Evolocumab (Monograph)

Brand name: Repatha
Drug class: Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Inhibitors
Chemical name: Immunoglobulin G, anti-(human neural apoptosis-regulated proteinase 1) (human monoclonal heavy chain), disulfide with human monoclonal light chain, dimer
Molecular formula: C₆₂₄₂H₉₆₄₈N₁₆₆₈O₁₉₉₆S₅₆
CAS number: 1256937-27-5

Medically reviewed by Drugs.com on Jan 16, 2023. Written by ASHP.

Introduction

Antilipemic agent; fully human IgG₂ monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9).

Uses for Evolocumab

Prevention of Cardiovascular Events

Used for secondary prevention to reduce risk of MI, stroke, and coronary revascularization in adults with established cardiovascular disease.

Has been shown to substantially reduce the risk of cardiovascular events when added to hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (i.e., statin)-based antilipemic therapy in high-risk patients with clinical atherosclerotic cardiovascular disease (ASCVD).

AHA/ACC cholesterol management guideline states that lifestyle modification is the foundation of ASCVD risk reduction. If pharmacologic therapy is needed, statins are first-line drugs of choice. Certain patient groups may benefit from the addition of a nonstatin drug such as a PCSK9 inhibitor if maximally tolerated statin therapy is insufficient to achieve goal reductions in LDL cholesterol concentrations. Patients who are intolerant of at least 2 statin therapies with one attempt using the lowest approved daily dosage may also be considered for treatment with nonstatin drugs.

Primary Hyperlipidemia

Used alone or in combination with other LDL-cholesterol lowering therapies as an adjunct to diet in adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) to reduce LDL-cholesterol concentrations.

Further reduces LDL-cholesterol concentrations by approximately 50–60% or more when added to maximally tolerated statin therapy or when used as monotherapy.

Current treatments for patients with HeFH include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation), first-line treatment with statins, and, if necessary, combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran). According to ACC, patients without clinical ASCVD with baseline LDL cholesterol concentrations greater than 190 mg/dL not due to secondary causes may be considered for ezetimibe and/or a PCSK9 inhibitor if they have not met certain thresholds of LDL cholesterol reduction on maximally tolerated statin therapy.

Homozygous Familial Hypercholesterolemia

Adjunct to other LDL-cholesterol lowering therapies in adults and pediatric patients ≥10 years of age with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-cholesterol concentrations. Designated an orphan drug by FDA for this use.

Further reduces LDL-cholesterol concentrations by approximately 30% when used adjunctively with other antilipemic agents.

Current treatments for patients with HoFH and clinical ASCVD include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation) and maximally tolerated dosages of statins. In patients with HoFH and ASCVD who do not achieve target reductions in LDL cholesterol with maximally tolerated doses of statins alone, ezetimibe and/or a PCSK9 inhibitor should be considered; other nonstatin options (e.g., bempedoic acid, inclisiran, evinacumab, lomitapide) may be considered if LDL cholesterol remains uncontrolled.

Evolocumab Dosage and Administration

General

Patient Monitoring

Assess LDL-cholesterol concentrations as clinically appropriate. LDL-cholesterol lowering effect may be measured as early as 4 weeks after initiating treatment. In patients receiving evolocumab 420 mg once monthly, LDL-cholesterol concentrations can vary during the dosing interval in some patients; measure LDL-cholesterol just prior to next scheduled dose.

Other General Considerations

Periodically reinforce adherence to lifestyle modifications. Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modifications that reduce the risk of ASCVD.

Administration

Sub-Q Administration

Administer sub-Q every 2 weeks or once monthly.

Commercially available as a prefilled manual syringe, prefilled auto-injector, and single-dose on-body infusor pump with prefilled cartridge.

A monthly dose of 420 mg can be administered using the on-body infusor with prefilled cartridge or by consecutively administering 3 prefilled syringes or auto-injectors within 30 minutes. Consider patient preference for dosing frequency and injection volume when determining method of administration.

Injection using a prefilled syringe or auto-injector may take up to 15 seconds to complete; injection using the on-body infusor with prefilled cartridge takes about 5 minutes to complete.

Instruct patients on proper techniques for self-administration using prefilled syringe or auto-injector or on-body infusor with prefilled cartridge. If on-body infusor with prefilled cartridge is used in pediatric patients, adult supervision is necessary.

Prior to administration, allow prefilled syringes and auto-injectors to warm to room temperature for ≥30 minutes, and on-body infusor with prefilled cartridges to warm to room temperature for ≥45 minutes.

Inject into abdomen (except for 2-inch area around navel), thigh, or upper arm; rotate injection sites. Do not administer into areas that are tender, bruised, erythematous, or indurated, or that have scars or stretch marks. Securely attach the on-body infusor with prefilled cartridge to a clean, firm, and flat skin surface that is less likely to have body hair or on which body hair can be trimmed; do not use on areas with wrinkles, skin folds, moles, or excessive hair.

Do not administer with other drugs at the same injection site.

If a dose is missed, administer as soon as possible within 7 days. If a dose is missed in a patient receiving the every-2-week regimen and the missed dose is not administered within 7 days, withhold dose and administer next dose at regularly scheduled time. If a dose is missed in a patient receiving the once-monthly regimen and the missed dose is not administered within 7 days, administer a dose and initiate a new dosing schedule starting on that date.

Contains no preservatives; for single use only.

Dosage

Pediatric Patients

Dyslipidemias

Heterozygous Familial Hypercholesterolemia

Sub-Q

Pediatric patients ≥10 years of age: 140 mg every 2 weeks or 420 mg once monthly (administered using on-body infusor with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).

When switching between the every-2-week and once-monthly dosage regimens, administer first dose of new regimen on the date of the next scheduled dose of previous regimen.

Homozygous Familial Hypercholesterolemia

Sub-Q

Pediatric patients ≥10 years of age: 420 mg once monthly (administered using on-body infusor with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes). Dosage may be increased to 420 mg every 2 weeks if clinically meaningful response not achieved within 12 weeks.

Adults

Prevention of Cardiovascular Events

Secondary Prevention in Adults with Established Cardiovascular Disease

Sub-Q

140 mg every 2 weeks or 420 mg once monthly (administered using on-body infusor with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).

When switching between the every-2-week and once-monthly dosage regimens, administer first dose of new regimen on the date of the next scheduled dose of previous regimen.

Dyslipidemias

Primary Hyperlipidemia (including Heterozygous Familial Hypercholesterolemia)

Sub-Q

140 mg every 2 weeks or 420 mg once monthly (administered using on-body infusor with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).

When switching between the every-2-week and once-monthly dosage regimens, administer first dose of new regimen on the date of the next scheduled dose of previous regimen.

Homozygous Familial Hypercholesterolemia

Sub-Q

420 mg once monthly (administered using on-body infusor with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).

Dosage may be increased to 420 mg every 2 weeks if clinically meaningful response not achieved within 12 weeks.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment: Data are lacking.

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

No specific dosage recommendations.

Other Special Populations

Dosage adjustments based on age, body weight, gender, or race not required.

Cautions for Evolocumab

Contraindications

History of serious hypersensitivity reaction to evolocumab or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., angioedema, rash, eczema, erythema, urticaria) reported, sometimes requiring discontinuance of therapy.

If manifestations of serious allergic reactions occur, discontinue drug and initiate standard of care treatment. Monitor patient until signs and symptoms resolve.

Latex Sensitivity

Some packaging components (i.e., needle covers of prefilled syringes and auto-injectors) contain natural latex proteins in the form of dry natural rubber (latex), and should not be handled by individuals sensitive to latex. The single-dose on-body infusor with prefilled cartridge is not made with natural rubber latex.

Immunogenicity

Development of non-neutralizing antibodies to evolocumab reported in adults but not in pediatric patients.

Specific Populations

Pregnancy

Insufficient data on evolocumab use in pregnant women to evaluate potential risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Adverse developmental effects not observed in animal studies; however, suppression of humoral immune response observed in infant monkeys exposed in utero to another PCSK9 inhibitor.

Pregnancy safety study at 800-772-6436 or [Web].

Lactation

Not known whether distributed into human milk. Human IgG is distributed into human milk; however, published data suggest that IgG antibodies present in human milk are not substantially distributed into the circulation of neonates and infants.

Weigh known benefits of breastfeeding against potential adverse effects of the drug on the infant, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy not established in pediatric patients with types of hyperlipidemia other than homozygous familial hypercholesterolemia or heterozygous familial hypercholesterolemia.

Safety and efficacy not established in children <10 years of age with homozygous familial hypercholesterolemia or heterozygous familial hypercholesterolemia.

Geriatric Use

No overall differences in efficacy or safety relative to younger adults; however, possibility of increased sensitivity cannot be ruled out.

Hepatic Impairment

Decreased plasma concentrations in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); however, not clinically important.

Safety and efficacy not established in patients with severe hepatic impairment.

Renal Impairment

Renal function not expected to affect pharmacokinetics of evolocumab.

