PCSK9 Agents Drug Class Prior Authorization Protocol Line of Business: Medicaid P & T Approval Date: February 21, 2018 Effective Date: April 1, 2018 This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutics Subcommittee. Drug Requiring Prior Authorization Review: Praluent (alirocumab), Repatha (evolocumab) Formulary Alternative: atorvastatin, ezetimibe Criteria: A. Drug: Praluent 1. Diagnosis: Heterozygous Familial Hypercholesterolemia Criteria: Must meet all of the following requirements: a. Familial hypercholesterolemia (FH) as established by 1 of the following: i. Presence of a mutation in LDLR, apolipoprotein B (ApoB), PCSK9, or ARH adaptor protein (LDLRAP1) gene. ii. Pre-treatment LDL level greater than 190 mg per dl or total cholesterol greater than 290 mg per dl in an adult or pre-treatment LDL level greater than 155 mg per dl or total cholesterol greater than 250 mg per dl in a child and tendo xanthomas in patient or a first-orsecond-degree relative. b. Medical record documentation (e.g. laboratory test results, chart notes) indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of highintensity statin therapy and will continue to receive high-intensity statin therapy (e.g. atorvastatin 40 mg or higher, rosuvastatin 20 mg or higher) at the maximally tolerated dose. ii. Patient has been adherent for 3 months (90 consecutive days) of the maximally tolerated statin therapy (e.g. atorvastatin, lovastatin,
iii. iv. pravastatin, rosuvastatin, or simvastatin at any dose) and will continue to receive the maximally tolerated dose and patient is unable to tolerate high-intensity statin as evidenced by myalgia (muscle symptoms without CK elevations) or myositis (muscle symptoms with CK elevations less than 10 times ULN). Patient has a labeled contraindication to all statins as documented in medical records. Patient has experienced rhabdomyolysis or muscle symptoms with CK elevations greater than or equal to 10 times ULN. c. Documentation indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of Zetia concurrently with the statin. ii. Patient has a labeled contraindication or intolerance to Zetia. d. Documentation indicating 1 of the following treated LDL levels while on a lipid lowering therapy, dated within the last month (30 days): i. LDL greater than or equal to 100 mg per dl with ASCVD. ii. LDL greater than or equal to 130 mg per dl without ASCVD. e. Not used in combination with another proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Juxtapid or Kynamro. Specialist: Cardiologist, Endocrinologist or Lipid Specialist Quantity Limit: N/A Duration of Therapy: 6 months (180 days) Reauthorization Criteria: Must meet all of the following requirements: a. Patient is adherent to therapy since the initial authorization. b. Patient continues concurrent use of the high-intensity statin or the statin at the maximally tolerated dose, unless documentation of the inability to take statins is provided. c. Documentation of LDL reduction while on Praluent/Repatha therapy. Duration of Reauthorization: 6 months (180 days) 2. Diagnosis: Clinical Atherosclerotic Cardiovascular Disease Criteria: Must meet all of the following requirements: a. Documentation of 1 of the following: i. Acute Coronary Syndromes. ii. History of Myocardial Infarction (MI) iii. Stable or unstable Angina iv. Coronary or other Arterial Revascularization v. Stroke vi. Transient Ischemic Attack (TIA) vii. Peripheral Arterial Disease presumed to be of Atherosclerotic origin
b. Medical record documentation (e.g. laboratory test results, chart notes) indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of highintensity statin therapy and will continue to receive high-intensity statin therapy (e.g. atorvastatin 40 mg or higher, rosuvastatin 20 mg or higher) at the maximally tolerated dose. ii. Patient has been adherent for 3 months (90 consecutive days) of the maximally tolerated statin therapy (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin at any dose) and will continue to receive the maximally tolerated dose and patient is unable to tolerate high-intensity statin as evidenced by myalgia (muscle symptoms without CK elevations) or myositis (muscle symptoms with CK elevations less than 10 times ULN). iii. Patient has a labeled contraindication to all statins as documented in iv. medical records. Patient has experienced rhabdomyolysis or muscle symptoms with CK elevations greater than or equal to 10 times ULN. c. Documentation indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of Zetia concurrently with the statin. ii. Patient has a labeled contraindication or intolerance to Zetia. d. Documentation indicating 1 of the following treated LDL levels while on a lipid lowering therapy, dated within the last month (30 days): i. LDL greater than or equal to 100 mg per dl with ASCVD. ii. LDL greater than or equal to 130 mg per dl without ASCVD. e. Not used in combination with another proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitor, Juxtapid or Kynamro. Specialist: Cardiologist, Endocrinologist or Lipid Specialist Quantity Limit: N/A Duration of Therapy: 6 months (180 days) Reauthorization Criteria: Must meet all of the following requirements: a. Patient is adherent to therapy since the initial authorization. b. Patient continues concurrent use of the high-intensity statin or the statin at the maximally tolerated dose, unless documentation of the inability to take statins is provided. c. Documentation of LDL reduction while on Praluent/Repatha therapy. Duration of Reauthorization: 6 months (180 days) B. Drug: Repatha
