Subject: Xenazine (tetrabenazine) Original Effective Date: 12/3/09. Policy Number: MCP-075 Revision Date(s): 10/30/2013; 7/10/2018

Transcription

1 Subject: Xenazine (tetrabenazine) Original Effective Date: 12/3/09 Policy Number: MCP-075 Revision Date(s): 10/30/2013; 7/10/2018 Review Date(s): 12/16/15; 6/15/2016; 3/21/2017 MCPC Approval Date: DISCLAIMER This Molina Clinical Policy (MCP) is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this MCP document and provide the directive for all Medicare members. SUMMARY OF EVIDENCE/POSITION STATEMENTS This policy addresses the coverage of Xenazine (tetrabenazine) for the indication of chorea associated with Huntington's disease (Huntington's Chorea) and for off-label use in the treatment of tardive dyskinesia. The intent of the Xenazine (tetrabenazine) policy is to ensure appropriate selection of patients for therapy based on product labeling, clinical guidelines, and clinical studies. This policy is intended to address coverage criteria that are appropriate for the majority of individuals/members with a particular disease, illness, or condition. Each member's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records. Huntington's Disease (HD) is a rare autosomal dominant neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric dysfunction. HD is caused by a mutation in the gene for a protein called huntingtin. The defect causes the cytosine, adenine, and guanine (CAG) building blocks of DNA to repeat many more times than is normal. Each child of a parent with HD has a chance of inheriting the HD gene. Symptoms of the disease, which gets progressively worse, include chorea (non-repetitive, non-periodic, involuntary jerking movements of face, trunk, or limbs often enhanced during voluntary movement), abnormal body postures, and changes in behavior, emotion, judgment, and cognition. Individuals with HD also develop impaired coordination, slurred speech, and difficulty feeding and swallowing. HD typically begins between ages 30 and 50. An earlier onset form called juvenile HD, occurs under age 20. Symptoms of juvenile HD differ somewhat from adult onset HD and include unsteadiness, rigidity, difficulty at school, and seizures. More than 30,000 Americans have HD. Annual incidence 0.38 per 100,000 and worldwide service-based Dynamed 2018 prevalence 2.71 per 100,000. A genetic test, coupled with a complete medical history and neurological and laboratory tests, helps physicians diagnose HD. Diagnosis confirmed by DNA analysis finding 36 CAG trinucleotide repeats in HTT gene. Page 1 of 23

