Medication Policy Manual. Topic: Juxtapid, lomitapide Date of Origin: May 16, 2013

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1 Medication Policy Manual Policy No: dru302 Topic: Juxtapid, lomitapide Date of Origin: May 16, 2013 Committee Approval Date: March 13, 2015 Next Review Date: March 2016 Effective Date: April 1, 2015 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Lomitapide (Juxtapid) is an oral medication used in the treatment of homozygous familial hypercholesterolemia. It is a microsomal triglyceride transfer protein (MTP) inhibitor that interrupts the assembly and secretion of very low-density lipoprotein (VLDL). dru302.2 Page 1 of 5

2 Policy/Criteria I. Most contracts require prior authorization approval of lomitapide prior to coverage. Lomitapide may be considered medically necessary in patients when criteria A and B below are met. A. Documentation of a diagnosis of homozygous familial hypercholesterolemia. AND B. Treatment with mipomersen was ineffective, not tolerated, or is contraindicated. II. Administration, Quantity Limitations, and Authorization Period A. OmedaRx considers lomitapide to be a self-administered medication. B. When prior authorization is approved, lomitapide may be authorized in quantities not to exceed the equivalent of 60 mg daily. C. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. III. Lomitapide is considered investigational when used for all other conditions, including, but not limited to: A. Heterozygous familial hypercholesterolemia B. Non-familial hyperlipidemia/ hypercholesterolemia C. In combination with mipomersen (Kynamro ) Position Statement Summary - Lomitapide is used for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare genetic disease characterized by abnormally elevated LDL cholesterol levels. - Because lomitapide is linked to uncommon but serious side effects, it should be reserved for conditions where potential benefit outweighs risk, such as HoFH. - Among the newer medications for HoFH, mipomersen is the best value for members. - The safety and effectiveness of lomitapide in conditions other than HoFH have not been established. Background - HoFH is a rare, genetic disease characterized by abnormally elevated LDL cholesterol levels and an increased risk for early onset coronary heart disease. LDL levels can range from 300 to over 1000 mg/dl. If not treated, affected patients often die in early adulthood. [1-3] - Treatment options include lomitapide, mipomersen, traditional lipid-lowering medications, and LDL-apheresis. dru302.2 Page 2 of 5

3 - Treatment guidelines for HoFH recommend treatment with high doses statins and LDLapheresis. These guidelines have not been updated since the approval of lomitapide and mipomersen. [4-7] - Diagnosis of HoFH is required as part of the FDA s Risk Evaluation and Mitigation Strategy (REMS) for both lomitapide and mipomersen. Diagnosis may include genetic testing. [13,14] Clinical Efficacy HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA Lomitapide demonstrated LDL reduction is patients with HoFH; however, there is currently no evidence that it improves clinically meaningful outcomes, such as cardiovascular morbidity and mortality. - A single-arm, open-label trial evaluated lomitapide in 29 patients with HoFH. [8] * Patients were also on maximally tolerated background therapy, including other lipid-lowering medications and LDL-apheresis. * Lomitapide reduced LDL between 24% and 62% (mean 38%) after 78 weeks of treatment. * Due to the number of patients discontinuing treatment early (21%) and lack of a control group, the precision of these results is uncertain. - It is not known whether LDL is an accurate predictor of clinically meaningful outcomes (e.g. cardiovascular morbidity and mortality) in patients with HoFH. - There is no evidence that lomitapide is safer or more effective than other treatments for HoFH, including mipomersen. There are no head-to-head trials comparing lomitapide to other treatments. INVESTIGATIONAL CONDITIONS - Heterozygous Familial Hypercholesterolemia Although not evaluated with lomitapide, small-scale trials have evaluated mipomersen (Kynamro) in heterozygous familial hypercholesterolemia. [9, 10] Mipomersen reduced LDL between 21% and 28%; however, due to differential attrition and small number of subjects, the precision of these results is uncertain. While these two trials were suggestive of an effect, it is not clear that mipomersen or lomitapide results in substantial improvement in clinically meaningful outcomes that outweighs any safety risk. Larger, better designed clinical trials are needed to establish clinical efficacy and safety in this setting. The FDA approved prescribing information for lomitapide states that it should not be used in patients with hypercholesterolemia who do not have homozygous hypercholesterolemia, as safety and effectiveness has not been established in this setting. [11] - Hyperlipidemia / Hypercholesterolemia dru302.2 Page 3 of 5