1. Diagnosis: Homozygous Familial Hypercholesterolemia and Heterozygous Familial Hypercholesterolemia. Criteria: Must all of the following requirements: a. Presence of a mutation in LDLR, apolipoprotein B (ApoB), PCSK9, or ARH adaptor protein (LDLRAP1) gene. i. Pre-treatment LDL level greater than 190 mg pr dl or total cholesterol greater than 290 mg per dl in an adult or pre-treatment LDL level greater than 155 mg dl or total cholesterol greater than 250 mg dl in a child and tendo xanthomas in patient or a first-or-second-degree relative. b. Medical record documentation (e.g. laboratory test results, chart notes) indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of highintensity statin therapy and will continue to receive high-intensity statin therapy (e.g. atorvastatin 40 mg or higher, rosuvastatin 20 mg or higher) at the maximally tolerated dose. ii. Patient has been adherent for 3 months (90 consecutive days) of the maximally tolerated statin therapy (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin at any dose) and will continue to receive the maximally tolerated dose and patient is unable to tolerate high-intensity statin as evidenced by myalgia (muscle symptoms without CK elevations) or myositis (muscle symptoms with CK elevations less than 10 times ULN). iii. Patient has a labeled contraindication to all statins as documented in iv. medical records. Patient has experienced rhabdomyolysis or muscle symptoms with CK elevations greater than or equal to 10 times ULN. c. Documentation indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of Zetia concurrently with the statin. ii. Patient has a labeled contraindication or intolerance to Zetia. d. Documentation indicating 1 of the following treated LDL levels while on a lipid lowering therapy, dated within the last month (30 days): i. LDL greater than or equal to 100 mg per dl with ASCVD. ii. LDL greater than or equal to 130 mg per dl without ASCVD. e. Not used in combination with another proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Juxtapid or Kynamro. Specialist: Cardiologist, Endocrinologist or Lipid Specialist Quantity Limit: N/A Duration of Therapy: 6 months (180 days) Reauthorization Criteria: Must meet all of the following requirements:
a. Patient is adherent to therapy since the initial authorization. b. Patient continues concurrent use of the high-intensity statin or the statin at the maximally tolerate dose, unless documentation of the inability to take statins is provided. c. Documentation of LDL reduction while on Praluent/Repatha therapy. Duration of Reauthorization: 6 months (180 days) 2. Diagnosis: Clinical Atherosclerotic Cardiovascular Disease Criteria: Must meet all of the following requirements: a. Documentation of 1 of the following: i. Acute Coronary Syndromes ii. History of Myocardial Infarction (MI) iii. Stable or unstable Angina iv. Coronary or other Arterial Revascularization v. Stroke. vi. Transient Ischemic Attack (TIA) vii. Peripheral Arterial Disease presumed to be of Atherosclerotic origin b. Medical record documentation (e.g. laboratory test results, chart notes) indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of highintensity statin therapy and will continue to receive high-intensity statin therapy (e.g. atorvastatin 40 mg or higher, rosuvastatin 20 mg or higher) at the maximally tolerated dose. ii. Patient has been adherent for 3 months (90 consecutive days) of the maximally tolerated statin therapy (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin at any dose) and will continue to receive the maximally tolerated dose and patient is unable to tolerate high-intensity statin as evidenced by myalgia (muscle symptoms without CK elevations) or myositis (muscle symptoms with CK elevations less than 10 times ULN). iii. Patient has a labeled contraindication to all statins as documented in iv. medical records. Patient has experienced rhabdomyolysis or muscle symptoms with CK elevations greater than or equal to 10 times ULN. c. Documentation indicating 1 of the following: i. Patient has been adherent for 3 months (90 consecutive days) of Zetia concurrently with the statin. ii. Patient has a labeled contraindication or intolerance to Zetia. d. Documentation indicating 1 of the following: i. LDL greater than or equal to 100 mg per dl with ASCVD. ii. LDL greater than or equal to 130 mg per dl without ASCVD. e. Not used in combination with another proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Juxtapid or Kynamro.