2 OFF-LABEL USE: Although tetrabenazine has only been approved in the US for the symptomatic management of chorea associated with Huntington's disease, the drug has been used with some success for the symptomatic management of other hyperkinetic movement disorders (also called hyperkinesias), including hemiballismus, senile chorea, tic disorder, Tourette's syndrome (Gilles de la Tourette's syndrome), and tardive dyskinesia. Clinical experience with tetrabenazine in tardive dyskinesia suggests that the drug is effective in the management of this condition, including in some AHFS 2018 severe and/or refractory cases. Off-label use Tardive dyskinesias (TDs) are involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated with long-term dopaminergic antagonist medications. Although TDs are associated with the use of neuroleptics, TDs apparently existed before the development of these agents. Patients with schizophrenia and other neuropsychiatric disorders are especially vulnerable to the development of TDs after exposure to conventional neuroleptics, anticholinergics, toxins, substances of abuse, and other agents. TDs are most common in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who have been treated with antipsychotic medication for long periods, however TDs may occasionally occur in other patients as well, such as people with fetal alcohol syndrome, other developmental disabilities, and other brain disorders are vulnerable to the development of TDs, even after receiving only one dose of the causative agent (primarily antipsychotics but may include gastric motility agents and antiemetics such as metoclopramide and prochlorperazine). According to the manufacturer, the condition is estimated to affect at least 500,000 people in the United States. The exact mechanism of TD is unknown; however is theorized to be due to upregulation and increased sensitivity of dopamine receptors and alteration in central nervous system neurotransmitter activity in response to chronic antagonism from DRBAs which leads to dysregulation of the brainstem skeletomotor circuit. Movements are involuntary and repetitive and usually involve the orofacial area, but may affect movement in other areas as well. TD usually presents after 1-2 years of chronic exposure to a DRBA but may occur as early as 3 months (or 1 month in patients 60 years old) The risk of development of TD is related to both the dose and duration of exposure to DRBAs Reported in about 20%-50% of patients treated with DRBAs Typical (first generation) antipsychotics may be more likely to cause TD than atypical (second generation) antipsychotics Though there is currently no validated measure that reflects the impact of TD on a patient's quality of life, the Abnormal Involuntary Movement Scale (AIMS) has been used in clinical and research settings to assess the general severity of symptoms and the impact of treatment. (Cited by ICER 2017) Xenazine (tetrabenazine) Acts as a reversible inhibitor of the human vesicular monamine transporter type 2 (VMAT-2) and thereby decreases the uptake of monoamines (including dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles and depletes the monoamine stores; hydroxytetrabenazine (HTBZ) also inhibits VMAT-2; weak binding affinity for dopamine D 2 receptors. Tetrabenazine is indicated for the treatment of chorea associated with Huntington's disease. Safety and efficacy of tetrabenazine in the management of chorea associated with Huntington's disease have been established primarily in a randomized, double-blind, placebo-controlled study (TETRA-HD) of 12 weeks' duration in 84 ambulatory adult AHFS 2018 patients with Huntington's disease. Serious side effects such as depression and suicidal thoughts and actions have been reported with the use of tetrabenazine, therefore, the risk versus benefit of tetrabenazine treatment must be carefully considered prior to Micromedex 2018 initiation of therapy. Page 2 of 23

3 Tetrabenazine has also been studied for the treatment of tardive dyskinesia, either as initial therapy or in patients who have responded poorly to other agents (e.g., reserpine, bromocriptine, clozapine). Indirect comparisons suggest tetrabenazine may be the most effective agent available for this disorder, although further studies assessing long-term Micromedex 2018 benefit and the propensity of the drug to aggravate the tardive dyskinesia are needed. In addition to tardive dyskinesia, tetrabenazine has been studied for the treatment of spontaneous and drug-induced dyskinesias. The drug may be useful in selected patients with Tourette syndrome refractory to haloperidol and idiopathic dystonia unresponsive to anticholinergics, although efficacy has tended to be lower in these disorders. Micromedex 2018 Combined use with pimozide and trihexyphenidyl may benefit some patients with severe dystonia. The only known advantage of deutetrabenazine over tetrabenazine is the need for less frequent dosing (BID instead of TID) at the higher end of the dosing range. Patients who have had an inadequate response to tetrabenazine may switch to deutetrabenazine in search of better efficacy; however there is no basis that the two products differ with respect to efficacy; furthermore, an attempt to show superiority of deutetrabenazine to tetrabenazine would seem futile. [Center for Drug Evaluation and Research. April 3, NDA ] Considering the unknown impact on improved function or quality of life, deutetrabenazine (Austedo) may increase the risk of depression, suicidality, and possible disease worsening is a factor when determining the clinical need for the treatment of chorea. Therefore, the benefits of treatment should outweigh the risks, or an option for severe, disabling disease. There are no studies comparing the efficacy or safety of tetrabenazine to any other active treatment. There is no high-quality evidence and lack of head-to-head studies to supporting the safety and efficacy of tetrabenazine over deutetrabenazine (Austedo). There were no randomized controlled trials of tetrabenazine for people with TD, no studies directly comparing valbenazine and deutetrabenazine, and no studies comparing any of the agents to other agents used off-label in TD treatment. Clinical trials have shown minimal adverse drug reactions associated with deutetrabenazine, including psychiatric adverse events, although patients with untreated or undertreated depression were not included in the trials. CLINICAL PRACTICE GUIDELINES Chorea associated with Huntington Disease The American Academy of Neurology (2012) recommends tetrabenazine, amantadine, or riluzole if the chorea warrants treatment. [Reference: Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the AAN, 2012] Tardive Dyskinesias (TDs) Treatment recommendations have been developed by the American Psychiatric Association and the American Academy of Neurology (AAN 2013). ICER 2017 Avoiding long-term use of antipsychotic agents for conditions where evidence of benefit is lacking or other treatment options are available is preferred. Therapy for TD has primarily focused on decreasing and then stopping the offending agent, and switching to a different antipsychotic if such agents are still deemed necessary. It is often not possible to stop the antipsychotic immediately because TD symptoms can worsen upon withdrawal. Though patients with TD symptoms may improve with these changes, complete resolution of symptoms is rare, and long- lasting or permanent symptoms can be seen, even in patients who successfully are taken off antipsychotics. ICER 2017 Therefore, other treatments have been sought to decrease symptoms of patients with TD, and guideline recommendations may change with the availability of safer and more effective treatment options. Page 3 of 23

