Clinical Policy: Evolocumab (Repatha) Form

Page 1 of 15 Clinical Policy: Evolocumab (Repatha) Reference Number: CP.PHAR.123 Effective Date: 10.01.15 Last Review Date: 02.26 Line of Business: Medicaid Coding Implications Revision Log

See Important Reminder at the end of this policy for important regulatory and legal information.

Description
Evolocumab (Repatha®) is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor antibody.

FDA Approved Indication(s) Repatha is indicated: • To reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults at increased risk for these events • As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in: o Adults with hypercholesterolemia o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH) o Adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH)

Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.

It is the policy of health plans affiliated with Centene Corporation® that Repatha is medically necessary when the following criteria are met:

I. Initial Approval Criteria
A. Primary Hypercholesterolemia (including HeFH) and Cardiovascular Event Risk Reduction (must meet all):

1. Diagnosis of one of the following (a, b, or c): a. HeFH, and both of the following (i and ii): i. Baseline LDL-C (prior to any lipid-lowering pharmacologic therapy) was one of the following (1 or 2): 1) If age < 20 years: ≥ 160 mg/dL; 2) If age ≥ 20 years: ≥ 190 mg/dL; ii. HeFH diagnosis is confirmed by one of the following (1 or 2): 1) World Health Organization (WHO)/Dutch Lipid Network familial hypercholesterolemia diagnostic criteria score of > 8 as determined by requesting provider (see Appendix D);
   2) Definite diagnosis per Simon Broome criteria (see Appendix D);

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Page 2 of 15 b. Primary hypercholesterolemia that is not HeFH, and both of the following (i and ii): i. Documentation of one of the following (1 or 2): 1) Presence of a genetically mediated form of primary hypercholesterolemia as evidenced by confirmatory genetic testing results; 2) A diagnosis of secondary hypercholesterolemia has been ruled out with absence of all of the following potential causes of elevated cholesterol (a - f):
a) Poor diet; b) Hypothyroidism; c) Obstructive liver disease; d) Renal disease; e) Nephrosis; f) Medications that have had a clinically relevant contributory effect on the current degree of the member’s elevated lipid levels including, but not limited to: glucocorticoids, sex hormones, antipsychotics, antiretrovirals, immunosuppressive agents, retinoic acid derivatives; ii. Baseline LDL-C (prior to any lipid-lowering pharmacologic therapy) was ≥ 190 mg/dL; c. Increased risk for CV events as evidenced by a history of atherosclerotic cardiovascular disease (ASCVD) including any one of the following conditions (i- vii): i. Acute coronary syndromes; ii. Clinically significant coronary heart disease (CHD) diagnosed by invasive or noninvasive testing (such as coronary angiography, stress test using treadmill, stress echocardiography, or nuclear imaging); iii. Coronary or other arterial revascularization;
iv. Myocardial infarction; v. Peripheral arterial disease presumed to be of atherosclerotic origin; vi. Stable or unstable angina; vii. Stroke or transient ischemic attack (TIA);

2. Prescribed by or in consultation with a cardiologist, endocrinologist, or lipid specialist;
3. Age is one of the following (a or b): a. If diagnosis is primary hypercholesterolemia (not including HeFH) or ASCVD: ≥ 18 years; b. If diagnosis is HeFH: ≥ 10 years;
4. For members ≥ 18 years old and on statin therapy, both of the following (a and b):
   a. Repatha is prescribed in conjunction with a statin at the maximally tolerated dose; b. Member has been adherent for at least the last 8 weeks to maximally tolerated doses of one of the following statin regimens (i or ii): i. A high intensity statin (see Appendix E); ii. A moderate or low intensity statin (see Appendix E), and member has one of the following (1 or 2): 1) Previous use of one high-intensity statin (i.e., atorvastatin ≥ 40 mg daily; rosuvastatin ≥ 20 mg daily [as a single-entity or as a combination

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Page 3 of 15 product]) for a minimum of 8 weeks continuously and LDL-C remained ≥ 70 mg/dL; 2) Member has tried both rosuvastatin and atorvastatin and has experienced skeletal-muscle related symptoms on both agents which also resolved upon discontinuation;

5. For members ≥ 18 years old and not on statin therapy, member meets one of the following (a or b): a. Statin therapy is contraindicated per Appendix F; b. For members who are statin intolerant, both of the following (i and ii): i. Member has tried at least two statins, one of which must be hydrophilic (pravastatin, fluvastatin, or rosuvastatin); ii. Member meets one of the following (1 or 2): 1) Member has documented statin risk factors (see Appendix G); 2) Member is statin intolerant due to statin-associated muscle symptoms (SAMS) and meets both of the following (a and b): a) Documentation of intolerable SAMS persisting at least two weeks, which disappeared with discontinuing the statin therapy and recurred with a statin re-challenge; b) Documentation of re-challenge with titration from lowest possible dose and/or intermittent dosing frequency (e.g., 1 to 3 times weekly);
6. Documentation of recent (within the last 60 days) LDL-C of one of the following (a or b): a. If member has ASCVD (i or ii): i. ≥ 70 mg/dL; ii. ≥ 55 mg/dL, and member is at very high risk (see Appendix I); b. If member has severe primary hypercholesterolemia (including HeFH): ≥ 100 mg/dL;
7. Treatment plan does not include coadministration with Leqvio®, Juxtapid® or Praluent®;

