Juxtapid (lomitapide)

Transcription

1 Juxtapid (lomitapide) Policy Number: Last Review: 06/2018 Origination: 07/2015 Next Review: 06/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Juxtapid when it is determined to be medically necessary because the criteria listed below are met. When Policy Topic is covered Juxtapid may be considered medically necessary when used in conjunction with a low fat diet and other lipid-lowering treatments, in patients 18 years of age and older, with a diagnosis of homozygous familial hypercholesterolemia. The patient must not have moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease. 1. Homozygous Familial Hypercholesterolemia [HoFH] [Initial and Continuing Therapy]. Approve Juxtapid for 12 months if the patient meets the following criteria (A, B, C, D, and E): A) The patient is aged 18 years; AND B) The patient meets one of the following (i, ii, iii or iv): i. The patient has had genetic confirmation of two mutant alleles at the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin kexin type 9 (PCSK9) or low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene locus; OR ii. The patient has an untreated low-density lipoprotein cholesterol (LDL-C) level > 500 mg/dl (prior to treatment with antihyperlipidemic agents); OR iii. The patient has a treated LDL-C level 300 mg/dl (after treatment with antihyperlipidemic agents but prior to agents such as Repatha [evolocumab injection iv. for subcutaneous {SC} use] or Kynamro [mipomersen injection for SC use]); OR The patient has clinical manifestations of HoFH (e.g., cutaneous xanthomas, tendon xanthomas, arcus cornea, tuberous xanthomas or xanthelasma); AND C) The patient meets one of the following (i and ii): i. The patient has tried Repatha (evolocumab injection for SC use) and has had an inadequate response according to the prescribing physician; OR ii. The patient is known to have two LDL-receptor negative alleles; AND D) The patient meets one of the following criteria (i or ii): i. The patient has tried one high-intensity statin therapy (i.e., atorvastatin 40 mg daily; rosuvastatin tablets 20 mg daily [as a single-entity or as a combination product])* for 8 continuous weeks AND the LDL-C level remains 70 mg/dl; OR ii. The patient has been determined to be statin intolerant by meeting one of the following criteria (a or b): a) The patient experienced statin-related rhabdomyolysis (Note: Statin-induced muscle breakdown that is usually associated with markedly elevated creatine kinase [CK] levels [at least 10 times the upper limit of normal], along with evidence of end organ damage which can include signs of acute renal injury [noted by substantial increases in serum creatinine{scr} levels {a 0.5 mg/dl increase in Scr or doubling of the Scr}] and/or myoglobinuria [myoglobin present in urine]); OR