4 The AAN published guidelines on the treatment of tardive syndromes in 2013, however valbenazine (Ingrezza) and deutetrabenazine (Austedo) have not been addressed in clinical practice guidelines. The 2013 AAN evidence-based guidelines for the treatment of TD did not make any level A (highest level of evidence for efficacy) treatment recommendations. Gingko biloba and clonazepam were recommended in the level B category. Based on AAN guidelines, tetrabenazine is possibly effective and may be considered in the treatment of patients with tardive dyskinesia (AAN 2013). CLASSIFICATION: Central Monoamine-Depleting Agent; Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor VMAT2 Inhibitors: Xenazine (tetrabenazine); Austedo (deutetrabenazine); Ingrezza (valbenazine) FDA INDICATIONS CHOREA ASSOCIATED WITH HUNTINGTON S DISEASE Treatment of chorea associated with Huntington disease Orphan drug designation: Treatment of Huntington Disease OFF-LABEL USE Tardive dyskinesia Data from a limited number of patients studied suggest that tetrabenazine may decrease the frequency and severity of tardive movements in patients with tardive dyskinesia. Additional data may be necessary to further F&C 2018 define the role of tetrabenazine in this condition. Based on American Academy of Neurology guidelines, tetrabenazine is possibly effective and may be F&C 2018 considered in the treatment of patients with tardive dyskinesia. Available as: Oral Tablets: 12.5 mg, 25 mg FDA Approved: Chorea associated with HD: August 15, 2008 Black Box Warnings Depression and suicidality Tetrabenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington disease. Anyone considering the use of tetrabenazine must balance the risks of depression and suicidality with the clinical need for control of chorea. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. Patients, their caregivers, and families should be informed of the risk of depression and suicidality, and should be instructed to report behaviors of concern promptly to the treating physician. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington disease. Tetrabenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression. REMS: No REMS at the time of this writing Page 4 of 23

5 RECOMMENDATIONS/COVERAGE CRITERIA Xenazine (tetrabenazine) may be authorized for members who meet ALL of the following criteria [ALL] 1. Prescriber specialty [ONE] Chorea associated with Huntington s Disease (HD): Prescribed by, or in consultation with, a board-certified neurologist with expertise in HD. Submit consultation notes if applicable. NOTE: Consultation notes must be submitted for initial request and for continuation of treatment requests at least ONCE annually. For Tardive Dyskinesia: Prescribed by, or in consultation with, a board-certified psychiatrist or neurologist. Submit consultation notes if applicable. NOTE: Consultation notes must be submitted for initial request and for continuation of treatment requests at least ONCE annually. 2. Diagnosis/Indication [ALL] Documentation of diagnosis required and may include clinical notes from the member s medical records including any relevant labs and/or tests, supporting the diagnosis [A OR B] A. CHOREA ASSOCIATED WITH HUNTINGTON S DISEASE [ALL] Diagnosis of chorea associated with Huntington s Disease confirmed by ONE (1) of the following: [ONE] Huntington Disease Mutation Analysis: indicating an expanded CAG repeat ( 36) in the huntington gene (HTT) (also known as HD gene). Documentation of laboratory result required. A positive family history of Huntington s Disease, with autosomal dominant inheritance pattern Clinical signs of Huntington s Disease. Submit documentation of clinical assessment indicating that the member has ONE (1) or more of the following clinical signs: [ONE OR MORE] Neurologic manifestations, may include but not limited to: [ONE OR MORE] Warby, SC.GeneReviews. o changes in eye movements (saccades) o decreased coordination o minor involuntary movements o alteration in executive functioning o depressed or irritable mood o chorea consisting of non-repetitive jerking movements of limbs, face, or trunk Fine motor voluntary movements may be impaired early in course of disease Dystonia (such as torticollis) Baseline evaluation of Total Chorea Score ([using the Unified Huntington s Disease Rating Scale (UHDRS)] OR equivalent test documenting chorea. Documentation required. MOLINA REVIEWER: Reauthorization requires positive response or demonstrated efficacy to therapy. Baseline score reviewed at Continuation of Therapy. Informational Note: Total Chorea Score (TCS), 1 of the items on the Unified Huntington s Disease Rating Scale (UHDRS; chorea is rated from 0 to 4 for 7 different parts of the body with lower scores representing less chorea; range, 0 to 28) Page 5 of 23