Specialist: Cardiologist, Endocrinologist or Lipid Specialist Quantity Limit: N/A Duration of Therapy: 6 months (180 days) Reauthorization Criteria: Must meet all of the following requirements: a. Patient is adherent to therapy since the initial authorization. b. Patient continues concurrent use of the high-intensity statin or the statin at the maximally tolerated dose, unless documentation of the inability to take statins is provided. c. Documentation of LDL reduction while on Praluent/Repatha therapy. Duration of Reauthorization: 6 months (180 days)
Clinical Justification: Simon-Broom Diagnostic Criteria Comparison of FDA-Approved Indications Heterozygous familial hypercholesterolemia in adults on maximally tolerated statin therapy who requires additional lowering of LDL. Adjunct to diet modification. Clinical atherosclerotic cardiovascular disease in adults on maximally tolerated statin therapy who requires additional lowering of LDL. Adjunct to diet modification. Homozygous familial hypercholesterolemia in adults on other LDL-lowering therapies who require additional lowering of LDL. Adjunct to diet modification. Praluent (alirocumab) X X Repatha (evolocumab) X X X 2017 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease For individuals at low risk (i.e., with no risk factors), an LDL-C goal <130 mg/dl is recommended.
For individuals at moderate risk (i.e., with 2or fewer risk factors and a calculated 10-year risk of less than 10%), an LDL-C goal <100 mg/dl is recommended. For individuals at high risk (i.e., with an ASCVD equivalent including diabetes or stage 3 or 4 CKD with no other risk factors, or individuals with 2 or more risk factors and a 10- year risk of 10%-20%), an LDL-C goal <100 mg/dl is recommended. For individuals at very high risk (i.e., with established or recent hospitalization for acute coronary syndrome (ACS); coronary, carotid or peripheral vascular disease; diabetes or stage 3 or 4 CKD with 1or more risk factors; a calculated 10-year risk greater than 20%; or heterozygous familial hypercholesterolemia [HeFH]), an LDL-C goal <70 mg/dl is recommended. For individuals at extreme risk (i.e., with progressive ASCVD, including unstable angina that persists after achieving an LDL-C <70 mg/dl, or established clinical ASCVD in individuals with diabetes, stage 3 or 4 CKD, and/or HeFH, or in individuals with a history of premature ASCVD (<55 years of age for males or <65 years of age for females), an LDL-C goal <55 mg/dl is recommended. Atherosclerotic Cardiovascular Disease Risk Categories and LDL-C Treatment Goals 2013 American College of Cardiology/American Heart Association Task Force Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
The Expert Panel makes no recommendation for or against specific LDL or non-hdl targets for the primary or secondary prevention of atherosclerotic cardiovascular disease (ASCVD) due to the absence of data on titration of drug therapy to specific goals. Secondary Prevention: High-intensity statin therapy should be initiated or continued as first-line therapy in women and men 75 years of age who have clinical ASCVD, unless contraindicated. Primary Prevention: High-intensity statin