are unknown.. 6.3 Postmarketing Experience. The following adverse reactions have been reported during post-approval use of PRALUENT. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactions: AngioedemaInfluenza-like illness. Hypersensitivity reactions: Angioedema. Influenza-like illness.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. During 13-week toxicology study of 75 mg/kg once weekly alirocumab in combination with 40 mg/kg once daily atorvastatin in adult monkeys, there were no effects of PRALUENT on the humoral immune response to keyhole limpet hemocyanin (KLH) after one to two months at exposures 100-fold greater than the exposure at the maximum recommended human dose of 150 mg every two weeks, based on AUC.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with alirocumab. The mutagenic potential of alirocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.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 6-month chronic toxicology study in sexually-mature monkeys subcutaneously administered at 5, 15, and 75 mg/kg/week at systemic exposures up to 103-fold the 150 mg every two weeks subcutaneous clinical dose based on serum AUC. In addition, there were no adverse alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in rat or monkey toxicology studies at systemic exposures up to 11-fold and 103-fold respectively, in the 6-month studies, compared to clinical systemic exposure following 150 mg every two weeks dose, based on serum AUC.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Alirocumab is human monoclonal antibody that binds to proprotein convertase subtilisin kexin type (PCSK9). PCSK9 binds to the low-density lipoprotein (LDL) receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.. 12.2 Pharmacodynamics. Alirocumab reduced free PCSK9 in concentration-dependent manner. Following single subcutaneous administration of alirocumab 75 or 150 mg, maximal suppression of free PCSK9 occurred within to hours. Free PCSK9 concentrations returned to baseline when alirocumab concentrations decreased below the limit of quantitation.. 12.3 Pharmacokinetics. AbsorptionAfter subcutaneous administration of 75 mg to 300 mg alirocumab, median times to maximum serum concentrations (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 pharmacokinetics analysis. slightly greater than dose proportional increase was observed, with 2.1-fold to 2.7-fold increase in total alirocumab concentrations for 2-fold increase in dose from 75 mg every weeks to 150 mg every weeks. Monthly dose normalized exposure with 300 mg every weeks treatment was similar to that of 150 mg every weeks. Steady state was reached after to doses with an accumulation ratio up to maximum of about 2-fold.. DistributionFollowing 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.. EliminationSpecific metabolism studies were not conducted, because alirocumab is 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 non-saturable proteolytic pathway.Based on 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 weeks or 150 mg every weeks.. Specific PopulationsA 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.. Renal ImpairmentSince 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 ImpairmentFollowing administration of 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 InteractionsThe median apparent half-life of alirocumab is reduced to 12 days when administered with statin; however, this difference is not clinically meaningful.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Adult Patients with Established Cardiovascular DiseaseStudy (ODYSSEY OUTCOMES, NTC01663402) was multicenter, double-blind, placebo-controlled trial in 18,924 adult patients (9462 PRALUENT; 9462 placebo) followed for up to years. Patients had an acute coronary syndrome (ACS) event to 52 weeks prior to randomization and were treated with lipid-modifying therapy (LMT) regimen that was statin-intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) or at maximally tolerated dose of statin, with or without other LMT. Patients were randomized to receive either PRALUENT 75 mg or placebo once every two weeks.At month 2, if additional LDL-C lowering was required based on pre-specified LDL-C criteria (LDL-C >=50 mg/dL), PRALUENT was adjusted to 150 mg every weeks. For patients who had their dose adjusted to 150 mg every weeks and who had two consecutive LDL-C values below 25 mg/dL, down-titration from 150 mg every weeks to 75 mg every weeks was performed. Patients on 75 mg every weeks who had two consecutive LDL-C values below 15 mg/dL were switched to placebo in blinded fashion. Approximately 2615 (27.7%) of 9451 patients treated with PRALUENT required dose adjustment to 150 mg every weeks. Of these 2615 patients, 805 (30.8%) were down-titrated to 75 mg every weeks. Overall, 730 (7.7%) of 9451 patients switched to placebo.A total of 99.5% of patients were followed for survival until the end of the trial. The median follow-up duration was 33 months.The mean age at baseline was 59 years (range 39-92), with 25% women, and 27% at least 65 years old. The trial population was 79% White, 3% Black, and 13% Asian; 17% identified as Hispanic/Latino ethnicity. The index ACS event was myocardial infarction in 83% of patients and unstable angina in 17% of patients. Prior to the index ACS event, 19% had prior myocardial infarction and 23% had coronary revascularization procedures (CABG/PCI). Selected additional baseline risk factors included hypertension (65%), diabetes mellitus (25%), New York Association class or II congestive heart failure (15%), and eGFR <60 mL/min/1.73 m2 (13%). Most patients (89%) were receiving statin-intensive therapy with or without other LMT at randomization. The mean LDL-C value at baseline was 92.4 mg/dL.PRALUENT significantly reduced the risk for the primary composite endpoint (time to first occurrence of coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization: p=0.0003). The results are presented in Table 2.Table 2: Cardiovascular Outcomes in Patients with Established Cardiovascular DiseaseEndpointPRALUENTN=9462PlaceboN=9462Hazard Ratio(95% CI)Cox-proportional hazards model with treatment as factor and stratified by geographic region (%)Incidence Rate per 100 Patient Years(95% CI)n (%)Incidence Rate per 100 Patient Years(95% CI)Primary composite endpointPrimary composite endpoint defined as: time to first occurrence of coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization 903(9.5%)3.5(3.3 to 3.8)1052(11.1%)4.2(3.9 to 4.4)0.85(0.78, 0.93)Components of the Primary Composite EndpointFirst occurrence of specified event at any time; patients may have experienced more than one adjudicated event CHD death205(2.2%)0.8(0.7 to 0.9)222(2.3%)0.8(0.7 to 0.9)0.92(0.76, 1.11)Non-fatal MIStatistical testing performed outside hierarchy; therefore not considered statistically significant 626(6.6%)2.4(2.2 to 2.6)722(7.6%)2.8(2.6 to 3.0)0.86(0.77, 0.96)Fatal or non-fatal ischemic stroke 111(1.2%)0.4(0.3 to 0.5)152(1.6%)0.6(0.5 to 0.7)0.73(0.57, 0.93)Unstable angina requiring hospitalization 37(0.4%)0.1(0.1 to 0.2)60(0.6%)0.2(0.2 to 0.3)0.61(0.41, 0.92)Mortality Endpoint (not statistically significant per pre-specified method to control for type error)All-cause mortality334(3.5%)1.2(1.1 to 1.4)392(4.1%)1.5(1.3 to 1.6)0.85(0.73, 0.98)The