6 B. TARDIVE DYSKINESIA [ALL] Diagnosis of schizophrenia, schizo-affective disorder, or a mood disorder for at least 3 months STABLE psychiatric status AND For member on maintenance medication(s) for schizophrenia or schizoaffective disorder, or mood disorders: Stable medication doses and therapy required. Documentation required. Diagnosis of antipsychotic-induced moderate to severe TD [as indicated by a score of 3 or 4 on item 8 (severity of abnormal movement overall) of the Abnormal Involuntary Movement Scale (AIMS)] Documentation required. [REFER to Appendix 1: Centrally-Acting Dopamine Receptor Blocking Agents (Neuroleptics)] Informational Note: Drugs that most commonly cause TD are older antipsychotic agents such as haloperidol, chlorpromazine, and thioridazine; other drugs that may be associated with TD include antidepressants (amitriptyline, fluoxetine, phenelzine, sertraline, and trazodone), anti-parkinson s drugs (levodopa), epilepsy drugs (phenobarbital and phenytoin), and metoclopramide. Baseline evaluation of TD by an Abnormal Involuntary Movement Scale (AIMS) greater than or equal to 10* OR equivalent test documenting tardive dyskinesia. *Documentation of the member s current AIMS score from items 1-7 (results range from 0 to 28, with higher scores indicating more severe involuntary movements) required. Informational Note The AIMS questionnaire is commonly used to measure the severity of TD symptoms, and the impact of treatment on TD. In the valbenazine and deutetrabenazine trials, it was based on the measurement of the first seven items on the twelve-point scoring tool (measuring four facial/oral movements; two measurements of movement in extremities; and one measuring movement in the trunk). A higher AIMS score reflects increased severity of TD symptoms, and a change in AIMS between baseline and follow-up was the primary outcome. It is unclear what amount of change in AIMS reflects a minimal clinically important difference, but it has been suggested to be 2-3 point change. In addition, an AIMS score reduction greater than or equal to 50% can define treatment response. Reference: ICER Institute for Clinical and Economic Review, Final Evidence Report: VMAT2 Inhibitors for Tardive Dyskinesia: Effectiveness and Value Both valbenazine and deutetrabenazine trials used an AIMS score reduction greater than or equal to 50% to define treatment response. 3. Age/Gender/Other restrictions [ALL] 18 years of age or older The safety and efficacy of tetrabenazine have not been established in children. No prior medical history of, or significant risk for: suicidal ideation, violent behavior, or unstable psychiatric symptoms. Documentation required. NOTE: Members with a history of depression and/or suicidal ideation must have an evaluation by an appropriate specialist or behavioral health provider prior to starting therapy and condition should be monitored while on therapy. Documentation required. US Boxed Warning: Use can increase risk for depression and suicidal thoughts and behavior in patients with Huntington disease; closely monitor for emergence or worsening of depression, suicidality, or unusual behavioral changes. Use with caution in patients with a history of depression or prior suicide attempts or ideation; monitor patients closely for new or worsening signs or symptoms of depression. Use is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression. Page 6 of 23