Common Adverse Effects

Adverse effects (reported in >5% of adults with primary hyperlipidemia): Nasopharyngitis, upper respiratory tract infection, influenza, back pain, injection site reactions (e.g., erythema, pain, bruising).

Adverse effects (reported in >5% of adults with established cardiovascular disease): Diabetes mellitus, nasopharyngitis, upper respiratory tract infection.

Drug Interactions

Specific Drugs

Drug	Interaction	Comments
HMG-CoA reductase inhibitors (statins)	Decreased peak plasma concentration and AUC of evolocumab by approximately 20%; however, not considered clinically important

Evolocumab Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 72% after sub-Q injection.

Onset

Following sub-Q administration, maximal suppression of free PCSK9 occurs within 4 hours.

Maximum LDL-cholesterol reduction occurred by 2 weeks after a single 140-mg dose and by 3 weeks after a single 420-mg dose.

Plasma Concentrations

Peak plasma concentrations achieved in approximately 3–4 days following single sub-Q dose.

Following multiple dosing, accumulation ratio is approximately two- to threefold; steady-state serum trough concentrations achieved by 12 weeks.

Special Populations

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), peak plasma concentrations and systemic exposure reduced by approximately 20–30 and 40–50%, respectively.

In patients with severe renal impairment (i.e., eGFR <30 mL/minute per 1.73 m²) or end-stage renal disease (ESRD) receiving hemodialysis, exposure decreased; however, reductions in PCSK9 concentrations in such patients were similar to those in patients with normal renal function (i.e., eGFR ≥90 mL/minute per 1.73 m²).

Exposure decreases with increasing body weight, but not considered clinically important.

Distribution

Extent

Crosses the placenta.

Not known whether distributed into milk.

Elimination

Elimination Route

Concentration-dependent. At low concentrations, occurs principally through saturable binding to the PCSK9 target; at high concentrations, occurs principally through a nonsaturable proteolytic pathway.

Half-life

Approximately 11–17 days.

Stability

Storage

Parenteral

Solution for Injection

2–8°C. Store in original carton to protect from light. Do not shake, freeze, or expose to direct sunlight.

May store prefilled syringes and auto-injectors and on-body infusors with prefilled cartridges at room temperature (20–25°C) in original carton, but must use within 30 days if stored under these conditions. Discard drug if not used within 30 days.

Actions

Fully human IgG₂ monoclonal antibody that binds to human PCSK9. Produced in genetically engineered mammalian (Chinese hamster ovary) cells.
PCSK9 is a serine protease produced principally in the liver. Major function of PCSK9 is to promote degradation of LDL receptors, the primary receptors responsible for clearing circulating LDL cholesterol.
Evolocumab binds specifically and with high affinity to PCSK9; inhibition of PCSK9 increases number of receptors available to clear LDL cholesterol, and consequently reduces plasma concentrations of LDL cholesterol.
Reductions in lipoprotein (a), apolipoprotein B, and other lipid fractions also demonstrated.
In patients with homozygous familial hypercholesterolemia, severity of mutation and corresponding residual LDL-receptor activity affects response to evolocumab therapy. Patients with 2 receptor-defective mutations (corresponding to relatively functional LDL-receptor activity) appear to derive the greatest benefit, patients with one negative mutation (corresponding to very little or no LDL-receptor activity) and one defective mutation have a lesser response; those with 2 receptor-negative mutations are not expected to respond at all.

Advice to Patients

Importance of reading manufacturer’s patient information and instructions for use prior to starting therapy and each time the prescription is refilled.
Importance of discontinuing evolocumab and promptly seeking medical attention if any signs or symptoms of serious hypersensitivity (e.g., severe pruritus, rash, or redness; swollen face; difficulty breathing) occur.
Importance of instructing patients and/or caregivers on the preparation and sub-Q administration of evolocumab, including use of the prefilled syringes and auto-injectors and on-body infusors with prefilled cartridges. Importance of informing patients that injection of evolocumab using the prefilled syringe or auto-injector may take up to 15 seconds to complete, and that injection of the drug using on-body infusor with prefilled cartridge takes about 5 minutes to complete. Importance of informing patients that adult supervision is necessary if the on-body infusor is used in pediatric patients.
Importance of patients informing their clinician if they have an allergy to latex.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of encouraging women who become pregnant while receiving evolocumab to participate in the pregnancy safety study. (See Pregnancy under Cautions.)
Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Evolocumab
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	140 mg/mL	Repatha (available as single-dose prefilled syringes and auto-injectors)	Amgen
		420 mg/3.5 mL	Repatha (available as single-dose Pushtronex system consisting of on-body infusor with prefilled cartridge)	Amgen