2 b) The patient experienced skeletal-related muscle symptoms (e.g., myopathy [muscle weakness] or myalgia [muscle aches, soreness, stiffness, or tenderness]) and meets both of the following criteria [(1) and (2)]: (1)The skeletal-related muscle symptoms (e.g., myopathy or myalgia) occurred while receiving separate trials of both atorvastatin and rosuvastatin (as single-entity or as combination products); AND (2)When receiving separate trials of both atorvastatin and rosuvastatin (as singleentity or as combination products) the skeletal-related muscle symptoms (e.g., myopathy, myalgia) resolved upon discontinuation of each respective statin therapy (atorvastatin and rosuvastatin); AND E) Juxtapid is prescribed by, or in consultation with, a cardiologist; an endocrinologist; or a physician who focuses in the treatment of cardiovascular (CV) risk management and/or lipid disorders. Juxtapid is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL-C, total-c, apolipoprotein B and non-hdl-c, in patients with HoFH.1 The effects of Juxtapid on CV morbidity and mortality have not been established.1 HoFH is a rare inherited condition in which LDL-C is not adequately removed from the body, resulting in high levels of circulating LDL-C.3-4 The 2014 HoFH position paper from the Consensus Panel on FH of the European Atherosclerosis Society states the diagnosis of HoFH is made based on genetic or clinical criteria.4 A definitive diagnosis can be made by genetic confirmation of two mutant alleles at the LDLR, APOB, PCSK9, or LDLRAP1 gene locus. However, in some patients genetic confirmation remains elusive. Historically, HoFH has been commonly diagnosed based on LDL-C levels such as an untreated LDL-C > 500 mg/dl, or a treated LDL-C 300 mg/dl. Also confirming the diagnosis is the presence of xanthomas (cutaneous or tendinous) before the age of 10 years or a family history of elevated LDL-C levels consistent with HeFH in both parents.4 Other clinical manifestations of HoFH include arcus cornea or xanthelasma. Statins are considered the first-line agents in the treatment of HoFH with or without other lipid modifying therapies. High-intensity statins are recommended as low-potency statins are generally inadequate for patients with FH.3-4 Repatha is indicated for the management of HoFH when used with other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis).5 The recommended dose is 420 mg SC once monthly (QM). In patients with HoFH with a baseline LDL-C of 349 mg/dl, the difference between Repatha and placebo in the mean percent LDL-C from baseline in a 12-week study was -31%. It is notable that patients known to have two LDL-receptor negative alleles (little or no residual function) did not respond to Repatha. Repatha is well-tolerated and is not associated with hepatotoxicity.5 Simvastatin, atorvastatin, and rosuvastatin are indicated for the management of patients with HoFH.6-8 Ezetimibe is also indicated for use in combination with atorvastatin or simvastatin in patients with HoFH.9 Ezetimibe/simvastatin tablets are indicated for use in HoFH. Another agent indicated as an adjunct to lipid-lowering medications and diet to modify lipid parameters (e.g., reduce LDL-C levels) in patients with HoFH is Kynamro, which also has a REMS program noting hepatotoxicity and hepatic steatosis.11 Guidelines from the NLA on FH state that HoFH should always be managed by a lipid specialist.3 The criteria also recognize situations in which patients are unable to take statin therapy (i.e., muscle related AEs) and that rechallenge with a different statin in such scenarios can lead to successful treatment with statin therapy. However, rhabdomyolysis, albeit rare, is a serious event and patients should not be rechallenged with statin therapy The criteria were developed based on nationally-recognized guidelines regarding lipid management, clinical data for Juxtapid and other antihyperlipidemic therapies (e.g., Repatha, statins, ezetimibe) as well as the professional opinion of specialized physicians. When Policy Topic is not covered Juxtapid is considered investigational in patients who are <18 years of age and in patients who do not have homozygous familial hypercholesterolemia.

3 1. Concurrent use of Juxtapid with Kynamro (mipomersen injection for SC use), Praluent (alirocumab for SC injection) or Repatha (evolocumab injection for SC use). Juxtapid has not been studied concomitantly with Kynamro, a medication indicated for use in patients with HoFH. Repatha, specifically indicated in HoFH, and Praluent are PCSK9 inhibitors and have not been studied concomitantly with Juxtapid therapy. 2. Use of Juxtapid in Patients with Heterozygous Familial Hypercholesterolemia (HeFH). The safety and effectiveness of Juxtapid have not been establsished in patients with hypercholesterolemia who do not have HoFH, including those with HeFH Use of Juxtapid in Patients with Other Forms of Hyperlipidemia (e.g., primary hyperlipidemia, mixed dyslipidemia). The safety and efficacy of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. Considerations Regulatory Status Juxtapid is a microsomal triglyceride transfer protein inhibitor indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-hdl-c) in patients with homozygous familial hypercholesterolemia (HoFH) (1). The Juxtapid label includes a boxed warning of the risk of hepatotoxicity. Juxtapid can cause elevations in transaminases. Juxtapid also increases hepatic fat (hepatic steatosis) with or without concomitant increases in transaminases. Hepatic steatosis associated with Juxtapid treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Juxtapid is contraindicated in patients with moderate or severe hepatic impairment (based on Child- Pugh category B or C), or active liver disease, including unexplained persistent elevations of serum transaminases. Before beginning treatment with Juxtapid, measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. During the first year, measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first. After the first year, do these tests at least every 3 months and before any increase in dose. Modify the dose of Juxtapid if elevations of transaminases are 3x ULN are observed. Discontinue treatment with Juxtapid if persistent or clinically significant elevations of transaminase occur or if the elevations are accompanied by clinical symptoms of liver injury or toxicity, increases in bilirubin 2x ULN, active liver disease (1). CYP3A4 inhibitors increase the exposure of Juxtapid, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with Juxtapid is contraindicated. Juxtapid has a pregnancy category X; therefore, it is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Based on animal data, Juxtapid may cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a negative pregnancy test before starting Juxtapid and should use effective contraception during therapy with Juxtapid (1).