7 4. Step/Conservative Therapy/Other condition Requirements [ALL APPLICABLE] FOR CHOREA ASSOCIATED WITH HUNTINGTON S DISEASE ONLY [ALL] Inadequate response, clinical intolerance, contraindication, or inappropriateness ALL of the following therapies. Documentation required: [ALL] Inadequate response is defined as failure to achieve and maintain improvement in TD symptoms after a compliant trial on the recommended dose for a sufficient period ONE (1) of the following medications or classes of medication, unless contraindicated or clinically significant adverse effects are experienced. Documentation required. [ONE] o Benzodiazepines o Amantadine o Antipsychotics Informational Note: Typical neuroleptics, atypical antipsychotics, benzodiazepines and anti-glutamatergic agents (amantadine) have been used off-label use in the treatment of chorea for many years. [The Cochrane database of systematic reviews. 2009] FOR TARDIVE DYSKINESIA (TD) ONLY [ALL] Inadequate response, clinical intolerance, contraindication, or inappropriate for member s condition required for ALL of the following therapies. Documentation required: [ALL] Inadequate response is defined as failure to achieve and maintain improvement in TD symptoms after a compliant trial on the recommended dose for a sufficient period Prescriber has reduced dose or discontinued medication(s) known to cause TD [Refer to Appendix 1] OR Prescriber switched from a first-generation to a second-generation antipsychotic [Refer to Appendix 1] OR Member is not a candidate for a trial of dose reduction, tapering, switching or discontinuation of the offending medication Additional pharmacologic interventions include the following: use of benzodiazepines, botulinum toxin injections, tetrabenazine, or anticholinergic drugs to control symptoms of TD, or paradoxically, resuming treatment with antipsychotic drugs in order to suppress TD (Tardive dyskinesia: Prevention and treatment. In: UpToDate). AND At least ONE (1) medication used to reduce TD symptoms [i.e. benzodiazepines (clonazepam)] [Refer to Appendix 2] *Off-label use of various pharmacologic options encompasses the standard treatment approach for controlling symptoms of tardive dyskinesia severe enough to warrant treatment. Page 7 of 23

8 Tetrabenazine (Xenazine) is not prescribed with nor intended for use in combination with the following therapies: [ANY] Other VMAT2 Inhibitors: [ANY] o Austedo (deutetrabenazine) o Ingrezza (valbenazine) MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate)] Reserpine QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents] 5. Contraindications/Exclusions to Xenazine (tetrabenazine) therapy [ANY] Authorization will not be granted if ANY of the following conditions apply [ANY] Non-FDA approved indications Hypersensitivity to Xenazine (tetrabenazine) or any ingredient in the formulation Actively suicidal or patients with untreated or inadequately treated depression Concomitant use of an MAOI or within 14 days of discontinuing therapy with an MAOI Concomitant use of reserpine or within 20 days of reserpine discontinuation Hepatic impairment NOTE: Members with a history of hepatic impairment, appropriate labs and/or additional documentation may be requested at the discretion of the Pharmacy/Medical Director Arrhythmias associated with a prolonged QT interval NOTE: Members with congenital long QT syndrome or arrhythmias associated with prolonged QT interval, or members at risk of prolonged QT interval: An EKG may be required prior to therapy and before increasing the dosage. Peer-to-Peer and/or additional documentation may be requested at the discretion of the Pharmacy/Medical Director. Exclusions Concomitant therapy with ANY of the following will NOT be authorized: [ANY] Other VMAT2 inhibitors: Ingrezza (valbenazine) or tetrabenazine (Xenazine) MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate)] Reserpine QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents] 6. Labs/Reports/Documentation required [ALL] All documentation for determination of medical necessity must be submitted for review. Prescriber to submit documentation as indicated in the criteria above, including but not limited to chart notes, applicable lab values and/or tests, adverse outcomes, treatment failures, or any other additional clinical information or clinical notes from the member s medical records supporting the diagnosis. Letters of support and/or explanation are often useful, but are not sufficient documentation unless ALL specific information required by this MCP is included. NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed necessary or appropriate by Molina Medical/Pharmacy staff. Page 8 of 23

