Introduction
Repatha® (evolocumab) is a fully human monoclonal antibody developed by Amgen Inc. that represents a significant advancement in lipid management therapy. As a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Repatha provides a novel approach to lowering low-density lipoprotein cholesterol (LDL-C) levels in patients who require additional lipid reduction beyond what can be achieved with maximally tolerated statin therapy.
Mechanism of Action
Repatha binds selectively and with high affinity to PCSK9, inhibiting its interaction with the low-density lipoprotein receptor (LDL-R). PCSK9 normally promotes degradation of LDL-R in hepatocytes. By inhibiting PCSK9, Repatha increases the number of LDL-R available on hepatocyte surfaces to clear LDL-C from the blood, resulting in significantly reduced circulating LDL-C levels. This mechanism is independent of and complementary to statin therapy, which works primarily by upregulating LDL-R expression.
Indications
- Primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) as an adjunct to diet and maximally tolerated statin therapy
- Homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering therapies
- Established cardiovascular disease to reduce risk of myocardial infarction, stroke, and coronary revascularization
- Primary prevention of cardiovascular events in adults with HeFH or clinical atherosclerotic cardiovascular disease
Dosage and Administration
Standard dosing:- 140 mg subcutaneously every 2 weeks OR
- 420 mg subcutaneously once monthly (three consecutive injections of 140 mg each)
- Administer subcutaneously in the thigh, abdomen, or upper arm
- Rotate injection sites
- Allow prefilled syringe or autoinjector to reach room temperature for 30 minutes before administration
- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: No dosage adjustment necessary
- Pediatric patients: Safety and effectiveness established for HeFH patients aged 10 years and older
- Geriatric patients: No dosage adjustment necessary
Pharmacokinetics
Absorption: Bioavailability is approximately 72% following subcutaneous administration. Maximum serum concentration reached in 3-4 days. Distribution: Steady-state volume of distribution is approximately 3.0-3.5 L. Minimal distribution beyond vascular space. Metabolism: Degraded via proteolytic enzymes into small peptides and amino acids. Not metabolized by cytochrome P450 enzymes. Elimination: Elimination half-life is approximately 11-17 days. Clearance occurs primarily via proteolytic catabolism.Contraindications
- History of serious hypersensitivity reaction to evolocumab or any component of the formulation
- Active hepatic disease (including unexplained persistent elevations in hepatic transaminases)
Warnings and Precautions
Hypersensitivity reactions: Serious reactions including angioedema have been reported. Discontinue treatment if serious hypersensitivity occurs. Hepatic effects: Monitor liver enzymes before initiation and periodically during treatment. Adverse cardiovascular effects: Although Repatha reduces cardiovascular events, monitor patients for potential cardiovascular changes. Injection site reactions: Erythema, pain, and bruising may occur. Rotate injection sites and proper technique can minimize reactions. Fetal risk: Based on animal data, may cause fetal harm. Use during pregnancy only if potential benefit justifies potential risk.Drug Interactions
No clinically significant pharmacokinetic interactions have been observed with:- Statins (atorvastatin, simvastatin, rosuvastatin)
- Ezetimibe
- Fenofibrate
- Warfarin
- Oral contraceptives
Adverse Effects
Common adverse reactions (≥2%):- Nasopharyngitis (6.1%)
- Upper respiratory tract infection (4.2%)
- Influenza (3.7%)
- Injection site reactions (3.1%)
- Back pain (2.9%)
- Allergic reactions (2.1%)
- Hypersensitivity reactions (<0.1%)
- Neurocognitive events (rare)
Monitoring Parameters
- LDL-C levels: Baseline and 4-8 weeks after initiation or dosage change
- Liver function tests: Baseline and periodically
- Creatine kinase: If muscle symptoms occur
- Cardiovascular status: Regular assessment
- Injection sites: For reactions and proper rotation
- Allergic reactions: Especially during initial treatment
Patient Education
- Instruct on proper injection technique using provided training materials
- Explain importance of continued dietary and lifestyle modifications
- Emphasize adherence to prescribed dosing schedule
- Teach recognition and reporting of injection site reactions
- Advise to report any symptoms of allergic reactions immediately
- Inform about potential flu-like symptoms during initial treatment
- Stress importance of regular follow-up and laboratory monitoring
- Discuss pregnancy planning and contraception requirements
References
1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. 2. Repatha® (evolocumab) prescribing information. Amgen Inc.; 2021. 3. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. 4. Stroes ES, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548. 5. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-340. 6. FDA-approved labeling for Repatha (evolocumab). U.S. Food and Drug Administration.