8. Dose does not exceed one of the following (a or b):
   a. 140 mg every 2 weeks;
   b. 420 mg per month. Approval duration: 12 months

   Approval duration: 12 months

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C. Other diagnoses/indications (must meet 1 or 2):

1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.PMN.16 for Medicaid; or

2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.PMN.53 for Medicaid.

   Approval duration: 12 months

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Page 6 of 15 B. Other diagnoses/indications (1 or 2):

1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.PMN.16 for Medicaid; or

2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.PMN.53 for Medicaid.

   III. Diagnoses/Indications for which coverage is NOT authorized:
   A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.PMN.53 for Medicaid or evidence of coverage documents.

   IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALT: alanine transaminase apo B: apolipoprotein B ASCVD: atherosclerotic cardiovascular disease CHD: coronary heart disease CV: cardiovascular FDA: Food and Drug Administration FH: familial hypercholesterolemia HeFH: heterozygous familial hypercholesterolemia HoFH: homozygous familial hypercholesterolemia LDL-C: low density lipoprotein cholesterol LDLR: low density lipoprotein receptor LDLRAP1: low density lipoprotein receptor adaptor protein 1 PCSK9: proprotein convertase subtilisin kexin 9
   SAMS: statin-associated muscle symptoms TIA: transient ischemic attack WHO: World Health Organization

   Appendix B: Therapeutic Alternatives
   This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
   Drug Name Dosing Regimen Dose Limit/ Maximum Dose atorvastatin (Lipitor®) 40 mg PO QD 80 mg/day rosuvastatin (Crestor®) 5 - 40 mg PO QD 40 mg/day pravastatin 10 - 80 mg PO QD 80 mg/day fluvastatin (Lescol®) 20 - 80 mg PO QD 80 mg/day Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic.

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Page 7 of 15 Appendix C: Contraindications/Boxed Warnings
• Contraindication(s): hypersensitivity • Boxed warning(s): none reported

Appendix D: Criteria for Diagnosis of HeFH
• Dutch Lipid Clinic Network criteria for Familial Hypercholesterolemia (FH) FH Criteria Points Member’s Score† Family History First-degree relative with known premature coronary and vascular disease
1 Place highest score here
(0, 1 or 2) First-degree relative with known LDL-C level above the 95th percentile 1 First-degree relative with tendinous xanthomata and/or arcus cornealis 2 Children aged < 18 years with LDL-C level above the 95th percentile 2 Clinical History Patient with premature coronary artery disease 2 Place highest score here
(0, 1 or 2) Patient with premature* cerebral or peripheral vascular disease 1 Physical Examination Tendinous xanthomata 6 Place highest score here (0, 4 or 6) Arcus cornealis prior to age 45 years 4 Cholesterol Levels - mg/dL (mmol/liter) LDL-C ≥ 330 mg/dL (≥ 8.5) 8 Place highest score here (0, 1, 3, 5 or 8) LDL-C 250 – 329 mg/dL (6.5 – 8.4) 5 LDL-C 190 – 249 mg/dL (5.0 – 6.4) 3 LDL-C 155 – 189 mg/dL (4.0 – 4.9) 1 DNA Analysis Functional mutation in the LDLR, apo B or PCSK9 gene 8 Place score here (0 or 8) TOTAL SCORE

Definite FH: > 8 Place total score here __ *Premature – men < 55 years or women < 60 years †Choose the highest score from each of the five categories and then add together for a total score. The five categories are 1) Family History, 2) Clinical History, 3) Physical Examination, 4) Cholesterol Levels, and 5) DNA Analysis.

• Simon Broome Register Group Definition of Definite FH (meets 1 and 2):

1. One of the following (a or b): a. Total cholesterol level above 7.5 mmol/l (290 mg/dl) in adults or a total cholesterol level above 6.7 mmol/l (260 mg/dl) for children under 16 b. LDL levels above 4.9 mmol/l (190 mg/dl) in adults (4.0 mmol/l in children) (either pre-treatment or highest on treatment)

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2. One of the following (a or b): a. Tendinous xanthomas in patient or relative (parent, child, sibling, grandparent, aunt, uncle) b. DNA-based evidence of an LDL receptor mutation or familial defective apo B- 100

   High Intensity Statin Therapy
   Daily dose shown to lower LDL-C, on average, by approximately ≥ 50% • Atorvastatin 40-80 mg Appendix E: High and Moderate Intensity Daily Statin Therapy for Adults • Rosuvastatin 20-40 mg

