REPATHA

Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin type 9 (PCSK9). Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. REPATHA is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous use. Each 1 mL prefilled single-dose SureClick ® autoinjector and prefilled single-dose syringe contains 140 mg evolocumab, acetate (1.2 mg), polysorbate 80 (0.1 mg), proline (25 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0. Each single-dose Pushtronex ® system (on-body infusor with prefilled cartridge) delivers a 3.5 mL solution containing 420 mg evolocumab, acetate (4.2 mg), polysorbate 80 (0.35 mg), proline (89 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0.

REPATHA is indicated: To reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults at increased risk for these events. As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in: adults with hypercholesterolemia. adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). REPATHA is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor indicated: To reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults at increased risk for these events. ( 1 ) As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in: adults with hypercholesterolemia. ( 1 ) adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). ( 1 ) adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). ( 1 )

In adults at increased risk for CV events or with hypercholesterolemia : The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. ( 2.1 ) If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. ( 2.1 ) In adults and pediatric patients aged 10 years and older with HeFH : The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. ( 2.1 ) If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. ( 2.1 ) In adults and pediatric patients aged 10 years and older with HoFH : The initial recommended dosage of REPATHA is 420 mg once monthly administered subcutaneously. ( 2.1 ) The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. ( 2.1 ) Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule. Administer REPATHA after the apheresis session is complete. ( 2.1 ) Assess LDL-C when clinically appropriate. The LDL-lowering effect of REPATHA may be measured as early as 4 weeks after initiation. ( 2.1 ) REPATHA is available as prefilled single-dose SureClick ® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex. Consider prescribing a presentation of REPATHA that does not contain dry natural rubber for individuals that are sensitive to latex. ( 2.3 , 16 ) Administer REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm. Rotate injection sites for each administration. ( 2.3 ) See Full Prescribing Information for important administration instructions. ( 2.3 ) 2.1 Recommended Dosage In adults at increased risk for CV events or with hypercholesterolemia: The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously [see Dosage and Administration (2.3) ] . If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. In adults and pediatric patients aged 10 years and older with HeFH: The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously [see Dosage and Administration (2.3) ] . If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. In adults and pediatric patients aged 10 years and older with HoFH: The initial recommended dosage of REPATHA is 420 mg once monthly administered subcutaneously [see Dosage and Administration (2.3) ] . The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule. Administer REPATHA after the apheresis session is complete. Assess LDL-C when clinically appropriate. The LDL-lowering effect of REPATHA may be measured as early as 4 weeks after initiation. When monitoring LDL-C for patients receiving REPATHA 420 mg once monthly, note that LDL-C can vary during the dosing interval in some patients; recommend measuring LDL-C just prior to the next scheduled dose [see Clinical Studies (14) ] . 2.2 Missed Doses If a dose is missed: Within 7 days from the missed dose, instruct the patient to administer REPATHA and resume the patient's original schedule. More than 7 days after the missed dose: For an every 2-week dose, instruct the patient to wait until the next dose on the original schedule. For a once-monthly dose, instruct the patient to administer the dose and start a new schedule based on this date. 2.3 Important Administration Instructions REPATHA is available as prefilled single-dose SureClick ® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex [see How Supplied/Storage and Handling (16) ] . Consider prescribing a presentation of REPATHA that does not contain dry natural rubber for individuals that are sensitive to latex [see Warnings and Precautions (5.1) ]. Train patients and/or caregivers on how to prepare and administer REPATHA, according to the Instructions for Use and instruct them to read and follow the Instructions for Use each time they use REPATHA. Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes for the prefilled single-dose SureClick ® autoinjector or prefilled single-dose syringe and for at least 45 minutes for the on-body infusor with prefilled cartridge if REPATHA has been refrigerated [see How Supplied/Storage and Handling (16) ] . Visually inspect REPATHA prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy, discolored, or contains particles. Administer REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. Avoid injecting into areas with scars or stretch marks. Rotate injection sites for each administration. The 420 mg dose of REPATHA can be administered: over 5 minutes by using the single-dose on-body infusor with prefilled cartridge, or by giving 3 injections consecutively within 30 minutes using the prefilled single-dose SureClick ® autoinjector or prefilled single-dose syringe.

REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in REPATHA. Serious hypersensitivity reactions including angioedema have occurred in patients treated with REPATHA [see Warnings and Precautions (5.1) ] . Patients with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in REPATHA. ( 4 )