9 CONTINUATION OF THERAPY Xenazine (tetrabenazine) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL] 1. Initial Coverage Criteria Member currently meets ALL initial coverage criteria Subsequent authorizations will require the Member to have an office visit and re-assessment for this condition annually to determine if continuation of treatment with requested medication is medically necessary. Chart notes or consultation notes (if applicable) must be submitted for initial request and for continuation of treatment requests at least ONCE annually. 2. Adherence to Therapy Adherence to therapy at least 85% of the time as verified by Prescriber and member s medication fill history (review Rx history for compliance) Therapy may be discontinued due to poor adherence upon recommendation of the Molina Medical Director when adherence <85% has been demonstrated in at least two months during the course of therapy 3. Labs/Reports/Documentation required [ALL] Continued clinical evaluation for symptoms of depression, psychosis, or aggressive behavior. NOTE: If member has these symptoms, Prescriber must provide documentation that these issues are addressed. Positive response to Xenazine (tetrabenazine) treatment, including: [ALL APPLICABLE] For CHOREA ASSOCIATED with HUNTINGTON S DISEASE [ONE] o Disease stabilization or improvement of Total Maximal Chorea Scores from baseline OR o Disease stabilization or improvement in chorea or tardive dyskinesia symptoms from baseline For TARDIVE DYSKINESIA: Disease stabilization or improvement in TD symptoms as documented by AIMS score (items 1-7): decrease from baseline by at least 2 points Informational Note The AIMS questionnaire is commonly used to measure the severity of TD symptoms, and the impact of treatment on TD. In the valbenazine and deutetrabenazine trials, it was based on the measurement of the first seven items on the twelve-point scoring tool (measuring four facial/oral movements; two measurements of movement in extremities; and one measuring movement in the trunk). A higher AIMS score reflects increased severity of TD symptoms, and a change in AIMS between baseline and follow-up was the primary outcome. It is unclear what amount of change in AIMS reflects a minimal clinically important difference, but it has been suggested to be 2-3 point change. In addition, an AIMS score reduction greater than or equal to 50% can define treatment response. Reference: ICER Institute for Clinical and Economic Review, Final Evidence Report: VMAT2 Inhibitors for Tardive Dyskinesia: Effectiveness and Value Both valbenazine and deutetrabenazine trials used an AIMS score reduction greater than or equal to 50% to define treatment response. Page 9 of 23

10 STABLE psychiatric status AND ALL of the following as applicable to member. Documentation required [ALL APPLICABLE] For members on maintenance medication(s) for schizophrenia or schizoaffective disorder, or mood disorders): Stable medication doses and therapy required. For members with a history of depression and/or suicidal thoughts or behaviors OR members with a current treatment for depression and/or suicidal thoughts or behaviors: [ALL] o Regular follow-up and recent evaluation for this condition by the Prescriber (neurologist or psychiatrist) or behavioral health provider is required. o Member is not experiencing suicidal thoughts or behaviors Xenazine (tetrabenazine) is not prescribed with nor intended for use in combination with the following therapies: [ANY] Other VMAT2 Inhibitors: [ANY] o Austedo (deutetrabenazine) o Ingrezza (valbenazine) MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate)] Reserpine QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents] 4. Discontinuation of Treatment Contraindications/Exclusions to Xenazine (tetrabenazine) therapy [ANY] Authorization will not be granted if ANY of the following conditions apply [ANY] Non-FDA approved indications Hypersensitivity to Xenazine (tetrabenazine) or any ingredient in the formulation Actively suicidal or patients with untreated or inadequately treated depression Concomitant use of an MAOI or within 14 days of discontinuing therapy with an MAOI Concomitant use of reserpine or within 20 days of reserpine discontinuation Hepatic impairment NOTE: Members with a history of hepatic impairment, appropriate labs and/or additional documentation may be requested at the discretion of the Pharmacy/Medical Director Arrhythmias associated with a prolonged QT interval NOTE: Members with congenital long QT syndrome or arrhythmias associated with prolonged QT interval, or members at risk of prolonged QT interval: An EKG may be required prior to therapy and before increasing the dosage. NOTE: Peer-to-Peer and/or additional documentation may be requested at the discretion of the Pharmacy/Medical Director. Exclusions Concomitant therapy with ANY of the following will NOT be authorized: [ANY] Other VMAT2 inhibitors: Ingrezza (valbenazine) or tetrabenazine (Xenazine) MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate)] Reserpine QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents] Page 10 of 23

