2015年8月27日-美国食品和药物管理局今天批准Repatha（evolocumab）注射液对某些病人谁不能得到他们的低密度脂蛋白（LDL）控制胆固醇与目前的治疗方案。
Repatha，批准了一类新的被称为PCSK9抑制剂药物的第二种药物，被批准用于除饮食和最大耐受他汀类药物治疗成人杂合子家族性高胆固醇血症（HeFH），纯合子家族性高胆固醇血症（HoFH），或使用临床动脉粥样硬化心血管疾病，如心脏发作或中风，谁需要额外降低低密度脂蛋白胆固醇。
家族性高胆固醇血症（既包括HeFH和HoFH）是一种遗传性疾病，导致高水平的低密度脂蛋白胆固醇。血液中的LDL胆固醇的高级别与心血管或心脏疾病。心脏疾病是头号死因的美国人，无论男女。据美国疾病控制和预防，大约61万的人死于心脏疾病，在美国每年-这相当于四分之一的死亡。
“Repatha提供了患者的家族性高胆固醇血症或已知有心血管疾病一直无法与他汀类药物足以降低他们的低密度脂蛋白胆固醇谁这一类新的药物另一种治疗选择，”约翰·詹金斯博士，新药办公室主任，药品审评中心和研究。 “心血管疾病是严重威胁美国人的健康，美国食品药品管理局是一个致力于促进发展的有效和安全的药物，并批准为解决这一重要的公共卫生问题。”Repatha是一种抗体针对特定的蛋白质，称为PCSK9 。 PCSK9降低受体对肝脏从血液中除去LDL胆固醇的数量。通过阻断PCSK9的工作能力，多种受体可摆脱从血液LDL胆固醇和，其结果，降低LDL胆固醇水平的。
Repatha的有效性和安全性于一体的52周安慰剂对照试验，并在参与者与原发性高脂血症8个12周的安慰剂对照试验，其中有两个项目进行了评估专门招收有HeFH和一个与会者，招收学员HoFH。在12周的研究中，329参与者HeFH，需要额外的LDL胆固醇的降低，尽管他汀类药物有或没有其他降脂治疗谁之一，患者随机接受Repatha或安慰剂治疗12周。参与者服用Repatha的平均减少了约60％的LDL胆固醇，与安慰剂相比。
Repatha的最常见的副作用包括鼻咽炎，上呼吸道感染，流感，腰痛，和反应，如发红，疼痛，或瘀伤其中注射是。过敏反应，如皮疹和荨麻疹，有报道使用Repatha的。患者应停止使用Repatha，并得到医疗帮助，如果他们出现严重的过敏反应症状。
多的临床试验表明，他汀类药物降低有一个心脏发作或中风的风险。试用评测添加Repatha他汀类药物降低心血管疾病风险的影响是持续的。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use REPATHA ™ safely and effectively. See full prescribing information for REPATHA .
REPATHA (evolocumab) injection, for subcutaneous use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
REPATHA is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody indicated as an adjunct to diet and:
Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C). (1.1)
Other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. (1.2)
Limitations of Use
The effect of REPATHA on cardiovascular morbidity and mortality has not been determined. (1.3)
DOSAGE AND ADMINISTRATION
Administer by subcutaneous injection. (2.1)
Primary hyperlipidemia with established clinical atherosclerotic CVD or HeFH: 140 mg every 2 weeks or 420 mg once monthly in abdomen, thigh, or upper arm. (2.1)
HoFH: 420 mg once monthly. (2.1)
To administer 420 mg, give 3 REPATHA injections consecutively within 30 minutes. (2.2)
See Dosage and Administration for important administration instructions. (2.2)
DOSAGE FORMS AND STRENGTHS
Injection: 140 mg/mL in a single-use prefilled syringe (3)
Injection: 140 mg/mL in a single-use prefilled SureClick® autoinjector (3)
CONTRAINDICATIONS
Patients with a history of a serious hypersensitivity reaction to REPATHA. (4)
WARNINGS AND PRECAUTIONS
Allergic Reactions: Rash and urticaria have occurred. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve. (5.1)
ADVERSE REACTIONS
Common adverse reactions in clinical trials (> 5% of patients treated with REPATHA and occurring more frequently than placebo): nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. (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.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1  INDICATIONS AND USAGE
1.1 Primary Hyperlipidemia
REPATHA™ is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).
1.2  Homozygous Familial Hypercholesterolemia
REPATHA is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.
1.3  Limitations of Use
The effect of REPATHA on cardiovascular morbidity and mortality has not been determined.
