EFFECTIVE 7/01/2020

Pharmacy Benefit Coverage Criteria

Effective Date ...... 7/1/2020 Next Review Date… ...... 3/1/2021 Coverage Policy Number ...... P0117

Tetrabenazine

Table of Contents Related Coverage Resources

Medical Necessity Criteria ...... 1 Genetic Testing for Hereditary and Multifactorial FDA Approved Indications ...... 2 Conditions Recommended Dosing ...... 2 Background ...... 3 References ...... 4

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Medical Necessity Criteria

Tetrabenazine (Xenazine®) is considered medically necessary when BOTH of the following criteria are met: • Treatment of ONE on the following: o Documented diagnosis of Huntington's disease when ALL of the following criteria are met: . Confirmed by genetic testing (for example, an expanded HTT CAG repeat sequence of at least 36) . Presence of chorea . Prescribed by or in consultation with a neurologist o Documented diagnosis of Hyperkinetic Dystonia when prescribed by or in consultation with a neurologist o Documented diagnosis of Hyperkinetic movement disorder associated with Tourette's syndrome when prescribed by or in consultation with a neurologist or a psychiatrist o Documented diagnosis of Tardive Dyskinesia when BOTH of the following criteria are met: . Individual has a history of treatment with a dopamine receptor blocking agent (for example, antipsychotics, metoclopramide, prochlorperazine) . Prescribed by or in consultation with a neurologist or a psychiatrist • Documented intolerance to 1 generic formulation of Xenazine

Initial authorization is up to 12 months.

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EFFECTIVE 7/01/2020 Tetrabenazine (Xenazine) is considered medically necessary for continued use when the following are met: • Individual continues to meet the initial criteria • Attestation of beneficial clinical response

Reauthorization for up to 12 months.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Tetrabenazine (Xenazine®) is considered experimental, investigational or unproven for ANY other use.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

*If you’re a Cigna provider, please log in to the Cigna for Health Care Professionals website and search for specific patients to view their covered medications.

FDA Approved Indications

FDA Approved Indication Xenazine is indicated for the treatment of chorea associated with Huntington’s disease.

Recommended Dosing

FDA Recommended Dosing The dose of Xenazine should be individualized.

Dosing Recommendations Up to 50 mg per day The starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. Xenazine should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse reactions such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Xenazine treatment or initiating other specific treatment (e.g., antidepressants).

Dosing Recommendations Above 50 mg per day Patients who require doses of Xenazine greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of Xenazine should then be individualized accordingly to their status as PMs or EMs.

Extensive and Intermediate CYP2D6 Metabolizers Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Xenazine above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg per day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Xenazine treatment or initiating other specific treatment (e.g., antidepressants). Poor CYP2D6 Metabolizers

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EFFECTIVE 7/01/2020 In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg.

Drug Availability Xenazine is available as oral tablets containing 12.5 mg or 25 mg of tetrabenazine.

Background

Therapeutic Alternatives Xenazine has an FDA approved generic therapeutic equivalent.

Professional Societies/Organizations American Academy of Neurology (AAN) evidence-based guidelines on pharmacologic treatment of chorea in Huntington Disease (HD) states that if chorea in HD requires treatment, clinicians should prescribe tetrabenazine, amantadine, or Rilutek (riluzole tablets) [Level B]. (Armstrong, 2012)

American Academy of Neurology (AAN) guidelines for the treatment of tardive syndromes (TDS) were updated in 2018 and define TDS as disorders that meet the following three criteria: (1) A history of at least 3 months’ total cumulative neuroleptic exposure. (2) The presence of at least “moderate” abnormal involuntary movements in one or more body areas or at least “mild” movements in 2 or more body areas. And (3), the absence of other conditions that might produce abnormal involuntary movements. The AAN states tardive dyskinesia (TD) symptoms include various involuntary movements, including lingual-facial-buccal movements. In comparison, the AAN states TDS includes not only lingual-facial-buccal dyskinesia but also the variant forms, collectively termed tardive syndromes. The guideline recommends valbenazine and deutetrabenazine, as first- line treatment options. The updated guideline also states tetrabenazine should be used only if valbenazine and deutetrabenazine are unavailable and second-line agents, such as gingko biloba or clonazepam, do not provide adequate relief. (Bhidayasiri, 2013 and 2018)

American Academy of Neurology (AAN) practice guideline recommendations for the treatment of tics in people with Tourette syndrome and chronic tic disorders state that the dopamine depleters, tetrabenazine, deutetrabenazine, and valbenazine, are lacking published, randomized, controlled trials in the treatment of tics but note that these drugs are increasingly used off-label. When appropriately dosed, these drugs are generally well-tolerated but may be associated with drowsiness, depression, and parkinsonism. (Pringsheim, 2019)

There are multiple controlled and uncontrolled trials conducted with tetrabenazine that included patients with dystonias. In retrospective trials, an overall moderate clinical improvement or better was seen in 161 out of 163 patients with dystonia treated with tetrabenazine. (Guay, 2010) A treatment algorithm for secondary dystonias was developed that notes tetrabenazine can be tried following a trial of an anticholinergic in children with severe secondary dystonias. In adults, tetrabenazine can be tried (alone or as combination therapy) following a low- dose trial of anticholinergic. Dressler, 2011)

Off Label Uses AHFS Drug Information 2019 Edition supports the following off-label uses: Hyperkinetic movement disorder associated with Tourette's syndrome and Tardive dyskinesia.

Comparative Studies There are no clinical studies comparing Xenazine with other therapeutic alternatives.

Generics The FDA’s generic drug approval process does not require the drug sponsor to repeat costly animal and clinical research on ingredients or dosage forms already approved for safety and effectiveness. Generic drugs must establish the following for approval: • contain the same active ingredients as the innovator drug(inactive ingredients may vary) • be identical in strength, dosage form, and route of administration

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EFFECTIVE 7/01/2020 • have the same use indications • be bioequivalent • meet the same batch requirements for identity, strength, purity, and quality • be manufactured under the same strict standards of FDA's good manufacturing practice regulations required for innovator products

A generic drug is the same as a brand-name drug in dosage, safety, strength, quality, the way it works, the way it is taken and the way it should be used. FDA requires generic drugs have the same high quality, strength, purity and stability as brand-name drugs. Not every brand-name drug has a generic drug. When new drugs are first made they have drug patents. Most drug patents are protected for 20 years. The patent, which protects the company that made the drug first, doesn't allow anyone else to make and sell the drug. When the patent expires, other drug companies can start selling a generic version of the drug. But, first, they must test the drug and the FDA must approve it.

References

1. Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2012; 79:597-603. 2. Bhidayasiri R, Fahn S, Weiner WJ, et al. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013; 81(5):463-469. 3. Bhidayasiri R, Jitkritsadakul O, Friedman JH, et al. Updating the recommendations for treatment of tardive syndromes: A systematic review of new evidence and practical treatment algorithm. J Neurol Sci. 2018; 389:67-75. 4. Dressler D. Nonprimary dystonias. Handb Clin Neurol. 2011; 100:513-538. 5. Guay DR. Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders. Am J Geriatr Pharmacother. 2010; 8(4):331-373. 6. Pringsheim T, Okun MS, Müller-Vahl K, et al. Practice guideline recommendations summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders. Neurology. 2019; 92:896-906. 7. Xenazine tablets [prescribing information]. Deerfield, IL: Lundbeck; September 2017. 8. McEvoy GK, ed. 2019. AHFS Drug Information® - 60th Ed. Bethesda, MD. American Society of Health- System Pharmacists.

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