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Mechanism of Action
US Drug Names
General Dosing Information
140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the previous regimen.
420 mg subcutaneously once monthly. Increase to 420 mg subcutaneously every 2 weeks if a clinically meaningful response is not attained in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule; administer after the apheresis session is complete.
420 mg/dose subcutaneously once monthly for most indications or every 2 weeks for homozygous familial hypercholesterolemia (HoFH).
420 mg/dose subcutaneously once monthly for heterozygous familial hypercholesterolemia (HeFH) or every 2 weeks for homozygous familial hypercholesterolemia (HoFH).
10 to 12 years: 420 mg/dose subcutaneously once monthly for heterozygous familial hypercholesterolemia (HeFH) or every 2 weeks for homozygous familial hypercholesterolemia (HoFH).
1 to 9 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
No dosage adjustment is needed for mild to moderate hepatic impairment (Child-Pugh A or B). Specific guidelines for dosage adjustments in severe hepatic impairment are not available.
No dosage adjustment is needed for mild to moderate renal impairment. Specific guidelines for dosage adjustments in severe renal impairment are not available.
Evolocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor indicated as an add-on treatment to reduce low density lipoprotein cholesterol (LDL-C) in adult patients with primary hyperlipidemia and patients 10 years and older with heterozygous or homozygous familial hypercholesterolemia. Evolocumab also is indicated to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease. During various clinical trials, evolocumab produced negative mean differences from placebo from baseline in LDL-C ranging from 31% to 71%. Evolocumab is recommended as second-line therapy in addition to maximally tolerated statin therapy in patients with clinical atherosclerotic cardiovascular disease (ASCVD) and comorbidities that still require 25% or greater LDL-C reduction. Factors to consider include cost, benefit of ASCVD risk reduction, dosing frequency requirements, and administration by subcutaneous injection.
For storage information, see the specific product information within the How Supplied section.
Single-use prefilled syringe administration
Single-use SureClick autoinjector administration
Single-use on-body infusor with prefilled cartridge (Pushtronex system) administration
Naso-pharyngitis (4% to 12%), upper respiratory tract infection (2.1% to 9.3%), influenza (1.2% to 9.1%), cough (1.2% to 4.5%), urinary tract infection (1.3% to 4.5%), and sinusitis (4.2%) were reported in evolocumab-treated patients during clinical trials. Influenza-like illness has been reported with postmarketing use of evolocumab.
Hypersensitivity reactions were reported in 5.1% of patients receiving evolocumab during clinical trials. The most common reactions included rash (1%), eczema (0.4%), erythema (0.4%), and urticaria (0.4%). Angioedema has been reported with postmarketing use. If signs or symptoms of serious hypersensitivity reactions or anaphylaxis occur, discontinue evolocumab treatment, treat with standard of care, and monitor until symptoms resolve.
Diarrhea (3%), gastroenteritis (3% to 6.1%), and nausea (1.8%) were reported in evolocumab-treated patients during clinical trials. Oropharyngeal pain was reported in 7% of pediatric patients.
Back pain (2.3% to 6.2%), arthralgia (1.8%), myalgia (4%), muscle spasms (1.3%), musculoskeletal pain (3.3%), fatigue (1.6%), and contusion (1%) were reported in evolocumab-treated patients during clinical trials.
Injection site reaction including erythema, pain, and bruising was reported in 3.2% of evolocumab-treated patients during clinical trials.
Hypertension (3.2%), headache (4%), and dizziness (3.7%) were reported in evolocumab-treated patients during clinical trials. Headache was reported in 11% of pediatric patients.
Antibody formation may occur with evolocumab. In a pool of placebo- and active-controlled clinical trials, 0.3% of adult patients treated with at least 1 dose of evolocumab tested positive for binding antibody development. Patients who tested positive for binding antibodies were tested for neutralizing antibodies, and none of the patients were positive for neutralizing antibodies. The development of anti-evolocumab antibodies was not detected in pediatric clinical trials. There is no evidence that the presence of anti-drug antibodies impacts the pharmacokinetics, clinical response, or safety of evolocumab.
During the cardiovascular outcomes trial, hyperglycemia (reported as diabetes mellitus) was reported in 8.8% of the patients receiving evolocumab compared to 8.2% placebo. The incidence of new-onset diabetes mellitus during the trial was 8.1% in those receiving evolocumab compared to 7.7% of those receiving placebo.