2  DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended subcutaneous dosage of REPATHA in patients with HeFH or patients with primary hyperlipidemia with established clinical atherosclerotic CVD is either 140 mg every 2 weeks OR 420 mg once monthly. When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.
The recommended subcutaneous dosage of REPATHA in patients with HoFH is 420 mg once monthly. In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function. 
If an every 2 week or once monthly dose is missed, instruct the patient to:
Administer REPATHA as soon as possible if there are more than 7 days until the next scheduled dose, or, 
Omit the missed dose and administer the next dose according to the original schedule.
2.2 Important Administration Instructions
To administer the 420 mg dose, give 3 REPATHA injections consecutively within 30 minutes.
Provide proper training to patients and/or caregivers on how to prepare and administer REPATHA prior to use, according to the Instructions for Use, including aseptic technique. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use REPATHA.
Keep REPATHA in the refrigerator. Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes. Do not warm in any other way. Alternatively, for patients and caregivers, REPATHA can be kept at room temperature (up to 25°C (77°F)) in the original carton. However, under these conditions, REPATHA must be used within 30 days [see How Supplied/Storage and Handling (16)].
Visually inspect REPATHA for particles and discoloration prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy or discolored or contains particles.
Administer REPATHA by subcutaneous injection into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use prefilled syringe or single-use prefilled autoinjector.
Do not co-administer REPATHA with other injectable drugs at the same injection site.
Rotate the injection site with each injection. 
3 DOSAGE FORMS AND STRENGTHS
REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution available as follows:
Injection: 140 mg/mL solution in a single-use prefilled syringe
Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector
4 CONTRAINDICATIONS
REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to REPATHA [see Warnings and Precautions (5.1)].
5  WARNINGS AND PRECAUTIONS
5.1  Allergic Reactions
Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with REPATHA, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve.
6 ADVERSE REACTIONS
The following adverse reactions are also discussed in other sections of the label:
Allergic Reactions [see Warnings and Precautions (5.1)]
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 Patients with Primary Hyperlipidemia and in Patients with Heterozygous Familial Hypercholesterolemia
REPATHA is not indicated for use in patients without familial hypercholesterolemia or atherosclerotic CVD [see Indications and Usage (1.1)].
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 (Study 2), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.1)]. 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, and 6% Hispanic. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients in Study 2, 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 Greater than or Equal to 3% of REPATHA-treated Patients and More Frequently than with Placebo in Study 2 