therapies are recommended for the following groups with risk 1) Individuals 21 years of age with LDL 190mg/dL; 2) Individuals 40-75 years of age with diabetes, LDL 70-189 mg/dl and 7.5% estimated 10-year ASCVD risk; 3) Individuals 40-75 years of age with LDL 70-189 mg/dl without clinical ASCVD or diabetes, and with an estimated 10-year ASCVD risk 7.5%. o Moderate-intensity statin therapy for the following groups with risk 1) Individuals 40-75 years of age with diabetes and LDL 70-189mg/dL; 2) Individuals 40-75 years of age, with LDL 70-189 mg/dl without clinical ASCVD or diabetes, and with an estimated 10-year ASCVD risk of 5% to <7.5%; 3) Individuals 40-75 years of age with LDL 70-189 mg/dl without clinical ASCVD or diabetes, and with an estimated 10-year ASCVD risk 7.5% High-risk patients who have a suboptimal response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a non-statin therapy. Intensity of Statin Therapy High-Intensity Statin Therapy Lowers LDL 50% Atorvastatin 40-80mg Rosuvastatin 20-40mg Moderate-Intensity Statin Therapy Lowers LDL by 30-50% Atorvastatin 10-20mg Rosuvastatin 5-10mg Simvastatin 20-40mg Pravastatin 40-80mg Lovastatin 40mg Fluvastatin 80mg Pitavastatin 2-4mg Low-Intensity Statin Therapy Lowers LDL by <30% Simvastatin 10mg Pravastatin 10-20mg Lovastatin 20mg Fluvastatin 20-40mg Pitavastatin 1mg National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) 2001
Definition of Statin Intolerance, International Lipid Expert Panel 2015 Inability to tolerate at least 2 statins, with at least one started at the lowest starting daily dose. Statin dose reduction is attempted for symptom and biomarker abnormality resolution, rather than discontinuation of statin therapy altogether. Intolerable symptoms or abnormal biomarker changes are reversible upon statin discontinuation, but reproducible by re-challenge of statins; if clinically appropriate. Symptoms or biomarker abnormalities are not attributable to established predispositions such as drug-drug interactions and conditions recognized to increase the risk of statin intolerance such as: hypothyroidism, concurrent illness, significant changes in physical activity/exercise and/or underlying muscle disease. Clinical Studies for Praluent: ODYSSEY Program The efficacy of Praluent was evaluated in five double-blind placebo-controlled studies that enrolled 3499 patients, consisted of 36% patients with heterozygous familial hypercholesterolemia (HeFH) and 54% non-fh with clinical atherosclerotic cardiovascular disease. All patients enrolled were receiving a maximally tolerated statin dose. The Praluent study group received 75mg every 2 weeks followed by criteria-based up-titration to 150mg every 2 weeks at week 12 for patients with suboptimal response. The primary efficacy endpoint, mean percent change in LDL, was measured at week 24. In Study 1 and Study 2, which enrolled both non-fh patients with clinical atherosclerotic cardiovascular disease and HeFH patients, the overall average baseline LDL was 112 mg/dl. At week 24, the treatment differences between Praluent and placebo in mean LDL percentage change were -58% (p <0.0001), and -43% (p <0.0001), respectively.
