Medication Policy Manual. Topic: Fabrazyme, agalsidase beta Date of Origin: February 17, 2015

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1 Medication Policy Manual Policy No: dru391 Topic: Fabrazyme, agalsidase beta Date of Origin: February 17, 2015 Committee Approval Date: March 13, 2015 Next Review Date: March 2016 Effective Date: July 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 Agalsidase beta (Fabrazyme) is an enzyme replacement therapy (ERT) indicated for the treatment of Fabry s disease, an X-linked genetically inherited progressive disorder characterized by a deficiency in an enzyme known as alpha-galactosidase A (alpha GAL-A). This enzyme is responsible for the breakdown of globotriaosylceramide (GL-3), a fatty substance that is present in cells throughout the body. Accumulation of GL-3 can lead to renal failure, heart and cerebrovascular disease, and reduced life expectancy. dru391.0 Page 1 of 6

2 Policy/Criteria I. Most contracts require prior authorization approval of agalsidase beta prior to coverage. Agalsidase beta may be considered medically necessary when criteria A, B, and C below are met. A. Alternative Site of Care - for Washington, Oregon, and Idaho commercial, fully insured members only (does not apply to Medicare) Agalsidase beta is administered in a non-hospital outpatient setting (also referred to as an alternative site of care ; such as a provider s office, an infusion center, or home infusion), unless both of the following criteria 1 and 2 below are met: 1. All non-hospital outpatient settings are greater than 10 miles further from the member s home than the hospital outpatient setting. AND 2. The member s home is not eligible for home infusion services (such as home is not within the service area or is deemed unsuitable for care by the home infusion provider). NOTE: Alternative Site of Care criteria will be waived for payment of the first dose, to allow for adequate transition time to arrange for a non-hospital outpatient setting for the infusion. AND B. A diagnosis of Fabry s disease confirmed by one of the following, depending on gender: Males: 1. Biochemical assay of alpha GAL-A enzyme activity in leukocytes of less than 20% of normal activity. OR 2. Genetic test revealing a mutation in the galactosidase-alpha (GLA) gene. Females: 1. Genetic test revealing a mutation in the galactosidase-alpha (GLA) gene. OR 2. Biological father is known to have Fabry s disease. AND C. One or more clinical signs or symptoms of Fabry s disease are present (See Appendix 1). dru391.0 Page 2 of 6

3 II. Administration, Quantity Limitations, and Authorization Period A. OmedaRx does not consider agalsidase beta to be a self-administered medication. B. When prior authorization is approved, agalsidase beta may be authorized for up to 26 infusions per year based on a total dose of less than or equivalent to 1 mg/kg every 2 weeks, in a non-hospital outpatient setting, unless waived per criteria I.A. above. NOTE: Alternative Site of Care criteria will be waived for payment of the first dose, to allow for adequate transition time to arrange for a non-hospital outpatient setting for the infusion. C. Authorization shall be reviewed at least annually to confirm that the medication is effective. Documentation by chart notes of disease stability or improvement in clinical symptoms must be provided. III. For Washington, Oregon, and Idaho commercial, fully insured members only (does not apply to Medicare) Agalsidase beta is considered not medically necessary when administered in a hospital outpatient setting, when an alternative site of care (non-hospital outpatient setting) is a treatment option (see Section I: Alternative Site of Care). Position Statement - Agalsidase beta is an ERT indicated for the long-term treatment of Fabry s disease, a rare disorder that predominantly affects males. - Misdiagnosis is common due to the rarity and non-specific manifestations of the disease. Diagnosis is confirmed in males through biochemical or genetic testing. In females, the sensitivity and specificity of alpha GAL-A activity is less than 50%; therefore, genetic testing is used to confirm Fabry s disease in this population, unless the father is known to have Fabry s disease. [1,2] - The population for which the approval of agalsidase beta was approved on had clinical manifestations of Fabry s disease. There is currently no high quality evidence indicating that treating asymptomatic patients with Fabry s disease leads to a reduced risk of long term clinical outcomes such as mortality. - Guidelines recommend treating all patients with confirmed Fabry s disease with ERT as soon as clinical signs and symptoms are observed. Patients being treated for Fabry s disease should be evaluated at least annually to assess disease stability or improvement in symptoms. Disease stability can be defined as a lower rate of decline in end-organ damage (renal and cardiac disease). [3] - Although studies have shown that agalsidase beta reduces GL-3, and stabilizes renal function and cardiac structure, there is no high quality evidence correlating these endpoints to long term clinical outcomes such as reduced mortality risk or reduction in renal and cardiovascular events. [4] dru391.0 Page 3 of 6