Kaplan-Meier estimates of the cumulative incidence of the primary endpoint over time is presented in Figure 1.Figure 1: Primary Composite Endpoint Cumulative Incidence over Years in ODYSSEY OUTCOMES. Figure 1. Primary HyperlipidemiaStudy (ODYSSEY LONG TERM, NCT01507831) was multicenter, double-blind, placebo-controlled trial that randomly assigned 1553 patients to PRALUENT 150 mg every weeks and 788 patients to placebo. All patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction. The mean age was 61 years (range 18-89), 38% were women, 93% were White, 3% were Black, and 5% were Hispanic/Latino. The average LDL-C at baseline was 122 mg/dL.The proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 8% among those treated with PRALUENT and 8% among those treated with placebo.At week 24, the treatment difference between PRALUENT and placebo in mean LDL-C percent change was -58% (95% CI: -61%, -56%; p-value: 0.0001).For additional results see Table and Figure 2.Table 3: Mean Percent Change from Baseline and DifferenceDifference is PRALUENT minus Placebo from Placebo in Lipid Parameters at Week 24 in ODYSSEY LONG TERMA pattern-mixture model approach was used with multiple imputation of missing post-treatment values based on patients own baseline value and multiple imputation of missing on-treatment values based on model including available on-treatment values Treatment GroupLDL-CTotal-CNon-HDL-CApo BWeek 24 (Mean Percent Change from Baseline)Placebo (n=788)1011PRALUENT 150 mg (n=1553)-58-36-49-50Difference from placebo (LS Mean)(95% CI)-58(-61, -56)-36(-37, -34)-50(-52, -47)-51(-53, -48)a The means were estimated based on all randomized patients, with multiple imputation of missing data taking into account treatment adherenceb Number of patients with observed dataFigure 2: Mean Percent Change from Baseline in LDL-C Over 52 Weeks in Patients on Maximally Tolerated Statin Treated with PRALUENT 150 mg Every Weeks and Placebo Every Weeks (ODYSSEY LONG TERM)a Study (ODYSSEY COMBO I, NCT01644175) was multicenter, double-blind, placebo-controlled trial that randomly assigned 209 patients to PRALUENT and 107 patients to placebo. Patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction.The mean age was 63 years (range 39-87), 34% were women, 82% were White, 16% were Black, and 11% were Hispanic/Latino. Mean baseline LDL-C was 102 mg/dL.The proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 11% among those treated with PRALUENT and 12% among those treated with placebo.At week 12, the mean percent change from baseline in LDL-C was -45% with PRALUENT compared to 1% with placebo, and the treatment difference between PRALUENT 75 mg every weeks and placebo in mean LDL-C percent change was -46% (95% CI: -53%, -39%).At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg every weeks for the remainder of the trial. The dose was up-titrated to 150 mg every weeks in 32 (17%) of 191 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean percent change from baseline in LDL-C was -44% with PRALUENT and -2% with placebo, and the treatment difference between PRALUENT and placebo in mean LDL-C percent change was -43% (95% CI: -50%, -35%; p-value: 0.0001).Studies (ODYSSEY FH I, NCT01623115) and (ODYSSEY FH II, NCT01709500) were multicenter, double-blind, placebo-controlled trials that, combined, randomly assigned 490 patients to PRALUENT and 245 patients to placebo. The trials were similar with regard to both design and eligibility criteria. All patients had HeFH, were taking maximally tolerated dose of statin with or without other lipid-modifying therapy, and required additional LDL-C reduction. The diagnosis of HeFH was made either by genotyping or clinical criteria (definite FH using either the Simon Broome or WHO/Dutch Lipid Network criteria). The mean age was 52 years (range 20-87), 45% were women, 94% were White, 1% were Black, and 3% were Hispanic/Latino. The average LDL-C at baseline was 141 mg/dL.Considering both trials together, the proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 6% among those treated with PRALUENT and 4% among those treated with placebo.At week 12, the treatment difference between PRALUENT 75 mg every weeks and placebo in mean LDL-C percent change was -48% (95% CI: -52%, -44%).At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg every weeks for the remainder of the trials. The dose was up-titrated to 150 mg every weeks in 196 (42%) of 469 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean treatment difference between PRALUENT and placebo in mean LDL-C percent change from baseline was -54% (95% CI: -59%, -50%; p-value: 0.0001). The LDL-C-lowering effect was sustained to week 52.For additional results see Table and Figure 3.Table 4: Mean Percent Change from Baseline and DifferenceDifference is PRALUENT minus Placebo from Placebo in Lipid Parameters at Week 12 and Week 24 in Patients with HeFH (ODYSSEY FH and FH II Pooled)A pattern-mixture model approach was used with multiple imputation of missing post-treatment values based on patients own baseline value and multiple imputation of missing on-treatment values based on model including available on-treatment values Treatment GroupLDL-CTotal-CNon-HDL-CApo BWeek 12 (Mean Percent Change from Baseline)Placebo (n=245)5452PRALUENT 75 mg (n=490)-43-27-38-34Difference from placebo (LS Mean)(95% CI)-48(-52, -44)-31(-34, -28)-42(-46, -39)-36(-39, -33)Week 24 (Mean Percent Change from Baseline)Placebo (n=245)7572PRALUENT 75 mg/150 mgDose was up-titrated to 150 mg every weeks in 196 (42%) patients treated for at least 12 weeks (n=490)-47-30-42-40Difference from placebo (LS Mean)(95% CI)-54(-59, -50)-36(-39, -33)-49(-53, -45)-42(-45, -39)a The means were estimated based on all randomized patients, with multiple imputation of missing data taking into account treatment adherenceb Number of patients with observed dataFigure 3: Mean Percent Change from Baseline in LDL-C Over 52 Weeks in Patients with HeFH on Maximally Tolerated Statin Treated with PRALUENT 75/150 mg Every Weeks and Placebo every weeks (ODYSSEY FH and FH II Pooled)a Study (ODYSSEY HIGH FH, NCT01617655) was multicenter, double-blind, placebo-controlled trial that randomly assigned 72 patients to PRALUENT 150 mg every weeks and 35 patients to placebo. Patients had HeFH with baseline LDL-C >=160 mg/dL while taking maximally tolerated dose of statin with or without other lipid-modifying therapy. The mean age was 51 years (range 18-80), 47% were women, 88% were White, 2% were Black, and 6% were Hispanic/Latino. The average LDL-C at baseline was 198 mg/dL.The proportion of patients who discontinued study drug prior to the 24-week primary endpoint was 10% among those treated with PRALUENT and 0% among those treated with placebo.At week 24, the mean percent change from baseline in LDL-C was -43% with PRALUENT and -7% with placebo, and the treatment difference between PRALUENT and placebo in mean LDL-C percent change was -36% (95% CI: -49%, -24%; p-value: <0.0001).Study (ODYSSEY CHOICE I, NCT01926782) was multicenter, double-blind, placebo-controlled trial that randomly assigned 458 patients with primary hyperlipidemia to PRALUENT 300 mg every weeks, 115 patients to PRALUENT 75 mg every weeks, and 230 patients to placebo. Patients were stratified based on whether or not they were treated