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
Antilipemic agent; fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9).1 3 6 7 10 11 12 19 34
Uses for Evolocumab
Adjunct to diet and maximally tolerated hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (i.e., statin) therapy in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-cholesterol concentrations.1 2 19
Further reduces LDL concentrations by approximately 50–60% or more when added to maximally tolerated statin therapy; however, effects on cardiovascular morbidity and mortality have not been established.1 4 18 19 22 23 26 32 34
Homozygous Familial Hypercholesterolemia
Adjunct to diet and other LDL-cholesterol lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia who require additional lowering of LDL-cholesterol concentrations.1 3 10 Designated an orphan drug by FDA for this use.9
Further reduces LDL concentrations by approximately 30% when used adjunctively with other antilipemic agents; however, effects on cardiovascular morbidity and mortality have not been established.1 3
Appears to be more effective in patients with relatively functional residual LDL-receptor activity.1 3 10 18 (See Actions.)
Evolocumab Dosage and Administration
Administer by sub-Q injection.1 Injection may take up to 15 seconds to complete.1
Instruct patients on proper techniques for self-administration using prefilled syringe or auto-injector provided by manufacturer.1 13 15 16 (See Advice to Patients.)
Prior to administration, allow prefilled syringes and auto-injectors to warm to room temperature for ≥30 minutes.1
Inject into abdomen (except for 2-inch area around navel), thigh, or upper arm; rotate injection sites.1 15 16 Do not administer into areas that are tender, bruised, erythematous, or indurated, or that have scars or stretch marks.1 15 16
Do not administer with other drugs at the same injection site.1
If a dose is missed, administer as soon as possible if more than 7 days left until next scheduled dose.1 Otherwise, skip missed dose and resume regular dosing schedule.1 34
Contains no preservatives; for single use only.1
Homozygous Familial HypercholesterolemiaSub-Q
Adolescents ≥13 years of age: 420 mg (administered as 3 consecutive 140-mg injections within 30 minutes) once monthly.1 13
Monitor serum LDL-cholesterol concentrations 4–8 weeks after initiation of therapy to assess response to drug.1
Primary Hypercholesterolemia in Patients with Heterozygous Familial Hypercholesterolemia or ASCVDSub-Q
140 mg every 2 weeks or 420 mg (administered as 3 consecutive 140-mg injections within 30 minutes) once monthly.1
Homozygous Familial HypercholesterolemiaSub-Q
420 mg (administered as 3 consecutive 140-mg injections within 30 minutes) once monthly.1
Monitor serum LDL-cholesterol concentrations 4–8 weeks after initiation of therapy to assess response to drug.1
Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.1
Severe hepatic impairment: Data are lacking.1
Mild or moderate renal impairment: No dosage adjustment necessary.1
Severe renal impairment: Data are lacking.1
No specific dosage recommendations.1
Other Special Populations
Dosage adjustments based on age, body weight, gender, or race not required.1
Cautions for Evolocumab
History of serious hypersensitivity reaction to evolocumab.1 (See Hypersensitivity under Cautions.)
Hypersensitivity reactions (e.g., rash, eczema, erythema, urticaria) reported.1
If manifestations occur, discontinue drug and initiate appropriate treatment.1 Monitor patient until resolution occurs.1
Some packaging components (i.e., needle covers and needle caps 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.1 27 28 29
Development of non-neutralizing antibodies to evolocumab reported.1 Long-term effects of continued therapy in the presence of such antibodies not known.1
No adequate and well-controlled studies of evolocumab in pregnant women.1 Weigh potential benefits versus possible risk to fetus.1
Adverse developmental effects not observed in animal studies with evolocumab; however, suppression of humoral immune response observed in infant monkeys exposed in utero to another PCSK9 inhibitor.1
Not known whether distributed into human milk.1 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.1
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.1
Safety and efficacy not established in pediatric patients with heterozygous familial hypercholesterolemia or ASCVD.1
Safety and efficacy not established in children <13 years of age with homozygous familial hypercholesterolemia.1
No overall differences in efficacy or safety relative to younger adults; however, possibility of increased sensitivity cannot be ruled out.1
Decreased plasma concentrations in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); however, not clinically important.1 17 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)
Safety and efficacy not established in patients with severe hepatic impairment.1
Renal function not expected to affect pharmacokinetics of evolocumab.1 (See Renal Impairment under Dosage and Administration.)