In Study 3, 4 and 5, which exclusively included HeFH patients with overall mean baseline LDL of 170 mg/dl, at week 24, the treatment differences between Praluent and placebo in mean LCL percentage change were -54% (p <0.0001), and -43% (p <0.0001). In the ODYSSEY LONG TERM trial, a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL of 70 mg/dl or more and were receiving maximum tolerated statin dose, the Praluent group had a lower rate of post hoc cardiovascular events (1.7% vs. 3.3%, HR 0.52, CI 0.31-0.90). Adverse effects were similar between Praluent and placebo group (81% vs. 82.5%), as were serious adverse events (18.7% vs. 19.5%). Clinical Studies for Repatha: FOURIER, LAPLACE-2, RUTHERFORD-2, OSLER-1 & OSLER-2 In the FOURIER double-blind, randomized, placebo-controlled trial, 24,564 patients with established cardiovascular disease with LDL-C 70 mg/dl and/or non-hdl-c 100 mg/dl despite high- or moderate-intensity statin therapy received either subcutaneous Repatha (140 mg ever 2 weeks or 420 mg once monthly) or placebo. Most patients were on a high- (69%) or moderate-intensity (30%) statin at baseline, and 5% were also taking ezetimibe. The mean LDL- C at baseline was 98 mg/dl. Repatha significantly reduced the risk for the primary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; p < 0.0001). The difference between the Repatha group and placebo in mean percentage change in LDL-C at week 12 was - 63% (95% CI: -63%,-62%); and at week 72 was -57% (95% CI: -58%,-56%). At week 48, the median LDL-C was 26 mg/dl in the Repatha group. In the LAPLACE-2 multicenter, double-blind, randomized controlled trial, 296 patients with atherosclerotic cardiovascular disease received an open label statin regimen and a 4-week lipid stabilization followed by random assignment to subcutaneous Repatha 140mg every 2 weeks, Repatha 420mg once monthly or placebo for 12 weeks. The mean baseline LDL after 4 weeks of maximum-dose statin therapy was 108 mg/dl. The difference between Repatha group and placebo in mean percentage change in LDL at week 12 was -71% (p< 0.0001) and -63% (p< 0.0001) for the 140mg every 2 weeks and 420 mg once monthly dosages, respectively. In the RUTHERFORD-2 multicenter, double-blind, randomized placebo-controlled, 12 weektrial, 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid lowering therapies were randomized to receive subcutaneous Repatha 140mg every 2 weeks, 420mg once monthly or placebo. The average baseline LDL was 156 mg/dl with 76% of patients on high-intensity statin therapy. The differences between Repatha and placebo in mean percent change in LDL at week 12 was -61% (p< 0.0001) and -60% (p< 0.0001) for the 140mg every 2 weeks and 420mg once monthly, respectively. In two open-label, randomized trials, OSLER-1 and OSLER-2, 4465 patients who had completed one of twelve phase 2 or phase 3 trials were randomly assigned to Repatha, either 140mg every 2
weeks or 420mg monthly plus standard therapy, or standard therapy alone. The study population included those on statin therapy (70%), high-intensity statin therapy (27%), as well as those who were statin-intolerant or who were on no other lipid lowering therapy. The median duration of follow-up was 11.1 months. In contrast to the standard therapy alone, the Repatha study group reduced the LDL by 61% (p< 0.001) from a median of LDL 120mg/dL to 48 mg/dl. The rate of cardiovascular events at 1 year including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack and heart failure, was reduced from 2.18% on standard therapy alone to 0.95% (p= 0.003, HR 0.47). The risk of adverse events were similar in both groups (69% vs. 64%) as were serious adverse events (7.5% in each group). References: 1.Sabatine MS, Giugliano RP, et al. N Engl J Med. 2015;372(16):1500. 2. Banach M, Rizzo M, Toth PP, et al. Statin intolerance an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015; 11(1):1-23. 3. Robinson JG, Farnier M, et al. N Engl J Med. 2015;372(16):1489. 4. Stone NJ, Robinson JG, Lichtenstein AH, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 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. Circulation. 2014; 129(25 Suppl 2):S1- S45. 5. Praluent [Product Information], Tarrytown, NY. Regeneron Pharmaceuticals, Inc. September 2017. 6. Repatha [Product Information], Thousand Oaks, CA. Amgen Pharmaceuticals, Inc. December 2017. 7. ATP III Final Report PDF. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation. 2002;106:3143-3421. 8. http://nlaresourcecenter.lipidjournal.com/content/pdfs/tables/4.pdf 9. http://www.ncbi.nlm.nih.gov/books/nbk53810 10. http://nlaresourcecenter.lipidjournal.com/content/pdfs/tables/3.pdf 11. NORD Guides for Physicians. The Physician s Guide to Homozygous Familial Hypercholesterolemia (HoFH): nordphysicianguides.org/homozygous-familialhypercholesterolemia. 12. Cuchel et al. Homozygous familial hypercholesterolemia: new insights and guidance for clinicians to improve detection and clinical management. European Heart Journal: June 2014. 13. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for the management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017; 23:1-87. 14. Lloyd-jones DM, Morris PB, Ballantyne CM, et al. 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL- Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease
Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017; 1. 2013. 2. Savaysa [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2017. 3. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. Change Control Date Change 02/21/2018 Added quantity limit Updated guidance of 2017 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease