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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 administration. 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. Each single-use 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.
The following adverse reactions are also discussed in other sections of the label:
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.
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† | 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; 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† (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 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%).
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.
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:
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:
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.
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.
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.
No information provided
Included as part of the PRECAUTIONS section.
Hypersensitivity reactions, including angioedema, have been reported in patients treated with REPATHA. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve. REPATHA is contraindicated in patients with a history of serious hypersensitivity reactions to evolocumab or any excipient in REPATHA [see Contraindications (4)].
The prefilled single-dose SureClick® autoinjector and prefilled single-dose syringe presentations of REPATHA that contain dry natural rubber (a derivative of latex) in the needle cover may cause an allergic reaction in individuals sensitive to latex. Instruct patients to inform their healthcare provider if they are sensitive to latex. Consider prescribing a presentation of REPATHA that does not contain dry natural rubber for individuals that are sensitive to latex [see How Supplied/Storage and Handling (16)].
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.
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.
No information provided
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)].
Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. 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.
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. Maximum LDL-C reduction occurred by 2 weeks after a single-dose of 140 mg of evolocumab and by 3 weeks after a single-dose of 420 mg of evolocumab.
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 of 18.6 µg/mL and AUClast mean of 188 day•µg/mL. Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean of 59.0 µg/mL and AUClast mean of 924 day•µg/mL. Following a single 420 mg intravenous dose, the mean systemic clearance was estimated to be 12 mL/hr. An approximate 2- to 3-fold accumulation was observed in trough serum concentrations (Cmin 7.21) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin 11.2), and serum trough concentrations approached steady-state by 12 weeks of dosing.
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%.
Following a single 420 mg intravenous dose, the mean steady-state volume of distribution was estimated to be 3.3 L.
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.
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.
Pediatric Patients
The pharmacokinetics of REPATHA were evaluated in 103 pediatric patients aged 10 to 17 years with HeFH (Study 6) [see Use in Specific Populations (8.4), and Clinical Studies (14)]. Following subcutaneous administration of 420 mg REPATHA once monthly, mean trough serum concentrations were 22.4 mcg/mL and 25.8 mcg/mL over the Week 12 and Week 24 time points, respectively. The pharmacokinetics of REPATHA were evaluated in 12 pediatric patients aged 11 to 17 years with HoFH (Study 9) [see Use in Specific Populations (8.4), and Clinical Studies (14)]. Following subcutaneous administration of 420 mg REPATHA once monthly, mean serum trough concentrations were 20.3 mcg/mL and 17.6 mcg/mL at Week 12 and Week 80, respectively.
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.
In a clinical trial of 18 patients with either normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2, n = 6), severe renal impairment (eGFR < 30 mL/min/1.73 m2, n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6), exposure to evolocumab after a single 140 mg subcutaneous dose was decreased in patients with severe renal impairment or ESRD receiving hemodialysis. Reductions in PCSK9 levels in patients with severe renal impairment or ESRD receiving hemodialysis was similar to those with normal renal function [see Use in Specific Populations (8.6)].
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 [see Use in Specific Populations (8.7)].
An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in adult patients co-administered with a high-intensity statin regimen. This difference is not clinically meaningful.
Advise the patient and/or caregiver to read the FDA-Approved Patient Labeling (Patient Information and Instructions for Use).
Inform patients that serious hypersensitivity reactions (e.g., angioedema) have been reported in patients treated with REPATHA. Advise patients on the symptoms of hypersensitivity reactions and instruct them to discontinue REPATHA and seek medical attention promptly, if such symptoms occur.
Instruct patients to inform their healthcare provider if they are sensitive to latex. Inform patients that 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, and the carton and Instructions for Use state if the product contains dry natural rubber. Advise latex-sensitive patients that the needle cover of the glass prefilled single-dose SureClick® autoinjector and prefilled single-dose syringe that contain dry natural rubber (a derivative of latex) may cause allergic reactions in individuals sensitive to latex. [see How Supplied/Storage and Handling (16)].
Advise women who are exposed to REPATHA during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Amgen at 1-800-77-AMGEN (1-800-772-6436) or https://wwwext.amgen.com/products/global-patient-safety/adverse-event-reporting [see Use in Specific Populations (8.1)].
Provide guidance to patients and caregivers on proper subcutaneous administration technique and how to use the prefilled single-dose SureClick® autoinjector, prefilled single-dose syringe, or single-dose on-body infusor with prefilled cartridge correctly. Inform patients that it may take up to 15 seconds to administer REPATHA using the prefilled single-dose SureClick® autoinjector or prefilled single-dose syringe and about 5 minutes to administer REPATHA using the single-dose on-body infusor with prefilled cartridge.
The single-dose on-body infusor with prefilled cartridge is not made with natural rubber latex.