concomitantly with statin.The mean age was 61 years (range 21-88), 42% were women, 87% were White, 11% were Black, and 3% were Hispanic/Latino.The proportion of patients who discontinued study drug prior to the 24-week primary endpoint was 12% among those treated with PRALUENT 300 mg every weeks, 14% among those treated with PRALUENT 75 mg every weeks, and 15% among those treated with placebo.In the cohort of patients on background statin, the mean LDL-C at baseline was 113 mg/dL. At week 12, the treatment difference between PRALUENT 300 mg every weeks and placebo in mean percent change in LDL-C from baseline was -54% (97.5% CI: -61%, -48%), and the treatment difference between PRALUENT 75 mg every weeks and placebo in mean percent change in LDL-C was -44% (97.5% CI: -53%, -35%) (Figure 4).Figure 4: Mean Percent Change from Baseline in LDL-C up to Week 12 in Patients on Concomitant Statin Treated with PRALUENT 75 mg Every Weeks, PRALUENT 300 mg Every Weeks or PlaceboThe means were estimated based on all randomized patients, with multiple imputation of missing data taking into account treatment adherenceAt week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was adjusted to 150 mg every weeks for the remainder of the trial. The dose was adjusted to 150 mg every weeks in approximately 20% of patients treated with PRALUENT 75 mg every weeks or 300 mg every weeks for at least 12 weeks.At week 24, the treatment difference between initial assignment to PRALUENT 300 mg every weeks and placebo in mean percent change in LDL-C from baseline was -56% (97.5% CI: -62%, -49%; p-value: <0.0001), and the treatment difference between initial assignment to PRALUENT 75 mg every weeks and placebo in mean percent change in LDL-C from baseline was -48% (97.5% CI: -57%, -39%).In the cohort of patients not treated with concomitant statin, the mean LDL-C at baseline was 142 mg/dL. The treatment difference between PRALUENT and placebo were similar to the cohort of patients treated with concomitant statin.Study (ODYSSEY ESCAPE, NCT02326220) was multicenter, double-blind, placebo-controlled trial that randomly assigned patients with HeFH who were undergoing LDL apheresis to PRALUENT 150 mg every weeks (N=41) or placebo (N=21). Patients were treated in combination with their usual LDL apheresis schedule for weeks. The mean age was 59 years (range 27-79), 42% were women, 97% were White, 3% were Black, and 0% were Hispanic/Latino. The mean LDL-C at baseline, measured before the apheresis procedure, was 181 mg/dL. The proportion of patients who discontinued study drug prior to the 6-week endpoint was 2% among those treated with PRALUENT 150 mg every weeks and 5% among those treated with placebo. At week 6, the mean percent change from baseline in pre-apheresis LDL-C was -53% in patients in the PRALUENT group compared to 1% in patients who received placebo.Study (ODYSSEY COMBO II, NCT01644188) was multicenter, double-blind, ezetimibe-controlled trial that randomly assigned 479 patients to PRALUENT 75 mg every weeks/150 mg every weeks and 241 patients to ezetimibe 10 mg/day. Patients were taking maximally tolerated dose of statin and required additional LDL-C reduction.The mean age was 62 years (range 29-88), 26% were women, 85% were White, 4% were Black, and 3% were Hispanic/Latino. Mean baseline LDL-C was 107 mg/dL.The proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 9% among those treated with PRALUENT and 10% among those treated with ezetimibe.At week 12, the mean percent change from baseline in LDL-C was -50% with PRALUENT compared to -22% with ezetimibe, and the treatment difference between PRALUENT and ezetimibe in mean LDL-C percent change was -28% (95% CI: -32%, -23%).At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg every weeks for the remainder of the trial. The dose was up-titrated to 150 mg every weeks in 82 (18%) of 446 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean percent change from baseline in LDL-C was -48% with PRALUENT and -20% with ezetimibe, and the treatment difference between PRALUENT and ezetimibe in mean LDL-C percent change was -28% (95% CI: -33%, -23%; p-value: <0.0001).Study 10 (ODYSSEY MONO, NCT01644474) was multicenter, double-blind, ezetimibe-controlled trial in patients with moderate CV risk, not taking statins or other lipid-modifying therapies, and baseline LDL-C between 100 mg/dL to 190 mg/dL that randomly assigned 52 patients to PRALUENT 75 mg every weeks and 51 patients to ezetimibe 10 mg/day.The mean age was 60 years (range 45-72), 47% were women, 90% were White and 10% were Black. Mean baseline LDL-C was 140 mg/dL.The proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 15% among those treated with PRALUENT and 14% among those treated with ezetimibe.At week 12, the mean percent change from baseline in LDL-C was -48% with PRALUENT compared to -19% with ezetimibe, and the treatment difference between PRALUENT 75 mg every weeks and ezetimibe in mean LDL-C percent change was -29% (95% CI: -37%, -22%). At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg every weeks for the remainder of the trial. The dose was up-titrated to 150 mg every weeks in 14 (30%) of 46 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean percent change from baseline in LDL-C was -45% with PRALUENT and -14% with ezetimibe, and the treatment difference between PRALUENT and ezetimibe in mean LDL-C percent change was -31% (95% CI: -40%, -22%; p-value: <0.0001).. Figure 2. Figure 3. Figure 4. HoFHStudy 11 (ODYSSEY HoFH, NCT03156621) was multicenter, double-blind, placebo-controlled trial that randomly assigned 45 adult patients to PRALUENT 150 mg every weeks and 24 adult patients to placebo. Patients were taking maximally tolerated doses of statins with or without other lipid-lowering therapy and required additional LDL-C reduction.Randomization was stratified by LDL apheresis treatment status. The diagnosis of HoFH was made by either clinical diagnosis, which included history of an untreated total cholesterol concentration >500 mg/dL together with either xanthoma before 10 years of age or with history of total cholesterol >250 mg in both parents, or by genetic testing. The mean age was 43 years (range 19-81), 51% were women, 78% were White, 3% were Black, 17% were Asian, and 3% were identified as Hispanic/Latino ethnicity. Mean baseline LDL-C was 283 mg/dL with 97% on statins, 72% on ezetimibe, and 14% on lomitapide. No patient discontinued from the study prior to the 12-week primary endpoint.At week 12, the treatment difference between PRALUENT and placebo in mean LDL-C percent change from baseline was -36% (95% CI: -51% to -20%; <0.0001) (see Figure 5). For the effect of PRALUENT on lipid parameters as compared to placebo, see Table 5.Patients with two LDL-receptor negative alleles (little to no residual function) had minimal to absent response to PRALUENT.Figure 5: LS Mean Percent Change from Baseline in LDL-C Over 12 Weeks in Patients with HoFH (ODYSSEY HoFH)Table 5: Effect of PRALUENT on Lipid Parameters in Patients with HoFH (LS Mean Percent Change from Baseline to Week 12 in ODYSSEY HoFH)Treatment GroupLDL-CApo BNon-HDL-CTotal CholesterolPlacebo (n=24)9787PRALUENT 150 mg every weeks (n=45)-27-23-25-20Difference from placebo (LS Mean) (95% CI)-36(-51, -20)-30(-42, -17)-33(-48, -18)-27(-39, -14). Figure 5.