Safety and efficacy not established in patients with severe renal impairment (i.e., estimated GFR <30 mL/minute per 1.73 m2).1
Common Adverse Effects
Nasopharyngitis,1 2 3 upper respiratory tract infection,1 3 influenza,1 3 back pain,1 2 injection site reactions (e.g., erythema, pain, bruising),1 cough,1 urinary tract infection,1 sinusitis,1 headache,1 2 myalgia,1 dizziness,1 musculoskeletal pain,1 3 hypertension,1 diarrhea,1 gastroenteritis.1 3
Very low levels of LDL cholesterol (e.g., <25 mg/dL) occurred in clinical studies.1 32 33 34 Although adverse consequences were not identified, long-term effects not known.1 18 34
Interactions for Evolocumab
HMG-CoA reductase inhibitors (statins)
Decreased peak plasma concentration and AUC of evolocumab by approximately 20%; however, not considered clinically important1
No dosage adjustment required1
Absolute bioavailability approximately 72% after sub-Q injection.1
Following sub-Q administration, maximal suppression of free PCSK9 occurs within 4 hours.1
Peak plasma concentrations achieved in approximately 3–4 days following single sub-Q dose.1 6
Following multiple dosing, accumulation ratio is approximately two- to threefold; steady-state serum trough concentrations achieved by 12 weeks.1
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.1
Exposure decreases with increasing body weight, but not considered clinically important.1
Crosses the placenta.1
Not known whether distributed into milk.1
Concentration-dependent.1 At low concentrations, occurs principally through saturable binding to the PCSK9 target; at high concentrations, occurs principally through a nonsaturable proteolytic pathway.1 10
Approximately 11–17 days.1
Solution for Injection
2–8°C.1 Store in original carton to protect from light.1 Do not shake, freeze, or expose to temperatures >25°C or direct sunlight.1 15 16
May store prefilled syringes and auto-injectors at room temperature (i.e., up to 25°C) in original carton, but must use within 30 days if stored under these conditions.1 Discard drug if not used within 30 days.1
Fully human IgG2 monoclonal antibody that binds to human PCSK9.1 3 4 6 7 10 11 12 Produced in genetically engineered mammalian (Chinese hamster ovary) cells.1
PCSK9 is a serine protease produced principally in the liver.6 7 10 11 12 Major function of PCSK9 is to promote degradation of LDL receptors, the primary receptors responsible for clearing circulating LDL cholesterol.1 17
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.1 3 6 7 10 17 19
Reductions in lipoprotein (a), apolipoprotein B, and other lipid fractions also demonstrated.1 2 3 4 32
In patients with homozygous familial hypercholesterolemia, severity of mutation and corresponding residual LDL receptor activity affects response to evolocumab therapy.1 3 10 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.1 3 10 (See Homozygous Familial Hypercholesterolemia under Uses.)
Advice to Patients
Importance of reading manufacturer’s patient information13 and instructions for use15 16 prior to starting therapy and each time the prescription is refilled.1
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.1 13 (See Hypersensitivity under Cautions.)
Importance of instructing patients and/or caregivers on the preparation and sub-Q administration of evolocumab, including use of the prefilled injection syringes and auto-injectors and proper aseptic technique.1 Importance of informing patients that injection of evolocumab may take up to 15 seconds to complete.1
Importance of patients informing their clinician if they have an allergy to latex.1
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.1 13
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 13 (See Pregnancy in Cautions.)
Importance of informing patients of other important precautionary information.1 (See Cautions.)
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.