11 ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD Consult the manufacturer's labeling for more detailed information on dosage and administration of this drug, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and monitoring. 1. Recommended Dosage [ALL] Huntington s chorea: Dose of tetrabenazine is determined individually for each patient The recommended starting dose is 12.5 mg orally once daily in the morning. After 1 week, the dose may be increased to 12.5 mg twice daily. Tetrabenazine should be titrated slowly at weekly intervals by 12.5 mg. If a dose of 37.5 mg to 50 mg per day is required, it should be given in divided doses 3 times a day. The maximum recommended single dose is 25 mg and the maximum daily dose is 100 mg. If intolerable side effects develop, titration should be stopped and the dose reduced. If the adverse event does not resolve, consider discontinuing therapy with tetrabenazine or initiating other specific treatments (e.g., antidepressants) Tardive Dyskinesia (off-label) Initiate at 50 mg/day in divided doses; if needed, may increase daily dose by 50 mg every 2 weeks up to a maximum of 150 mg/day in divided doses. Additional data may be necessary to further define the role of tetrabenazine in this condition. Note: Dose is individualized based on efficacy and tolerance. 2. Authorization Limit [ALL] Quantity limit: 25 mg per dose; 50mg per day EXCEPTIONS: For doses greater than 50 mg/day of Xenazine (tetrabenazine): [ALL] CYP2D6 genotyping is required: Documentation of CYP 2D6 genotyping results are required and indicates member is a CYP 2D6 intermediate or extensive metabolizer [Documentation required] NOTE: Daily doses above 50 mg should not be administered without CYP2D6 genotyping to Micromedex, PI determine whether the patient is a poor, intermediate, or extensive metabolizer. An adequate trial of 50 mg per day dosing with an inadequate response. Chart documentation of trial and inadequate response is required. Maximum Dose: Dosage does not exceed 100 mg daily using the fewest number of tablets per day to permit three times per day dosing NOTE: Requests for doses greater than the maximum recommended dose of 100mg will not be authorized for any member. Dispensing limit: Only a 1-month supply may be dispensed at a time Page 11 of 23

12 Duration authorization: [ALL] Initial: 6 months Continuation: 6 months Continuation of treatment: Re-authorization is required every 6 months to determine effectiveness of therapy and continued need based on documented positive clinical response. Subsequent renewals will be authorized upon verification of marked clinical improvement demonstrated by objective improvement in these selected markers. Refer to Continuation of Therapy section. 3. Route of Administration [ALL] Xenazine (tetrabenazine) is considered a self-administered medication Xenazine (tetrabenazine) is deemed appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility will not be authorized. If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider. These agents must be dispensed through a participating pharmacy. Page 12 of 23

13 COVERAGE EXCLUSIONS This policy addresses the coverage of Xenazine (tetrabenazine) for the treatment of adult patients chorea associated with Huntington's disease (Huntington's Chorea) AND for the treatment of tardive dyskinesia when appropriate criteria are met. All other uses of Xenazine (tetrabenazine) that are not an FDA-approved indication or not included in the Coverage Criteria section of this policy are considered not medically necessary. This is subject to change based on research and medical literature, or at the discretion of Molina Healthcare. *Pharmaceutical samples: The use of pharmaceutical samples (from the prescriber or manufacturer assistance program) will not be considered when evaluating the medical condition, prior prescription history, or as continuation of therapy. *FDA-approved indication does not, in itself, dictate coverage. Molina Clinical Policy may not recommend coverage for all FDA-approved indications. Please review this Policy in its entirety for indications covered by Molina Healthcare. Page 13 of 23