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data in Table are derived from primary hyperlipidemia placebo-controlled trials that included 2476 patients treated with PRALUENT 75 mg and/or 150 mg every weeks, including 2135 exposed for months and 1999 exposed for more than year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were women, 90% were White, 4% were Black or African American, and 3% were Asian.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 Patients and More Frequently Than with PlaceboAdverse ReactionsPlacebo (N=1276)%PRALUENT75 mg every weeks and 150 mg every weeks combined (N=2476)%Nasopharyngitis11.111.3Injection site reactionsIncludes erythema/redness, itching, swelling, pain/tenderness 5.17.2Influenza4.65.7Urinary tract infection4.64.8Diarrhea4.44.7Bronchitis3.84.3Myalgia3.44.2Muscle spasms2.43.1Sinusitis2.73.0Cough2.32.5Contusion1.32.1Musculoskeletal pain1.62.1Adverse 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 median of 27 weeks and 618 patients were exposed to ezetimibe for median of 24 weeks, the types and frequencies of common adverse reactions were similar to those listed above.In cardiovascular outcomes trial in which 9451 patients were exposed to PRALUENT for median of 31 months and 9443 patients were exposed to placebo for median of 32 months, common adverse reactions (greater than 5% of patients treated with PRALUENT and occurring more frequently than placebo) included non-cardiac chest pain (7.0% PRALUENT, 6.8% placebo), nasopharyngitis (6.0% PRALUENT, 5.6% placebo), and myalgia (5.6% PRALUENT, 5.3% placebo).In the HoFH placebo-controlled trial in which 45 patients were exposed to PRALUENT for median of 12 weeks and 24 patients were exposed to placebo for median of 12 weeks, no additional adverse reactions were identified.. Local Injection Site ReactionsIn pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every weeks, 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 greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo.In 48-week placebo-controlled trial evaluating PRALUENT 300 mg every weeks and 75 mg every weeks, in which all patients received an injection of drug or placebo every weeks, local injection site reactions were reported more frequently in patients treated with PRALUENT 300 mg every weeks as compared to those receiving PRALUENT 75 mg every weeks or placebo (16.6%, 9.6%, and 7.9%, respectively). Three patients (0.7%) treated with PRALUENT 300 mg every weeks discontinued treatment due to local injection site reactions versus no patients (0%) in the other treatment groups.In cardiovascular outcomes trial, 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 patients (<0.1%), respectively.. Hypersensitivity ReactionsHypersensitivity reactions were reported more frequently in 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 AbnormalitiesIn the primary hyperlipidemia trials, 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 times the upper limit of normal occurred in 1.7% of patients treated with PRALUENT and 1.4% of patients treated with placebo.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. PRALUENT is contraindicated in patients with history of serious hypersensitivity reaction to alirocumab or any of the excipients in PRALUENT. Hypersensitivity vasculitis, angioedema, and hypersensitivity reactions requiring hospitalization have occurred [see Warnings and Precautions (5.1)]. History of serious hypersensitivity reaction to alirocumab or any of the excipients in PRALUENT. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Alirocumab is human monoclonal antibody (IgG1 isotype) that targets proprotein convertase subtilisin kexin type (PCSK9). Alirocumab is PCSK9 inhibitor produced by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture. Alirocumab consists of two disulfide-linked human heavy chains, each covalently linked through disulfide bond to human kappa light chain. single N-linked glycosylation site is located in each heavy chain within the CH2 domain of the Fc constant region of the molecule. The variable domains of the heavy and light chains combine to form the PCSK9 binding site within the antibody. Alirocumab has an approximate molecular weight of 146 kDa.PRALUENT is sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous use. PRALUENT 75 mg/mL or 150 mg/mL solution for subcutaneous injection in single-dose pre-filled pen is supplied in siliconized mL Type-1 clear glass syringe.Each 75 mg/mL pre-filled pen contains 75 mg alirocumab, histidine (8 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.Each 150 mg/mL pre-filled pen contains 150 mg alirocumab, histidine (6 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. In adults with established cardiovascular disease or with primary hyperlipidemia, including HeFH (2.1):The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously.For patients receiving PRALUENT 300 mg every weeks, measure LDL-C just prior to the next scheduled dose, because LDL-C can vary between doses in some patients.If the LDL-C response is inadequate, the dosage may be adjusted 150 mg subcutaneously every weeks. In adults with HeFH undergoing LDL apheresis or in adults with HoFH (2.1):The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously.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 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. (2.3)To administer the 300 mg dose, give two 150 mg PRALUENT injections consecutively at two different injection sites. (2.3). In adults with established cardiovascular disease or with primary hyperlipidemia, including HeFH (2.1):The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously.For patients receiving PRALUENT 300 mg every weeks, measure LDL-C just prior to the next scheduled dose, because LDL-C can vary between doses in some patients.If the LDL-C response is inadequate, the dosage may be adjusted 150 mg subcutaneously every weeks. The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously.. For patients receiving PRALUENT 300 mg every weeks, measure LDL-C just prior to the next scheduled dose, because LDL-C can vary between doses in some patients.. If the LDL-C response is inadequate, the dosage may be adjusted 150 mg subcutaneously every weeks.. In adults with HeFH undergoing LDL apheresis or in adults with HoFH (2.1):The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously.PRALUENT can be administered without regard to the timing of LDL apheresis. The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously.. 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 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. (2.3). To administer the 300 mg dose, give two 150 mg PRALUENT injections consecutively at two different injection sites. (2.3). 2.1 Recommended Dosage. In adults with established cardiovascular disease or with primary hyperlipidemia, including HeFH:The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].For patients receiving PRALUENT 300 mg every 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 150 mg subcutaneously every weeks. In adults with HeFH undergoing LDL apheresis or in adults with HoFH:The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].