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†	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

†includes erythema, pain, bruising
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, and 5% Hispanic. 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 Greater than 1% of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Studies 

Placebo (N = 1224) %	REPATHA† (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

140 mg every 2 weeks and 420 mg once monthly combined
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 (Study 2) 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.
Allergic Reactions
Allergic reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebo-treated patients, respectively. The most common allergic 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%).
Neurocognitive Events
In placebo-controlled trials, neurocognitive events were reported in less than or equal to 0.2% in REPATHA-treated and placebo-treated patients.
Low LDL-C Levels
In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1988 patients treated with REPATHA had at least one LDL-C value < 25 mg/dL. Changes to background lipid-altering therapy were not made in response to low LDL-C values, and REPATHA dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by REPATHA are unknown.
Musculoskeletal Events
Musculoskeletal adverse reactions were reported in 14.3% of REPATHA-treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for REPATHA and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia
In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 4), 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.3)]. 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%)
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. 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, 0.1% of patients treated with at least one dose of REPATHA tested positive for binding antibody development. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.
There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA, but the long-term consequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of 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 with the incidence of antibodies to other products may be misleading.
8  USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month. In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses. The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically. No assessment for immune suppression was conducted with evolocumab in infant monkeys. Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier. FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester. Consider the benefits and risks of REPATHA and possible risks to the fetus before prescribing REPATHA to pregnant women.
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.
Data
Animal Data
In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. No test of humoral immunity in infant monkeys was conducted with evolocumab.
8.2 Lactation
Risk Summary
There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REPATHA and any potential adverse effects on the breastfed infant from REPATHA or from the underlying maternal condition. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.
8.4 Pediatric Use
The safety and effectiveness of REPATHA in combination with diet and other LDL-C-lowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebo-controlled trial that included 10 adolescents (ages 13 to 17 years old) with HoFH [see Clinical Studies (14.3)]. In this trial, 7 adolescents received REPATHA 420 mg subcutaneously once monthly and 3 adolescents received placebo. The effect of REPATHA on LDL-C was generally similar to that observed among adult patients with HoFH. Including experience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with REPATHA, with a median exposure duration of 9 months. The safety profile of REPATHA in these adolescents was similar to that described for adult patients with HoFH.
The safety and effectiveness of REPATHA have not been established in pediatric patients with HoFH who are younger than 13 years old.
The safety and effectiveness of REPATHA have not been established in pediatric patients with primary hyperlipidemia or HeFH.
8.5  Geriatric Use
In controlled studies, 1420 patients treated with REPATHA were ≥ 65 years old and 171 were ≥ 75 years old. 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 in patients with mild to moderate renal impairment. No data are available in patients with severe renal impairment [see Clinical Pharmacology (12.3)].
8.7  Hepatic Impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].
11  DESCRIPTION
Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin 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 injection. Each 1 mL single-use prefilled syringe and single-use prefilled SureClick® autoinjector 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.
12.2  Pharmacodynamics
Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours. Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation.
12.3  Pharmacokinetics
Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9. Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 18.6 (7.3) μg/mL and AUClast mean (SD) of 188 (98.6) day•μg/mL. Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean (SD) of 59.0 (17.2) μg/mL and AUClast mean (SD) of 924 (346) day•μg/mL. Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr. An approximate 2- to 3-fold accumulation was observed in trough serum concentrations (Cmin [SD] 7.21 [6.6]) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin [SD] 11.2 [10.8]), and serum trough concentrations approached steady state by 12 weeks of dosing.
Absorption
Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and estimated absolute bioavailability was 72%.
Distribution
Following a single 420 mg intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L.
Metabolism and Elimination
Two elimination phases were observed for REPATHA. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of REPATHA is largely through a non-saturable proteolytic pathway. REPATHA was estimated to have an effective half-life of 11 to 17 days.
Specific Populations
The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance, across all approved populations [see Use in Specific Populations (8.5)].
The exposure of evolocumab decreased with increasing body weight. These differences are not clinically meaningful.
Renal Impairment
Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab. Patients wih severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) have not been studied.
Hepatic Impairment
Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean Cmax and 40-50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients.
Pregnancy
The effect of pregnancy on evolocumab pharmacokinetics has not been studied [see Use in Specific Populations (8.1)].
Drug Interaction Studies
An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in patients co-administered with a high-intensity statin regimen. This difference is not clinically meaningful and does not impact dosing recommendations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg administered every 2 weeks. There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38- and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. The mutagenic potential of evolocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
There were no adverse effects on fertility (including estrous cycling, sperm analysis, mating performance, and embryonic development) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10, 30, and 100 mg/kg every 2 weeks. The highest dose tested corresponds to systemic exposures up to 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. In addition, there were no adverse evolocumab-related effects on surrogate markers of fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) in a 6-month chronic toxicology study in sexually mature monkeys subcutaneously administered evolocumab at 3, 30, and 300 mg/kg once weekly. The highest dose tested corresponds to 744- and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
13.2 Animal Toxicology and/or Pharmacology
During a 3-month toxicology study of 10 and 100 mg/kg once every 2 weeks evolocumab in combination with 5 mg/kg once daily rosuvastatin in adult monkeys, there were no effects of evolocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after 1 to 2 months exposure. The highest dose tested corresponds to exposures 54- and 21-fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. Similarly, there were no effects of evolocumab on the humoral immune response to KLH (after 3 to 4 months exposure) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg once weekly evolocumab corresponding to exposures 744- and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
14  CLINICAL STUDIES
14.1  Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease
Study 1 was a multicenter, double-blind, randomized controlled trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. The trial included 296 patients with atherosclerotic CVD who received REPATHA or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. Among these patients, the mean age at baseline was 63 years (range: 32 to 80 years), 45% were ≥ 65 years old, 33% women, 98% White, 2% were Black, < 1% Asian and 5% Hispanic or Latino. After 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dL.
In these patients with atherosclerotic CVD who were on maximum-dose statin therapy, the difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -71% (95% CI: -81%, -61%; p < 0.0001) and -63% (95% CI: -76%, -50%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 3 and Figure 1.
Table 3. Effect of REPATHA on Lipid Parameters in Patients with Atherosclerotic CVD on Atorvastatin 80 mg, Rosuvastatin 40 mg, or Simvastatin 40 mg (Mean % Change from Baseline to Week 12 in Study 1) 