4 In a small, randomized, placebo-controlled trial in 84 patients with hypercholesterolemia, lomitapide reduced LDL 30%; however, due to subject disposition and a small number of subjects, the precision of these results in uncertain. [12] While suggestive of an effect, it is not clear that lomitapide results in substantial improvement in clinically meaningful outcomes that outweighs any safety risk. Larger, better designed clinical trials are needed to establish clinical efficacy and safety in this setting. The FDA approved prescribing information for lomitapide states that it should not be used in patients with hypercholesterolemia who do not have homozygous hypercholesterolemia, as safety and effectiveness has not been established in this setting. [11] - In combination with mipomersen (Kynamro) The safety and effectiveness of lomitapide have not been studied in combination with mipomersen. Safety - The most common adverse reactions reported with an incidence of at least 20% include: diarrhea, nausea, vomiting, dyspepsia, and elevations in liver transaminases. [11] - Lomitapide has a boxed warning for risk of elevated transaminases and hepatic steatosis. Liver transaminases should be monitored prior to initiation of lomitapide and monthly thereafter. Lomitapide should be discontinued is persistent or significant elevations are observed. [11] - Lomitapide is a CYP3A4 substrate. Co-administration with strong CYP3A4 inhibitors or inducers may alter the exposure to lomitapide. [11] - Because of potential serious side effects, the FDA has initiation a Risk Evaluation and Mitigation (REMS) program to ensure lomitapide is only used in homozygous familial hypercholesterolemia. [13] Dosing - The recommended dose of lomitapide is 5 mg to 60 mg orally once daily. [11] - The safety and effectiveness of higher doses have not been established. Cross References Branded Lipid-Modifying Medications, dru336 Kynamro, mipomersen, dru301 dru302.2 Page 4 of 5

5 Codes Number Description N/A References 1. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis Aug;223(2): doi: /j.atherosclerosis Epub 2012 Feb 16. Review. PubMed PMID: Rosenson RS, de Ferranti SD, et al. Primary disorders of LDL-cholesterol metabolism. In: UpToDate, Freeman MW (ed), UpToDate, Waltham, MA, Rosenson RS, de Ferranti SD, et al. Treatment of drug resistant hypercholesterolemia. In: UpToDate, Freeman MW (ed), UpToDate, Waltham, MA, DeMott K, Nherera L, et al. Clinical Guidelines and Evidence Review for Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. 5. National Heart, Lung, and Blood Institute. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. [cited 4/10/2013]; Available from: 6. American Heart Association. Cardiovascular risk reduction in high-risk pediatric patients: endorsed by the American Academy of Pediatrics. Circulation Dec 12;114(24): Epub 2006 Nov 27. Review. PubMed PMID: Goldberg AC, Hopkins PN, et al. National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol Jun;5(3 Suppl):S1-8. doi: / j.jacl Epub 2011 Apr 12. PubMed PMID: Cuchel M, Meagher EA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet Jan 5;381(9860):40-6. doi: /S (12) Epub 2012 Nov 2. PMID: Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation Nov 6;126(19): doi: /CIRCULATIONAHA Epub 2012 Oct 11. PubMed PMID: Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol May 15;105(10): doi: /j.amjcard Epub 2010 Mar 30. PubMed PMID: Juxtapid [package insert]. Cambridge, MA: Aegerion Pharmaceuticals; August Samaha FF, McKenney J, Bloedon LT, et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med Aug;5(8): doi: /ncpcardio1250. Epub 2008 May 27. PubMed PMID: Juxtapid Risk Evaluation and Mitigation Strategy [cited 4/10/2013]; Available from: atientsandproviders/ucm pdf. 14. TEC Assessment April "Speciality Pharmacy Report #5-2013; lomitapide (Juxtapid)." BlueCross and BlueShield Association Technology Evaluation Center. dru302.2 Page 5 of 5