4 The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH. The effect of Juxtapid on cardiovascular morbidity and mortality has not been determined. Because of the risk of hepatotoxicity associated with Juxtapid therapy, Juxtapid is available through a restricted program under the REMS. Under the Juxtapid REMS, only certified healthcare providers and pharmacies may prescribe and distribute Juxtapid (1). Safety and effectiveness have not been established in pediatric patients (1). Description of Procedure or Service Juxtapid is a microsomal triglyceride transfer protein inhibitor used to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol, apolipoprotein B (apo-b), and non-high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Juxtapid is intended for use in combination with a low fat diet, supplying <20% of energy from fat, and other lipid-lowering treatments. Juxtapid directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL. The inhibition of the synthesis of VLDL leads to reduced levels of plasma LDL-C (1). Rationale Summary Juxtapid is a microsomal triglyceride transfer protein inhibitor indicated as an adjunct to a low-fat diet and other lipid lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-hdl-c) in patients with homozygous familial hypercholesterolemia (HoFH). Juxtapid carries a boxed warning of hepatotoxicity which requires frequent liver function monitoring. Juxtapid is contraindicated in pregnancy. Concomitant administration of Juxtapid with moderate or strong CYP3A4 inhibitors, or in patients with moderate or severe hepatic impairment or active liver disease is contraindicated (1). Prior approval is required to ensure the safe, clinically appropriate and cost effective use of Juxtapid while maintaining optimal therapeutic outcomes. References 1. Juxtapid [package insert]. Cambridge MA; Aegerion Pharmaceuticals, Inc. August Cuchel M, Meagher EA, du Toit Theron H, et al, for the Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860); [Supplementary appendix]. 3. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients. J Clin Lipidol. 2011;5:S1-S8. 4. Cuchel M, Bruckert E, Ginsberg HN, et al, for the European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolemia of the European Atherosclerosis Society. Eur Heart J. 2014;35: Repatha injection for subcutaneous use [prescribing information]. Thousand Oaks, CA: Amgen; July Zocor tablets [prescribing information]. Whitehouse Station, NJ: Merck; March Lipitor tablets [prescribing information]. New York, NY: Pfizer; March Crestor tablets [prescribing information]. Wilmington, DE: AstraZeneca; May Zetia tablets [prescribing information]. Whitehouse Station, NJ: Merck; August Vytorin tablets [prescribing information]. Whitehouse Station, NJ: Merck; March 2015.

5 11. Kynamro solution for subcutaneous injection [prescribing information]. Kastle Therapeutics; Chicago, IL: May Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol. 2014;8:S58-S Guyton JR, Bays HE, Grundy SM, Jacobson TA. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol. 2014;8:S72-S81. Billing Coding/Physician Documentation Information Juxtapid is a pharmacy benefit. Juxtapid is an oral capsule. The Adult initial dose is 5mg/day. The maximum dose is 60mg/day. Measure transaminases prior to each dose adjustment. Dosage Lomitapide Dosage Titration 1 Duration of administration before considering increase to next dosage 5 mg daily At least 2 weeks 10 mg daily At least 4 weeks 20 mg daily At least 4 weeks 40 mg daily At least 4 weeks 60 mg daily Maximum recommended dosage Additional Policy Key Words ; Kynamro; Praluent; Repatha Policy Implementation/Update Information 07/2015 New policy titled Juxtapid (lomitapide) 07/2016 Annual review- no changes to policy statement 07/2017 Annual review- no changes to policy statement 06/2018 Annual review-updated approval criteria; added references State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.