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo every 2 weeks (n = 42)	7	2	5	4
REPATHA 140 mg every 2 weeks† (n = 105)	-64	-56	-49	-38
Mean difference from placebo (95% CI)	-71 (-81, -61)	-58 (-67, -49)	-55 (-62, -47)	-42 (-48, -36)
Placebo once monthly (n = 44)	5	5	3	3
REPATHA 420 mg once monthly† (n = 105)	-58	-47	-46	-32
Mean difference from placebo (95% CI)	-63 (-76, -50)	-52 (-63, -41)	-49 (-58, -39)	-36 (-43, -28)

Estimates based on a multiple imputation model that accounts for treatment adherence
†140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C
Figure 1. Effect of REPATHA on LDL-C in Patients with Atherosclerotic CVD when Combined with Statins (Mean % Change from Baseline to Week 12 in Study 1)
Estimates based on a multiple imputation model that accounts for treatment adherence
Error bars indicate 95% confidence intervals
Study 2 was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 139 patients with atherosclerotic CVD who received protocol-determined background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or REPATHA 420 mg administered subcutaneously once monthly. Among these patients, the mean age at baseline was 59 years (range: 35 to 75 years), 25% were ≥ 65 years, 40% women, 80% White, 3% Black, 5% Asian, and < 1% Hispanic or Latino. After stabilization on the assigned background therapy, the mean baseline LDL-C was 105 mg/dL.
In these patients with atherosclerotic CVD on maximum-dose atorvastatin therapy with or without ezetimibe, the difference between REPATHA 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was -54 % (95% CI: -65%, -42%; p ˂ 0.0001) (Table 4 and Figure 2). For additional results see Table 4.
Table 4. Effect of REPATHA on Lipid Parameters in Patients with Atherosclerotic CVD on Atorvastatin 80 mg with or without Ezetimibe 10 mg daily (Mean % Change from Baseline to Week 52 in Study 2) 

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo once monthly (n = 44)	2	3	0	3
REPATHA 420 mg once monthly (n = 95)	-52	-41	-40	-28
Mean difference from placebo (95% CI)	-54 (-65, -42)	-44 (-56, -32)	-40 (-50, -30)	-31 (-39, -24)

Estimates based on a multiple imputation model that accounts for treatment adherence
Figure 2. Effect of REPATHA 420 mg Once Monthly on LDL-C in Patients with Atherosclerotic CVD on
Atorvastatin 80 mg with or without Ezetimibe 10 mg Daily
Estimates based on a multiple imputation model that accounts for treatment adherence
Error bars indicate 95% confidence intervals
14.2  Heterozygous Familial Hypercholesterolemia (HeFH) 
Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies. Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome criteria (1991). In Study 3, 38% of patients had clinical atherosclerotic cardiovascular disease. The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were ≥ 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black. The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high-intensity statin therapy.
In these patients with HeFH on statins with or without other lipid lowering therapies, the differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (95% CI: -67%, -55%; p < 0.0001) and -60% (95% CI: -68%, -52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 5.
Table 5. Effect of REPATHA on Lipid Parameters in Patients with HeFH (Mean % Change from Baseline to Week 12 in Study 3) 

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo every 2 weeks (n = 54)	-1	-1	-1	-2
REPATHA 140 mg every 2 weeks† (n = 110)	-62	-56	-49	-42
Mean difference from placebo 95% CI	-61 (-67, -55)	-54 (-60, -49)	-49 (-54, -43)	-40 (-45, -36)
Placebo once monthly (n = 55)	4	4	4	2
REPATHA 420 mg once monthly† (n = 110)	-56	-49	-44	-37
Mean difference from placebo 95% CI	-60 (-68, -52)	-53 (-60, -46)	-48 (-55, -41)	-39 (-45, -33)

Estimates based on a multiple imputation model that accounts for treatment adherence
†140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C
14.3 Homozygous Familial Hypercholesterolemia (HoFH)
Study 4 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hypercholesterolemia (HoFH). In this trial, 33 patients received subcutaneous injections of 420 mg of REPATHA once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other. The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received REPATHA. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents.
In these patients with HoFH, the difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -31% (95% CI: -44%, -18%; p < 0.0001). For additional results see Table 6.
Patients known to have two LDL-receptor negative alleles (little to no residual function) did not respond to REPATHA.
Table 6. Effect of REPATHA on Lipid Parameters in Patients with HoFH (Mean % Change from Baseline to Week 12 in Study 4) 

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo once monthly (n = 16)	9	8	4	8
REPATHA 420 mg once monthly (n = 33)	-22	-20	-17	-17
Mean difference from placebo 95% CI	-31 (-44, -18)	-28 (-41, -16)	-21 (-33, -9)	-25 (-36, -14)

Estimates based on a multiple imputation model that accounts for treatment adherence
16 HOW SUPPLIED/STORAGE AND HANDLING
REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution for subcutaneous injection supplied in a single-use prefilled syringe or a single-use prefilled SureClick® autoinjector. Each single-use prefilled syringe or single-use prefilled SureClick® autoinjector of REPATHA is designed to deliver 1 mL of 140 mg/mL solution.

140 mg/mL single-use prefilled syringe	1 pack	NDC 55513-750-01
140 mg/mL single-use prefilled SureClick® autoinjector	1 pack	NDC 55513-760-01
140 mg/mL single-use prefilled SureClick® autoinjector	2 pack	NDC 55513-760-02
140 mg/mL single-use prefilled SureClick® autoinjector	3 pack	NDC 55513-760-03

Pharmacy
Store refrigerated at 2° to 8°C (36° to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
For Patients/Caregivers
Store refrigerated at 2° to 8°C (36° to 46°F) in the original carton. Alternatively, REPATHA can be kept at room temperature (up to 25°C (77°F)) in the original carton; however, under these conditions, REPATHA must be used within 30 days. If not used within the 30 days, discard REPATHA.
Protect REPATHA from direct light and do not expose to temperatures above 25°C (77°F).
17 PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling [Patient Information and Instructions for Use (IFU)] before the patient starts using REPATHA, and each time the patient gets a refill as there may be new information they need to know.
Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the single-use prefilled autoinjector or single-use prefilled syringe correctly (see Instructions for Use leaflet). Inform patients that it may take up to 15 seconds to inject REPATHA.
Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the glass prefilled syringe and the autoinjector.
For more information about REPATHA, go to www.REPATHA.com or call 1-844-REPATHA (1-844-737-2842).
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=709338ae-ab8f-44a9-b7d5-abaabec3493a