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 weeks after initiation.. In adults with established cardiovascular disease or with primary hyperlipidemia, including HeFH:The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].For patients receiving PRALUENT 300 mg every 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 150 mg subcutaneously every weeks. The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].. For patients receiving PRALUENT 300 mg every 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 150 mg subcutaneously every weeks.. In adults with HeFH undergoing LDL apheresis or in adults with HoFH:The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].PRALUENT can be administered without regard to the timing of LDL apheresis. The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].. 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 weeks after initiation.. 2.2 Missed Doses. If dose is missed:Within days from the missed dose, instruct the patient to administer PRALUENT and resume the patients original schedule.More than days after the missed dose:For every week dose, instruct the patient to wait until the next dose on the original schedule.For every week dose, instruct the patient to administer the dose and start new schedule based on this date. Within days from the missed dose, instruct the patient to administer PRALUENT and resume the patients original schedule.. More than days after the missed dose:For every week dose, instruct the patient to wait until the next dose on the original schedule.For every week dose, instruct the patient to administer the dose and start new schedule based on this date. For every week dose, instruct the patient to wait until the next dose on the original schedule.. For every week dose, instruct the patient to administer the dose and start new schedule based on this date.. 2.3 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.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 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.To administer the 300 mg dose, give two 150 mg PRALUENT injections consecutively at two different injection sites.. 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.. 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 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.. To administer the 300 mg dose, give two 150 mg PRALUENT injections consecutively at two different injection sites.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. PRALUENT injection is clear, colorless to pale yellow solution available as follows:75 mg/mL single-dose pre-filled pen150 mg/mL single-dose pre-filled pen. 75 mg/mL single-dose pre-filled pen. 150 mg/mL single-dose pre-filled pen. Injection: 75 mg/mL or 150 mg/mL in single-dose pre-filled pen. (3).

GERIATRIC USE SECTION.

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.

HEPATIC IMPAIRMENT SUBSECTION.

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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. PRALUENT injection is clear, colorless to pale yellow solution, supplied as follows:StrengthPackage SizeNDC75 mg/mL single-dose pre-filled pen1 pen61755-020-012 pens61755-020-02150 mg/mL single-dose pre-filled pen1 pen61755-021-012 pens61755-021-02The needle shield is not made with natural rubber latex.. Store in refrigerator at 36F to 46F (2C to 8C) in the original carton to protect from light. Do not freeze. Do not shake.PRALUENT may be kept at room temperature up to 77F (25C) in the original carton for 30 days. If not used within the 30 days, discard PRALUENT.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity with PRALUENT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PRALUENT in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In cardiovascular outcomes trial, 5.5% (504/9091) of patients treated with PRALUENT 75 mg and/or 150 mg every weeks had anti-drug antibodies (ADA) detected after initiating treatment compared with 1.6% (149/9097) of patients treated with placebo. Persistent ADA responses, defined as at least consecutive post-baseline samples with positive ADA separated by at least 16-week period, were observed in 0.7% of patients treated with PRALUENT and 0.4% of patients treated with placebo. Neutralizing antibody (NAb) responses were observed in 0.5% of patients treated with PRALUENT and in <0.1% of patients treated with placebo. Efficacy based on reductions in LDL-C was mostly similar in patients with or without ADA. However, some patients treated with PRALUENT with persistent or neutralizing antibodies experienced attenuation in LDL-C efficacy.A higher incidence of injection site reactions were observed in patients with treatment-emergent ADA compared to patients who were ADA negative (7.5% vs 3.6%). In pool of ten placebo-controlled and active-controlled trials of patients treated with PRALUENT 75 mg and/or 150 mg every weeks as well as in separate clinical study of patients treated with PRALUENT 75 mg every weeks or 300 mg every weeks (including some patients with dose adjustment to 150 mg every weeks), the incidence of detecting ADA and NAb was similar to the results from the trial described above.The long-term consequences of continuing PRALUENT treatment in the presence of ADA are unknown.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. PRALUENT(R) is indicated:To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease. As an adjunct to diet, alone or in combination with other low density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C.As an adjunct to other LDL-C-lowering therapies in adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C.. To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease. As an adjunct to diet, alone or in combination with other low density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C.. As an adjunct to other LDL-C-lowering therapies in adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C.. PRALUENT is PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor indicated:To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease. (1)As adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C. (1)As an adjunct to other LDL-C-lowering therapies in adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C. (1). To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease. (1). As adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C. (1). As an adjunct to other LDL-C-lowering therapies in adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-Approved Patient Labeling (Patient Information and Instructions for Use).. PregnancyAdvise women who are exposed to PRALUENT during pregnancy that there is pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Regeneron at 844-734-6643 [see Use in Specific Populations (8.1)]. Hypersensitivity ReactionsInform patients that serious hypersensitivity reactions (e.g., angioedema) have been reported in patients treated with PRALUENT. Advise patients on the symptoms of hypersensitivity reactions and instruct them to discontinue PRALUENT and seek medical attention promptly, if such symptoms occur.. AdministrationProvide guidance to patients and caregivers on proper subcutaneous injection technique and how to use the pre-filled pen. Inform patients that it may take up to 20 seconds to inject PRALUENT. Inform patients the pre-filled pen should be allowed to warm to room temperature for 30 to 40 minutes prior to use if refrigerated.

INSTRUCTIONS FOR USE SECTION.

Instructions For Use PRALUENT(R) (PRAHL-u-ent) (alirocumab) Injection, for Subcutaneous Injection Single-Dose Pre-Filled Pen (75 mg/mL) Important InformationThe device is single-dose disposable pen. It contains 75 mg of PRALUENT (alirocumab) in mL.The PRALUENT pen contains medicine prescribed by your healthcare provider.The medicine is injected under your skin and can be given by yourself or someone else (caregiver).It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider.This pen can only be used for single injection, and must be discarded after use.Read all of the instructions carefully before using the PRALUENT pen.Follow these instructions every time you use PRALUENT pen.Do not touch the yellow safety cover.Do not use the pen if it has been dropped or damaged.Do not use the pen if the blue cap is missing or not securely attached.Do not re-use pen.Storage of PRALUENT Store unused pens in the refrigerator at 36F to 46F (2C to 8C) in the original carton to protect from light.Do not freeze. Do not expose the pen to extreme heat or direct sunlight. Do not shake.PRALUENT should be allowed to warm to room temperature for 30 to 40 minutes before use.If needed, PRALUENT may be kept at room temperature up to 77F (25C) for 30 days in the original carton to protect from light. Do not store above 77F (25C). After PRALUENT is removed from the refrigerator it must be used within 30 days or thrown away.Keep the PRALUENT pens and all medicines out of the reach of children. Keep this leaflet. If you have questions, ask your healthcare provider or call 1-844-PRALUENT (1-844-772-5836).The parts of the PRALUENT pen are shown in this picture.Step A: Getting ready for your injectionBefore you start you will need:the PRALUENT pen1 alcohol wipe1 cotton ball or gauzea puncture-resistant container (see Step B8)A1: Look at the label on the pen.Check that you have the correct product and the correct dose.Check the expiration date: do not use if this date has passed.A2: Look at the window.Check the liquid is clear, colorless to pale yellow and free from particles (see Figure A).You may see an air bubble. This is normal.Do not use if the window appears solid yellow (see Figure B).Do not use this medicine if the solution is discolored or cloudy, or if it contains visible flakes or particles.A3: Let the pen warm up at room temperature for 30 to 40 minutes.This is important for administering the entire dose and helps minimize discomfort.Take PRALUENT out of the refrigerator to warm up before using.Do not heat the pen, let it warm up on its own.Do not put the pen back in the refrigerator.A4: Prepare the injection site.Wash your hands with soap and water and dry with towel.Clean skin in the injection area with an alcohol wipe.You can inject into your (see below picture):thighsstomach (except for the inch area around your navel)upper arms You can stand or sit to give yourself an injection.Important:Change (rotate) your injection site each time you give yourself an injection. If you need to use the same injection site, make sure it is not the same spot on the site you used last time.Do not inject into areas where the skin is injured, tender, hard, red, or hot. Do not inject PRALUENT into areas with visible veins, scars or stretch marks.Step B: How to give your injectionB1: After completing all steps in Step A: Getting ready for your injection, pull off the blue cap. Do not pull off the cap until you are ready to inject.Do not put the blue cap back on.B2: Hold the PRALUENT pen like this.Do not touch the yellow safety cover.Make sure you can see the window.B3: Press the yellow safety cover on your skin at roughly 90 angle.Press and firmly hold the pen against your body until the yellow safety cover is no longer visible. The pen will not work if the yellow safety cover is not depressed fully.If needed, pinch the skin to make sure the injection site is firm.B4: Push and immediately release the green button with your thumb.You will hear click. Your injection has now started.The window will start to turn yellow.B5: Keep holding the pen against your skin after releasing the button. The injection may take up to 20 seconds.The time required for injection to give the entire dose may be longer than for other injectable medicines.B6: Check the window has turned yellow, before removing the pen.Do not remove the pen until the entire window has turned yellow. Your injection is complete when the window has turned completely yellow, you may hear second click.If the window does not turn completely yellow, call 1-844-772-5836 for help. Do not give yourself second dose without speaking to your healthcare provider.B7: Pull pen away from your skin.Do not rub the skin after the injection.If you see any blood, press cotton ball or gauze on the site until the bleeding stops.B8: Discard pen and cap.Do not put the blue cap back on.Throw away pen and cap in puncture-resistant container immediately after they have been used.Disposing of used pens:Put your used pens in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) pens and caps in your household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Keep PRALUENT and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: Regeneron Pharmaceuticals, Inc. Tarrytown, NY 10591 U.S. License 1760PRALUENT is registered trademark of Regeneron Pharmaceuticals, Inc.(C)2020 Regeneron Pharmaceuticals, Inc. All rights reserved.Revised: May 2020. The device is single-dose disposable pen. It contains 75 mg of PRALUENT (alirocumab) in mL.. The PRALUENT pen contains medicine prescribed by your healthcare provider.. The medicine is injected under your skin and can be given by yourself or someone else (caregiver).. It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider.. This pen can only be used for single injection, and must be discarded after use.. Read all of the instructions carefully before using the PRALUENT pen.. Follow these instructions every time you use PRALUENT pen.. Do not touch the yellow safety cover.. Do not use the pen if it has been dropped or damaged.. Do not use the pen if the blue cap is missing or not securely attached.. Do not re-use pen.. Store unused pens in the refrigerator at 36F to 46F (2C to 8C) in the original carton to protect from light.. Do not freeze. Do not expose the pen to extreme heat or direct sunlight. Do not shake.. PRALUENT should be allowed to warm to room temperature for 30 to 40 minutes before use.. If needed, PRALUENT may be kept at room temperature up to 77F (25C) for 30 days in the original carton to protect from light. Do not store above 77F (25C). After PRALUENT is removed from the refrigerator it must be used within 30 days or thrown away.. Keep the PRALUENT pens and all medicines out of the reach of children.. the PRALUENT pen. alcohol wipe. cotton ball or gauze. puncture-resistant container (see Step B8). Check that you have the correct product and the correct dose.. Check the expiration date: do not use if this date has passed.. Check the liquid is clear, colorless to pale yellow and free from particles (see Figure A).. You may see an air bubble. This is normal.. Do not use if the window appears solid yellow (see Figure B).. Do not use this medicine if the solution is discolored or cloudy, or if it contains visible flakes or particles.. This is important for administering the entire dose and helps minimize discomfort.. Take PRALUENT out of the refrigerator to warm up before using.. Do not heat the pen, let it warm up on its own.. Do not put the pen back in the refrigerator.. Wash your hands with soap and water and dry with towel.. Clean skin in the injection area with an alcohol wipe.. You can inject into your (see below picture):thighsstomach (except for the inch area around your navel)upper arms thighs. stomach (except for the inch area around your navel). upper arms. You can stand or sit to give yourself an injection.. Change (rotate) your injection site each time you give yourself an injection. If you need to use the same injection site, make sure it is not the same spot on the site you used last time.. Do not inject into areas where the skin is injured, tender, hard, red, or hot. Do not inject PRALUENT into areas with visible veins, scars or stretch marks.. Do not pull off the cap until you are ready to inject.. Do not put the blue cap back on.. Do not touch the yellow safety cover.. Make sure you can see the window.. Press and firmly hold the pen against your body until the yellow safety cover is no longer visible. The pen will not work if the yellow safety cover is not depressed fully.. If needed, pinch the skin to make sure the injection site is firm.. You will hear click. Your injection has now started.. The window will start to turn yellow.. The injection may take up to 20 seconds.. The time required for injection to give the entire dose may be longer than for other injectable medicines.. Do not remove the pen until the entire window has turned yellow. Your injection is complete when the window has turned completely yellow, you may hear second click.. If the window does not turn completely yellow, call 1-844-772-5836 for help. Do not give yourself second dose without speaking to your healthcare provider.. Do not rub the skin after the injection.. If you see any blood, press cotton ball or gauze on the site until the bleeding stops.. Do not put the blue cap back on.. Throw away pen and cap in puncture-resistant container immediately after they have been used.. Put your used pens in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) pens and caps in your household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Figure. Figure. Figure. Figure. Figure. Picture A. Figure B. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers 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 breastmilk IgG antibodies do not enter the neonatal and infant circulation in substantial amounts.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with alirocumab. The mutagenic potential of alirocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.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 6-month chronic toxicology study in sexually-mature monkeys subcutaneously administered at 5, 15, and 75 mg/kg/week at systemic exposures up to 103-fold the 150 mg every two weeks subcutaneous clinical dose based on serum AUC. In addition, there were no adverse alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in rat or monkey toxicology studies at systemic exposures up to 11-fold and 103-fold respectively, in the 6-month studies, compared to clinical systemic exposure following 150 mg every two weeks dose, based on serum AUC.. 13.2 Animal Toxicology and/or Pharmacology. During 13-week toxicology study of 75 mg/kg once weekly alirocumab in combination with 40 mg/kg once daily atorvastatin in adult monkeys, there were no effects of PRALUENT on the humoral immune response to keyhole limpet hemocyanin (KLH) after one to two months at exposures 100-fold greater than the exposure at the maximum recommended human dose of 150 mg every two weeks, based on AUC.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 75 mg/mL Pen Carton. NDC 61755-020-01 Rx ONLYPraluent(R) alirocumabInjection75 mg/mLOne Pre-filled PenFor subcutaneous injection only. Single-dose.Carton contains: One single-dose pre-filled pen, the Package Insert,Patient Information, and Instructions for Use.75 mg/mLOPEN HEREREGENERON. PRINCIPAL DISPLAY PANEL 75 mg/mL Pen Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of PRALUENT have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Alirocumab reduced free PCSK9 in concentration-dependent manner. Following single subcutaneous administration of alirocumab 75 or 150 mg, maximal suppression of free PCSK9 occurred within to hours. Free PCSK9 concentrations returned to baseline when alirocumab concentrations decreased below the limit of quantitation.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter subcutaneous administration of 75 mg to 300 mg alirocumab, median times to maximum serum concentrations (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 pharmacokinetics analysis. slightly greater than dose proportional increase was observed, with 2.1-fold to 2.7-fold increase in total alirocumab concentrations for 2-fold increase in dose from 75 mg every weeks to 150 mg every weeks. Monthly dose normalized exposure with 300 mg every weeks treatment was similar to that of 150 mg every weeks. Steady state was reached after to doses with an accumulation ratio up to maximum of about 2-fold.. DistributionFollowing 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.. EliminationSpecific metabolism studies were not conducted, because alirocumab is 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 non-saturable proteolytic pathway.Based on 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 weeks or 150 mg every weeks.. Specific PopulationsA 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.. Renal ImpairmentSince 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 ImpairmentFollowing administration of 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 InteractionsThe median apparent half-life of alirocumab is reduced to 12 days when administered with statin; however, this difference is not clinically meaningful.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been reported during post-approval use of PRALUENT. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactions: AngioedemaInfluenza-like illness. Hypersensitivity reactions: Angioedema. Influenza-like illness.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from clinical trials and postmarketing reports on PRALUENT use in pregnant women are insufficient to evaluate for 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 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 dataIn 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 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 to 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.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)4/2021Dosage and Administration (2.1)4/2021Dosage and Administration (2.3)4/2021Contraindications (4)4/2021.

RENAL IMPAIRMENT SUBSECTION.

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)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: April 2021Patient InformationPRALUENT(R) (PRAHL-u-ent)(alirocumab)injection, for subcutaneous useWhat is PRALUENTPRALUENT is an injectable prescription medicine used: in adults with cardiovascular disease to reduce the risk of heart attack, stroke, and certain types of chest pain conditions (unstable angina) requiring hospitalization.along with diet, alone or together with other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including type of high cholesterol called heterozygous familial hypercholesterolemia), to reduce low-density lipoprotein cholesterol (LDL-C) or bad cholesterol.along with other LDL-lowering treatments in adults with type of high cholesterol called homozygous familial hypercholesterolemia, who need additional lowering of LDL-C.It is not known if PRALUENT is safe and effective in children.Who should not use PRALUENTDo not use PRALUENT if you are allergic to alirocumab or to any of the ingredients in PRALUENT. See the end of this leaflet for complete list of ingredients in PRALUENT.What should tell my healthcare provider before using PRALUENTBefore you start using PRALUENT, tell your healthcare provider about all of your medical conditions, including allergies, and if you:are pregnant or plan to become pregnant. It is not known if PRALUENT will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking PRALUENT.are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take PRALUENT or breastfeed. You should not do both without talking to your healthcare provider first.If you are pregnant during PRALUENT treatment, you are encouraged to call Regeneron at 1-844-734-6643 to share information about the health of you and your baby.Tell your healthcare provider or pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use PRALUENTSee the detailed Instructions for Use that comes with this Patient Information about the right way to prepare and give your PRALUENT injections.Use PRALUENT exactly as your healthcare provider tells you to use it.PRALUENT comes as single-dose (1 time) pre-filled pen (autoinjector). Your healthcare provider will prescribe the dosage that is best for you.If your healthcare provider decides that you or caregiver can give the injections of PRALUENT, you or your caregiver should receive training on the right way to prepare and give PRALUENT. Do not try to inject PRALUENT until you have been shown the right way by your healthcare provider or nurse.PRALUENT is injected under the skin (subcutaneously) every weeks or every weeks (monthly).If your healthcare provider prescribes you the monthly dose, you will give yourself separate injections in row, using different pen for each injection and different injection sites.Do not inject PRALUENT together with other injectable medicines at the same injection site.Always check the label of your pen to make sure you have the correct medicine and the correct dose of PRALUENT before each injection.If you forget to use PRALUENT or are not able to take the dose at your regular time, inject your missed dose as soon as you remember, within days. Then, if you inject every weeks take your next dose in weeks from the day you missed your dose or if you inject every weeks take your next dose in weeks from the day you missed your dose. This will put you back on your original schedule.If you missed dose by more than days and you inject every weeks wait until your next scheduled dose to re-start PRALUENT or if you inject every weeks start new schedule from the time you remember to take your dose.If you are not sure when to re-start PRALUENT, ask your healthcare provider or pharmacist.If you use more PRALUENT than you should, talk to your healthcare provider or pharmacist.Do not stop using PRALUENT without talking with your healthcare provider. If you stop using PRALUENT, your cholesterol levels can increase.What are the possible side effects of PRALUENT PRALUENT can cause serious side effects, including:allergic reactions. PRALUENT may cause allergic reactions that can be severe and require treatment in hospital. Stop using PRALUENT and call your healthcare provider or go to the nearest hospital emergency room right away if you have any symptoms of an allergic reaction including: severe rashrednesshivessevere itchingtrouble breathingswelling of the face, lips, throat or tongueThe most common side effects of PRALUENT include:redness, itching, swelling, pain, or tenderness at the injection sitesymptoms of the common coldflu or flu-like symptomsTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all of the possible side effects of PRALUENT. Ask your healthcare provider or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of PRALUENT.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use PRALUENT for condition for which it was not prescribed. Do not give PRALUENT to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information summarizes the most important information about PRALUENT. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about PRALUENT that is written for health professionals. For more information about PRALUENT, go to www.PRALUENT.com or call 1-844-PRALUENT (1-844-772-5836).What are the ingredients in PRALUENTActive ingredient: alirocumabInactive ingredients: histidine, polysorbate 20, sucrose, and Water for Injection, USP. Manufactured by: Regeneron Pharmaceuticals, Inc. Tarrytown, NY 10591, U.S. License 1760; PRALUENT is registered trademark of Regeneron Pharmaceuticals, Inc. (C)2021 Regeneron Pharmaceuticals, Inc. All rights reserved.. in adults with cardiovascular disease to reduce the risk of heart attack, stroke, and certain types of chest pain conditions (unstable angina) requiring hospitalization.. along with diet, alone or together with other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including type of high cholesterol called heterozygous familial hypercholesterolemia), to reduce low-density lipoprotein cholesterol (LDL-C) or bad cholesterol.. along with other LDL-lowering treatments in adults with type of high cholesterol called homozygous familial hypercholesterolemia, who need additional lowering of LDL-C.. are pregnant or plan to become pregnant. It is not known if PRALUENT will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking PRALUENT.. are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take PRALUENT or breastfeed. You should not do both without talking to your healthcare provider first.. See the detailed Instructions for Use that comes with this Patient Information about the right way to prepare and give your PRALUENT injections.. Use PRALUENT exactly as your healthcare provider tells you to use it.. PRALUENT comes as single-dose (1 time) pre-filled pen (autoinjector). Your healthcare provider will prescribe the dosage that is best for you.. If your healthcare provider decides that you or caregiver can give the injections of PRALUENT, you or your caregiver should receive training on the right way to prepare and give PRALUENT. Do not try to inject PRALUENT until you have been shown the right way by your healthcare provider or nurse.. PRALUENT is injected under the skin (subcutaneously) every weeks or every weeks (monthly).. If your healthcare provider prescribes you the monthly dose, you will give yourself separate injections in row, using different pen for each injection and different injection sites.. Do not inject PRALUENT together with other injectable medicines at the same injection site.. Always check the label of your pen to make sure you have the correct medicine and the correct dose of PRALUENT before each injection.. If you forget to use PRALUENT or are not able to take the dose at your regular time, inject your missed dose as soon as you remember, within days. Then, if you inject every weeks take your next dose in weeks from the day you missed your dose or if you inject every weeks take your next dose in weeks from the day you missed your dose. This will put you back on your original schedule.. If you missed dose by more than days and you inject every weeks wait until your next scheduled dose to re-start PRALUENT or if you inject every weeks start new schedule from the time you remember to take your dose.If you are not sure when to re-start PRALUENT, ask your healthcare provider or pharmacist.. If you use more PRALUENT than you should, talk to your healthcare provider or pharmacist.. Do not stop using PRALUENT without talking with your healthcare provider. If you stop using PRALUENT, your cholesterol levels can increase.. allergic reactions. PRALUENT may cause allergic reactions that can be severe and require treatment in hospital. Stop using PRALUENT and call your healthcare provider or go to the nearest hospital emergency room right away if you have any symptoms of an allergic reaction including:. severe rash. redness. hives. severe itching. trouble breathing. swelling of the face, lips, throat or tongue. redness, itching, swelling, pain, or tenderness at the injection site. symptoms of the common cold. flu or flu-like symptoms. Active ingredient: alirocumab. Inactive ingredients: histidine, polysorbate 20, sucrose, and Water for Injection, USP.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. In adults with established cardiovascular disease or with primary hyperlipidemia, including HeFH:The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].For patients receiving PRALUENT 300 mg every 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 150 mg subcutaneously every weeks. In adults with HeFH undergoing LDL apheresis or in adults with HoFH:The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].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 weeks after initiation.. In adults with established cardiovascular disease or with primary hyperlipidemia, including HeFH:The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].For patients receiving PRALUENT 300 mg every 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 150 mg subcutaneously every weeks. The recommended starting dose of PRALUENT is either 75 mg once every weeks or 300 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].. For patients receiving PRALUENT 300 mg every 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 150 mg subcutaneously every weeks.. In adults with HeFH undergoing LDL apheresis or in adults with HoFH:The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].PRALUENT can be administered without regard to the timing of LDL apheresis. The recommended dose of PRALUENT is 150 mg once every weeks administered subcutaneously [see Dosage and Administration (2.3)].. 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 weeks after initiation.

STORAGE AND HANDLING SECTION.

Store in refrigerator at 36F to 46F (2C to 8C) in the original carton to protect from light. Do not freeze. Do not shake.PRALUENT may be kept at room temperature up to 77F (25C) in the original carton for 30 days. If not used within the 30 days, discard PRALUENT.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from clinical trials and postmarketing reports on PRALUENT use in pregnant women are insufficient to evaluate for 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 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 dataIn 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 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 to 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 SummaryThere 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 mothers 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 breastmilk IgG antibodies do not enter the neonatal and infant circulation in substantial amounts.. 8.4 Pediatric Use. The safety and effectiveness of PRALUENT have not been established in pediatric patients.. 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions: hypersensitivity vasculitis, angioedema, and other hypersensitivity reactions requiring hospitalization, have been reported with PRALUENT treatment. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with PRALUENT, treat according to the standard of care, and monitor until signs and symptoms resolve. (5.1). 5.1 Hypersensitivity Reactions. Hypersensitivity reactions, including hypersensitivity vasculitis, angioedema, and other hypersensitivity reactions requiring hospitalization, have been reported with PRALUENT treatment. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with PRALUENT, treat according to the standard of care, and monitor until signs and symptoms resolve. PRALUENT is contraindicated in patients with history of serious hypersensitivity reaction to alirocumab or any excipient in PRALUENT [see Contraindications (4)].