Evolocumab
1. Drug Name
Generic Name: Evolocumab
Brand Name: Repatha
2. Drug Classification
Class: Antihyperlipidemic agent
Subclass: PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) inhibitor
3. Mechanism of Action
PCSK9 Inhibition: Evolocumab is a fully human monoclonal antibody targeting PCSK9, a protein involved in the regulation of LDL receptors on liver cells. By binding to PCSK9, evolocumab prevents it from degrading LDL receptors, thereby increasing the availability of these receptors to clear LDL cholesterol (LDL-C) from the blood.
Impact on Lipid Levels: Results in significant reduction of LDL cholesterol, as well as moderate reductions in total cholesterol, ApoB, and non-HDL cholesterol, with no significant effect on HDL or triglyceride levels.
4. Pharmacokinetics
Absorption:
Bioavailability: Approximately 72% following subcutaneous administration.
Time to Peak: Maximum serum concentration reached in 3-4 days.
Distribution:
Volume of Distribution (Vd): Approximately 3.3 liters.
Protein Binding: Primarily binds to target PCSK9.
Metabolism:
Degraded through nonspecific catabolic pathways as a monoclonal antibody.
Excretion:
Half-Life: Around 11-17 days.
Special Populations:
No significant pharmacokinetic changes observed with mild-to-moderate renal or hepatic impairment.
5. Indications
Primary Indications:
Atherosclerotic Cardiovascular Disease (ASCVD): As an adjunct to diet and maximally tolerated statin therapy for adults with established ASCVD requiring additional LDL-C reduction.
Heterozygous Familial Hypercholesterolemia (HeFH): Adjunct therapy for patients who are not adequately controlled with other lipid-lowering therapies.
Homozygous Familial Hypercholesterolemia (HoFH): Indicated as an adjunct to other lipid-lowering therapies for patients with HoFH.
Off-Label Uses: May be used for severe hypercholesterolemia in statin-intolerant patients.
6. Dosage and Administration
Adults:
Standard Dosing: 140 mg subcutaneously every two weeks or 420 mg once monthly, based on patient needs.
Administration: Subcutaneous injection, commonly in the thigh, abdomen, or upper arm.
Renal/Hepatic Impairment: No specific dose adjustments recommended.
7. Contraindications
Absolute Contraindications:
Known hypersensitivity to evolocumab or any component of the formulation.
Relative Contraindications:
Caution in severe hepatic impairment due to limited safety data.
8. Warnings and Precautions
Hypersensitivity Reactions: May include rash, pruritus, and in rare cases, severe allergic reactions.
Immunogenicity: Some patients may develop anti-evolocumab antibodies; however, this does not appear to affect clinical efficacy.
Neurocognitive Effects: Small risk of cognitive side effects such as confusion and memory issues in patients on PCSK9 inhibitors; monitor if neurocognitive symptoms arise.
9. Adverse Effects
Common:
Injection Site Reactions: Pain, redness, itching, or swelling.
Respiratory Tract Symptoms: Nasopharyngitis, upper respiratory infections.
Less Common but Significant:
Hypersensitivity: Rash, urticaria, or more severe hypersensitivity in some cases.
Serious Adverse Effects:
Neurocognitive Side Effects: Rare cases of cognitive impairment (e.g., memory loss, confusion).
10. Drug Interactions
Statins and Other Lipid-Lowering Agents: Commonly co-administered, and no adverse interactions have been noted.
CYP450: No metabolism via CYP450 enzymes, reducing the likelihood of drug-drug interactions.
11. Clinical Pharmacology
Pharmacodynamics: Evolocumab increases hepatic LDL receptors and enhances LDL clearance, contributing to significant LDL-C reduction. Reductions in total cholesterol, non-HDL cholesterol, and apolipoprotein B have also been observed.
Effect on Cardiovascular Outcomes: Shown to reduce major cardiovascular events in high-risk populations with established ASCVD.
12. Special Populations
Pregnancy: Category B; insufficient data to establish safety, so use only if clearly needed.
Lactation: Unknown if excreted in human milk; caution advised.
Pediatrics: Safety and efficacy for pediatric use established for patients aged 10 years and older in familial hypercholesterolemia.
Geriatrics: No dosage adjustment required.
Renal and Hepatic Impairment: Generally well-tolerated, but caution with severe hepatic impairment.
13. Therapeutic Uses
Lipid-Lowering Therapy: For patients with severe hypercholesterolemia or those intolerant to statins or insufficiently managed with statins alone.
ASCVD Risk Reduction: Shown to reduce the risk of cardiovascular events in patients with ASCVD who require additional LDL-C lowering beyond standard therapy.
Familial Hypercholesterolemia: Specifically beneficial for heterozygous and homozygous familial hypercholesterolemia populations.
14. Monitoring and Follow-Up
Lipid Profile Monitoring: Assess LDL-C levels every 4-6 weeks after initiation or dosage adjustment, then every 6-12 months.
Adverse Effect Monitoring: Observe for hypersensitivity reactions and monitor neurocognitive symptoms if they arise.
Liver Function: Although no routine monitoring is mandated, baseline liver function tests are recommended if concomitant hepatic stressors are present.
15. Overdose Management
Symptoms: No specific overdose symptoms reported due to high therapeutic index.
Management: Supportive care; monitor for adverse effects, particularly hypersensitivity reactions, and manage symptomatically.
16. Patient Counseling Information
Administration Instructions: Instruct patients on proper injection technique and rotating injection sites to avoid irritation.
Potential Side Effects: Inform patients of possible local site reactions and mild flu-like symptoms.
Storage: Store in the refrigerator; can be kept at room temperature for up to 30 days if needed.
Regular Monitoring: Stress the importance of regular follow-up for lipid profile assessments and adherence to treatment.