Injection, for subcutaneous use
Repatha (available as single-use prefilled syringes and auto-injectors)
AHFS DI Essentials. © Copyright 2018, Selected Revisions June 3, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
1. Amgen Inc. Repatha (evolocumab) injection prescribing information. Thousand Oaks, CA; 2015 Sept.
2. 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; 385:331-40. [PubMed 25282519]
3. Raal FJ, Honarpour N, Blom DJ et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 385:341-50. [PubMed 25282520]
4. Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1500-9. [PubMed 25773607]
5. . Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991; 303:893-6. [PubMed 1933004]
6. Cicero AF, Colletti A, Borghi C. Profile of evolocumab and its potential in the treatment of hyperlipidemia. Drug Des Devel Ther. 2015; 9:3073-82. [PubMed 26109850]
7. Reiner Z. Management of patients with familial hypercholesterolaemia. Nat Rev Cardiol. 2015; 12:565-75. [PubMed 26076948]
8. Ito MK, McGowan MP, Moriarty PM et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5(3 Suppl):S38-45.
9. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed [2014 01 10].
10. Page MM, Watts GF. Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology. Expert Opin Drug Metab Toxicol. 2015; 11:1505-15. [PubMed 26293511]
11. Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis. 2014; 107:58-66. [PubMed 24373748]
12. Gouni-Berthold I, Berthold HK. PCSK9 antibodies for the treatment of hypercholesterolemia. Nutrients. 2014; 6:5517-33. [PubMed 25470376]
13. Amgen Inc. Repatha (evolocumab) injection patient information. Thousand Oaks, CA; 2015 Aug.
14. Marais AD, Blom DJ. Recent advances in the treatment of homozygous familial hypercholesterolaemia. Curr Opin Lipidol. 2013; 24:288-94. [PubMed 23839331]
15. Amgen Inc. Repatha (evolocumab) injection single-use prefilled SureClick autoinjector instructions for use. Thousand Oaks, CA; 2015 Aug.
16. Amgen Inc. Repatha (evolocumab) injection single-use prefilled syringe instructions for use. Thousand Oaks, CA; 2015 Aug.
17. Markham A. Evolocumab: First Global Approval. Drugs. 2015; 75:1567-73. [PubMed 26323342]
18. US Food and Drug Administration. Summary Review: BLA# 125522. From FDA website.
19. . Evolocumab (Repatha)--a second PCSK9 inhibitor to lower LDL-Cholesterol. Med Lett Drugs Ther. 2015; 57:140-1. [PubMed 26445204]
20. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011; 32:1769-818. [PubMed 21712404]
22. Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 Inhibitors--The Clinical Benefit of Lipid Drugs. N Engl J Med. 2015; 373:1588-91. [PubMed 26444323]
23. White CM. Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab. Ann Pharmacother. 2015; 49:1327-35. [PubMed 26424774]
24. Blom DJ, Hala T, Bolognese M et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014; 370:1809-19. [PubMed 24678979]
26. Doggrell SA, Lynch KA. Is there enough evidence with evolocumab and alirocumab (antibodies to proprotein convertase substilisin-kexin type, PCSK9) on cardiovascular outcomes to use them widely? Evaluation of Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-1509, and Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1488-99. Expert Opin Biol Ther. 2015; :1-5.
27. Food and Drug Administration. Natural rubber-containing medical devices; user labeling. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1997; 62:51021-30.
28. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1998; 63:50660-704.
29. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119) Fed Regist. 1996; 61:32617-21.
30. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015; 372:2387-97. [PubMed 26039521]
31. Navarese EP, Kolodziejczak M, Schulze V et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015; 163:40-51. [PubMed 25915661]
32. Reviewers' comments (personal observations) on evolocumab.
33. US Food and Drug Administration. Briefing document from the endocrinologic and metabolic drugs advisory committee. June 10, 2015. From FDA website.
34. Amgen. Thousand Oaks, CA: Personal Communication.
248. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III Report. From AHA web site.
269. Grundy SM, Cleeman JI, Bairey Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004; 110: 227-39.
350. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2889-934. [PubMed 24239923]
352. Eckel RH, Jakicic JM, Ard JD et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2960-84. [PubMed 24239922]
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- Drug class: PCSK9 inhibitors
Other brands: Repatha