4 - Agalsidase beta is administered intravenously in doses of up to 1 mg/kg every 2 weeks. [5] - New technologies and pharmaceuticals allow therapeutic services, such as infusion therapy, to be administered safely, effectively, and much less costly outside of the hospital outpatient setting. Alternative sites of care (such as doctor s offices, infusion centers, and home infusion) are well-established, accepted by physicians, and reduce the overall cost of care. Clinical Efficacy - There is low certainty in the evidence for the use of agalsidase beta in the treatment of Fabry s disease based on one high-quality Cochrane systematic review. [4] o Three randomized, double-blind controlled studies evaluating the efficacy of agalsidase beta versus placebo in a total of 146 subjects were identified for inclusion in the systematic review. All subjects had clinical evidence of Fabry s disease. o Study duration ranged from five to 35 months. Primary endpoints included changes in GL-3 levels in tissue, number of renal, cardiac and cerebrovascular events, and death. o One fair confidence trial reported no statistically significant difference in renal, cardiac, and cerebrovascular events, and death between agalsidase beta and placebo. o One low-confidence trial reported statistically significant reductions in GL-3 favoring agalsidase beta versus placebo. Mean difference in GL-3 ranged from mcg/ml (95% CI -1.18,-0.62) in the heart to mcg/ml (95% CI -2.09,- 1.31) in the kidney. Study flaws included incomplete information regarding subject disposition, method of randomization, blinding and concealment of allocation. o None of the trials evaluated pain (e.g. acroparaesthesia and Fabry crises) as a primary outcome. - Despite low certainty evidence, it is likely that agalsidase beta reduces GL-3 levels in plasma and tissues based on several years of clinical experience; however, there is no high quality evidence to correlate improvement in this parameter with clinically meaningful outcomes (e.g. reduced risk of death, and renal, cardiovascular, and cerebrovascular events). Additional studies enrolling larger number of subjects for longer durations are needed to fully elucidate the long-term clinical benefit of agalsidase beta. - There is currently no FDA approved alternative ERT for the treatment of Fabry s disease. Another ERT known as agalsidase alfa (Replagal ) is only available outside the U.S. [6] - Uniform recommendations for the use of ERT in the treatment of Fabry s disease do not exist, but guidelines based on the opinions of experts with experience in treating patients with Fabry s disease recommend that ERT be initiated as soon as clinical manifestations are observed. [3] dru391.0 Page 4 of 6

5 Safety [5] - Agalsidase beta is generally well tolerated. Infusion-related reactions are most common, and include chills, fever, fatigue, peripheral edema, pain, cold intolerance, shortness of breath, nausea, flushing and headache. - Pretreatment with an antipyretic and/or antihistamine, or reducing the infusion rate may help to minimize infusion related reactions. - Rare cases of anaphylaxis and severe allergic reactions have been reported. As such, appropriate medical support measures should be readily available when agalsidase beta is administered. Alternative Site of Care: - Use of an alternative site of care, including non-hospital outpatient infusion centers and home infusion services, is an accepted standard medical practice. These alternative sites of care offer high-quality services for patients and reduce the overall cost of care, as compared to a hospital-based infusion center. - All medications infused outside of a hospital setting (at an alternative site of care) have undergone an evaluation for safe infusion and development of infusion standards, including adverse drug reaction (ADR) management and reporting algorithms. - For use of an alternative site of care, every patient undergoes a patient assessment during the intake process by the infusion provider, which includes evaluation of individual clinical assessment parameters. These parameters may include, but are not limited to, previous tolerance of products (such as IVIG), assessment of kidney function, risk factors for developing thromboembolic events, and venous access. - For use of home infusion services, an assessment is conducted to determine whether or not the home is a safe, appropriate site of care, with adequate support for infusion in the home. - Because these alternative site of care providers need time to arrange for assessment and coordinate the first dose of each new medication, the first dose of infused medications may be covered in a hospital-based infusion center, if needed, to allow adequate time for a seamless transition of care. This may include arranging for delivery of medications and/or patient education, such as for self-administration of medications such as subcutaneous immune globulin (SCIG). dru391.0 Page 5 of 6

6 Appendix 1: Clinical Manifestations of Fabry s Disease [3] Elevated GL-3 levels in plasma and/or tissues Intermittent pain in extremities (acroparesthesias) Episodic episodes of acute pain lasting hours to days (Fabry crises) Skin lesions (angiokeratomas) Corneal opacity Hypohydrosis/hyperhidrosis Heat, cold, and exercise intolerance Renal manifestations (e.g. polyuria, polydipsia, proteinuria, end-stage renal disease) Gastrointestinal problems (e.g. abdominal pain and diarrhea) Cardiac manifestations (e.g. ventricular hypertrophy, valvular disease, coronary artery disease) Cerebrovascular manifestations (e.g. stroke, hemiparesis, vertigo/dizziness, tinnitus, nystagmus, hemiataxia, memory and hearing loss) Codes Number Description HCPCS J0180 Injection, agalsidase beta, 1 mg ICD Lipodoses: Fabry s disease References 1. Mauer, M. Clinical features and diagnosis of Fabry disease. In: UpToDate, Curhan, GC. (Ed). UptoDate, Waltham, MA, Laney, DA, Bennett, RL, Clarke, V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. Journal of genetic counseling Oct;22(5): PMID: Desnick, RJ, Brady, R, Barranger, J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138: PMID: El Dib, RP, Nascimento, P, Pastores, GM. Enzyme replacement therapy for Anderson-Fabry disease. The Cochrane database of systematic reviews. 2013;2:CD PMID: Fabrazyme [package insert]. Cambridge, MA: Genzyme Corporation May Mauer, M, Kopp, J. Treatment of Fabry Disease. In: UpToDate, Curhan, GC. (Ed). UptoDate, Waltham, MA, dru391.0 Page 6 of 6