   Moderate Intensity Statin Therapy Daily dose shown to lower LDL-C, on average, by approximately 30% to 50% • Atorvastatin 10-20 mg • Fluvastatin XL 80 mg • Fluvastatin 40 mg BID • Lovastatin 40 mg • Pitavastatin 1-4 mg • Pravastatin 40-80 mg • Rosuvastatin 5-10 mg • Simvastatin 20-40 mg

   Low Intensity Statin Therapy Daily dose shown to lower LDL-C, on average, by < 30% • Simvastatin 10 mg • Pravastatin 10-20 mg • Lovastatin 20 mg • Fluvastatin 20-40 mg Appendix F: Statin Contraindications Statins • Decompensated liver disease (development of jaundice, ascites, variceal bleeding, encephalopathy) • Laboratory-confirmed acute liver injury or rhabdomyolysis resulting from statin treatment • Pregnancy, actively trying to become pregnant, or nursing • Immune-mediated hypersensitivity to the HMG-CoA reductase inhibitor drug class (statins) as evidenced by an allergic reaction occurring with at least TWO different statins In July 2021, the FDA requested removal of the contraindication against use of statins in pregnant women. Because the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients, contraindicating these drugs in all pregnant women is not appropriate.
   https://www.fda.gov/safety/medical-product-safety-information/statins-drug-safety-communication-fda- requests-removal-strongest-warning-against-using-cholesterol

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Page 9 of 15 Appendix G: Statin Risk Factors Statin Risk Factors • Multiple or serious comorbidities, including impaired renal or hepatic function • Unexplained alanine transaminase (ALT) elevations > 3 times upper limit of normal, or active liver disease • Concomitant use of drugs adversely affecting statin metabolism
• Age > 75 years, or history of hemorrhagic stroke • Asian ancestry

Appendix H: General Information • FDA Endocrinologic and Metabolic Drugs Advisory Committee briefing documents for another PCSK-9 inhibitor, Praluent, discuss the questionable determination of statin intolerance, stating: “many patients who are not able to take statins are not truly intolerant of the pharmacological class.”
• Patients should remain on concomitant therapy with a statin if tolerated due to the established long term cardiovascular benefits. • Examples of genetically mediated primary hypercholesterolemia include but are not limited to the following: o Familial hypercholesterolemia o Familial combined hyperlipidemia (FCHL) o Polygenic hypercholesterolemia o Familial dysbetalipoproteinemia • The diagnosis of SAMS is often on the basis of clinical criteria. Typical SAMS include muscle pain and aching (myalgia), cramps, and weakness. Symptoms are usually bilateral and involve large muscle groups, including the thigh, buttock, back, and shoulder girdle musculature. In contrast, cramping is usually unilateral and may involve small muscles of the hands and feet. Symptoms may be more frequent in physically active patients. Symptoms often appear early after starting stain therapy or after an increase in dose and usually resolve or start to dissipate within weeks after cessation of therapy, although it may take several months for symptoms to totally resolve. Persistence of symptoms for more than 2 months after drug cessation should prompt a search for other causes or for underlying muscle disease possibly provoked by statin therapy. The reappearance of symptoms with statin rechallenge and their disappearance with drug cessation offers the best evidence that the symptoms are truly SAMS. • Pravastatin, fluvastatin, and rosuvastatin are hydrophilic statins which have been reported to confer fewer adverse drug reactions than lipophilic statins.

Appendix I: Criteria for Defining Patients at Very High Risk of Future ASCVD Events2 Very high risk is defined as having either a history of multiple major ASCVD events OR 1 major ASCVD event and multiple high-risk conditions: • Major ASCVD events: o Recent acute coronary syndrome (within the past 12 months) o History of myocardial infarction (other than recent acute coronary syndrome event listed above) o History of ischemic stroke

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Page 10 of 15 o Symptomatic peripheral artery disease (history of claudication with ankle-brachial index < 0.85 or previous revascularization or amputation) • High-risk conditions: o Age ≥ 65 years o HeFH o History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s) o Diabetes o Hypertension o Chronic kidney disease (estimated glomerular filtration rate [eGFR] 15-59 mL/min/1.73 m2) o Current tobacco smoking o Persistently elevated LDL-C (LDL-C ≥ 100 mg/dL [≥ 2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe o History of congestive heart failure

V. Dosage and Administration
Indication Dosing Regimen Maximum Dose Primary hypercholesterolemia (including HeFH) or hypercholesterolemia with increased risk for CV events 140 mg SC Q2 weeks or 420 mg SC once monthly 420 mg/month
HoFH 420 mg SC once monthly; Dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule 420 mg/2 weeks

VI. Product Availability
• Prefilled syringe and SureClick autoinjector (not made with latex): 140 mg/mL • Prefilled syringe and SureClick autoinjector (contains dry natural rubber): 140 mg/mL • Prefilled cartridge Pushtronex system (on-body infusor): 420 mg/3.5 mL