The following adverse reactions are also discussed in other sections of the label: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Common (> 5% of patients treated with REPATHA and more frequently than placebo) adverse reactions in adults with: Primary hypercholesterolemia: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. ( 6 ) Established CVD: diabetes mellitus, nasopharyngitis and upper respiratory tract infection. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults with Primary Hypercholesterolemia The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks) . The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races. Adverse Reactions in a 52 - Week Controlled Trial In a 52-week, double-blind, randomized, placebo-controlled trial, 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14) ] . The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian; 6% identified as Hispanic ethnicity. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients are shown in Table 1. Adverse reactions led to discontinuation of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to REPATHA treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively). Table 1. Adverse Reactions Occurring in ≥ 3% of REPATHA-treated Patients and More Frequently than with Placebo in a 52-Week Trial Placebo (N = 302) % REPATHA (N = 599) % Nasopharyngitis 9.6 10.5 Upper respiratory tract infection 6.3 9.3 Influenza 6.3 7.5 Back pain 5.6 6.2 Injection site reactions includes erythema, pain, bruising 5.0 5.7 Cough 3.6 4.5 Urinary tract infection 3.6 4.5 Sinusitis 3.0 4.2 Headache 3.6 4.0 Myalgia 3.0 4.0 Dizziness 2.6 3.7 Musculoskeletal pain 3.0 3.3 Hypertension 2.3 3.2 Diarrhea 2.6 3.0 Gastroenteritis 2.0 3.0 Adverse Reactions in Seven Pooled 12 - Week Controlled Trials In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly. The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian; 5% identified as Hispanic ethnicity. Adverse reactions reported in at least 1% of REPATHA-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2. Table 2. Adverse Reactions Occurring in ≥ 1% of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Trials Placebo (N = 1224) % REPATHA 140 mg every 2 weeks and 420 mg once monthly combined (N = 2052) % Nasopharyngitis 3.9 4.0 Back pain 2.2 2.3 Upper respiratory tract infection 2.0 2.1 Arthralgia 1.6 1.8 Nausea 1.2 1.8 Fatigue 1.0 1.6 Muscle spasms 1.2 1.3 Urinary tract infection 1.2 1.3 Cough 0.7 1.2 Influenza 1.1 1.2 Contusion 0.5 1.0 Adverse Reactions in Eight Pooled Controlled Trials (Seven 12 - Week Trials and One 52 - Week Trial) The adverse reactions described below are from a pool of the 52-week trial and seven 12-week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively. Local Injection Site Reactions Injection site reactions occurred in 3.2% and 3.0% of REPATHA-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in REPATHA-treated patients and placebo-treated patients were 0.1% and 0%, respectively. Hypersensitivity Reactions Hypersensitivity reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebo-treated patients, respectively. The most common hypersensitivity reactions were rash (1.0% versus 0.5% for REPATHA and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%). Adverse Reactions in the Cardiovascular Outcomes Trial In a double-blind, randomized, placebo-controlled cardiovascular outcomes trial, 27,525 patients received at least one dose of REPATHA or placebo [see Clinical Studies (14) ] . The mean age was 62.5 years (range: 40 to 86 years), 45% were 65 years or older, 9% were 75 years or older, 25% women, 85% White, 2% Black and 10% Asian; 8% identified as Hispanic ethnicity. Patients were exposed to REPATHA or placebo for a median of 24.8 months; 91% of patients were exposed for ≥ 12 months, 54% were exposed for ≥ 24 months and 5% were exposed for ≥ 36 months. The safety profile of REPATHA in this trial was generally consistent with the safety profile described above in the 12- and 52-week controlled trials involving patients with primary hypercholesterolemia. Common adverse reactions (> 5% of patients treated with REPATHA and occurring more frequently than placebo) included diabetes mellitus (8.8% REPATHA, 8.2% placebo), nasopharyngitis (7.8% REPATHA, 7.4% placebo), and upper respiratory tract infection (5.1% REPATHA, 4.8% placebo). Among the 16,676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the trial was 8.1% in patients treated with REPATHA compared with 7.7% in patients that received placebo. Adverse Reactions in Pediatric Patients with HeFH In a 24-week, randomized, placebo-controlled, double-blind trial of 157 pediatric patients with HeFH, 104 patients received 420 mg REPATHA subcutaneously once monthly [see Clinical Studies (14) ] . The mean age was 13.7 years (range: 10 to 17 years), 56% were female, 85% White, 1% Black, 1% Asian, and 13% other; 8% identified as Hispanic ethnicity. Common adverse reactions (> 5% of patients treated with REPATHA and occurring more frequently than placebo) included: Nasopharyngitis (12% versus 11%) Headache (11% versus 2%) Oropharyngeal pain (7% versus 0%) Influenza (6% versus 4%) Upper respiratory tract infection (6% versus 2%) Adverse Reactions in Adults and Pediatric Patients with HoFH In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH, 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14) ] . The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other. The adverse reactions that occurred in at least two (6.1%) REPATHA-treated patients, and more frequently than in placebo-treated patients, included: Upper respiratory tract infection (9.1% versus 6.3%) Influenza (9.1% versus 0%) Gastroenteritis (6.1% versus 0%) Nasopharyngitis (6.1% versus 0%) In a multicenter, open-label 5-year extension study, 106 patients with HoFH, including 14 pediatric patients, received 420 mg of REPATHA subcutaneously once monthly or every 2 weeks [see Clinical Studies (14) ] . The mean age was 34 years (range: 13 to 68 years), 51% were women, 80% White, 12% Asian, 1% Native American, and 7% other; 5% identified as Hispanic ethnicity. No new adverse reactions were observed during the open-label extension study. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. 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 REPATHA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In a pool of placebo- and active-controlled clinical trials, 0.3% (48 out of 17,992) of adult patients treated with at least one dose of REPATHA tested positive for the development of binding antibodies. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies. The development of anti-evolocumab antibodies was not detected in clinical trials of pediatric patients treated with REPATHA. There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA. 6.3 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of REPATHA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions: Angioedema Influenza-like illness

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. For convenience, REPATHA may be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton for 30 days. If not used within the 30 days, discard REPATHA.