Evolocumab is contraindicated in patients with a history of a serious evolocumab hypersensitivity reaction. Hypersensitivity reactions, including angioedema, rash, and urticaria, have been reported during treatment with evolocumab. Some hypersensitivity reactions resulted in discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue evolocumab, provide appropriate care, and monitor until signs and symptoms resolve.
The needle cover of the glass prefilled syringe and the autoinjector contain dry natural rubber (a derivative of latex), which may cause an allergic reaction in individuals with latex hypersensitivity.
Available data from clinical trials and postmarketing reports on the use of evolocumab in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No effects on pregnancy or neonatal or infant development were observed when monkeys were given evolocumab from organogenesis through parturition at dose exposures up to 12 times the maximum recommended human dose. Measurable evolocumab serum concentrations were observed in infant monkeys at birth at comparable concentrations in maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier. Monoclonal antibodies are transported across the placenta in increasing amounts especially near term; therefore, there is a potential for evolocumab to be transmitted from mother to the developing fetus. Before administering evolocumab to a pregnant woman, consider the benefits and risks of treatment to the mother and the possible risks to the fetus. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to evolocumab; information about the registry can be obtained at mothertobaby.org-ongoinf-study/repatha or by calling 1-800-772-6436.
According to the manufacturer, there is no information on evolocumab presence in human milk, effects on milk production, or effects on the breastfed infant. Human IgG is present in human milk, but data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.
The Pushtronex system, a single-use on-body infuser for evolocumab should not be exposed to a Magnetic Resonance environment, such as magnetic resonance imaging (MRI).
Evolocumab is a human monoclonal IgG2 antibody that binds to and inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) binding to low-density lipoprotein receptors (LDLR). PCSK9 binds to LDLR on the hepatocyte surface to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL; with evolocumab inhibiting the binding of PCSK9 to LDLR, the number of LDLRs available to clear LDL increases, thereby lowering LDL-C concentrations.
Evolocumab is administered subcutaneously. At low concentrations, evolocumab is eliminated primarily via saturable binding to proprotein convertase subtilisin/kexin type 9 (PCSK9). At higher concentrations, evolocumab is eliminated mainly through a non-saturable proteolytic pathway. The estimated effective half-life of evolocumab is 11 to 17 days. Maximum LDL-C reduction occurred 2 weeks after a single dose of 140 mg and 3 weeks after a single dose of 420 mg.
Affected cytochrome P450 isoenzymes and drug transporters: none
The median time to maximum serum evolocumab concentration (Tmax) after administration of single doses of 140 mg or 420 mg is 3 to 4 days. Maximum suppression of free circulating PCSK9 occurs within 4 hours after a single subcutaneous dose of evolocumab 140 mg or 420 mg and returns to baseline once evolocumab concentrations are undetectable. Evolocumab exhibits non-linear pharmacokinetics. An approximate 2- to 3-fold accumulation is observed in trough serum concentrations after 140 mg doses administered every 2 weeks or 420 mg doses administered monthly. Steady state is reached within 12 weeks of dosing. The absolute bioavailability after subcutaneous administration is 72%.
The mean maximum serum concentration (Cmax) and mean AUC are lower (20 to 30% and 40 to 50%, respectively) in patients with mild and moderate hepatic impairment. Evolocumab has not been studied in patients with severe hepatic impairment.
Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab.
Children and Adolescents 10 to 17 years
Mean trough serum concentrations of evolocumab were 22.4 mcg/mL and 25.8 mcg/mL over Week 12 and Week 24 time points, respectively, during clinical trials in 103 pediatric patients with heterozygous familial hypercholesteremia (HeFH).
Mean trough serum concentrations of evolocumab were 20.3 mcg/mL and 17.6 mcg/mL over Week 12 and Week 80 time points, respectively, during clinical trials in 12 pediatric patients with homozygous familial hypercholesteremia (HoFH).
Age was not shown to have an effect on the pharmacokinetics of evolocumab.
Gender was not shown to have an effect on the pharmacokinetics of evolocumab.
Race was not shown to have an effect on the pharmacokinetics of evolocumab.
Evolocumab exposure has been found to decrease with increasing body weight; however, these differences are not clinically meaningful.
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