14 SUMMARY OF CLINICAL EVIDENCE Measuring Efficacy The most clinically valuable tools for monitoring chorea, Huntington s Disease progression, and treatment effects include standardized scales which measure symptom severity. UHDRS Assessing chorea, prior and after initiating pharmacologic therapy, is usually performed by the Unified Huntington s Disease Rating Scale (UHDRS), a research tool which has been developed by the Huntington Study Group to provide a uniform assessment of the clinical features and course of HD. Unified Huntington's Disease Rating Scale (UHDRS) has undergone extensive reliability and validity testing. This scale has been used as a major outcome measure by the Huntington Study Group in controlled clinical trials. A majority of studies use the chorea subscale of the UHDRS to evaluate response to tetrabenazine on chorea symptoms due to HD. Studies that have used the UHDRS Chorea Score as a primary outcome for efficacy report an aggregate score that is based on rating chorea in seven body regions (face, buccal-oral-lingual, trunk and each of 4 limbs). The chorea is scored based on a 0-4 rating score with 0 = no chorea, 1=slight/intermittent, 2=mild/common or moderate/intermittent, 3=moderate/common and 4 = marked chorea. These scores are combined to make the UHDRS chorea score, which has a range of 0 to 28. AIMS score The Abnormal Involuntary Movement Scale (AIMS) is a 12-item clinician-rated scale used to assess the severity of dyskinesias. For the purposes of measuring chorea in clinical trials, typically only the first seven items are used. AIMS score is similar to the UHDRS score, in that a 0 to 4 rating is given for chorea movement for seven different body regions (face, lips, jaw, tongue, upper extremities, lower extremities, and trunk movements). The rating scale is as follows: 0=no chorea, 1=minimal, 2=mild, 3=moderate, 4=severe.. 5 point response scale Non-validated response scales have been used in studies evaluating TBZ response in HD chorea; however these response scales measure the effect on chorea movements with a 1-5 rating, with 1=marked improvement and 5=worsening of symptoms. The limitations with these scales are the lack of psychometric testing which may limit the generalizability of their results as well as their interpretation. These scales are useful because they provide a quick and easy way to assess the patient s response to TBZ and reflect improvements in their HD chorea. PIVOTAL TRIALS Tetrabenazine (Xenazine) vs. placebo TETRA-HD: Tetrabenazine was evaluated in a randomized, double-blind, placebo-controlled, 12-week study enrolling 84 ambulatory patients with Huntington disease. Patients received tetrabenazine (54 patients) or placebo (30 patients); the tetrabenazine dose was increased over 7 weeks to a maximum dose of 100 mg/day, and until the desired antichoreic effect or intolerable adverse reactions occurred. Therapy with tetrabenazine was initiated with 12.5 mg once daily for 1 week, with upward titration to 12.5 mg twice daily, 12.5 mg 3 times daily, and then 12.5 mg increments weekly with continued dosing 3 times daily. The primary outcome was the change from baseline in the chorea score of the Unified Huntington Disease Rating Scale (UHDRS). The UHDRS score was reduced by 5 units in chorea severity with tetrabenazine compared with a reduction of 1.5 units with placebo (P < ). A reduction in chorea of at least 3 UHDRS units occurred in 69% of tetrabenazinetreated patients compared with 20% of placebo-treated patients (P < ). The tetrabenazine-related reduction in chorea was not related to age, gender, trinucleotide repeat length, gender of affected parent, baseline clinical global impression of severity, or baseline chorea score. Clinical global improvement was also improved to a greater extent in the tetrabenazine group. An improvement in global improvement score to at least 3 (corresponding to at least minimal global improvement) occurred in 69% of patients treated with tetrabenazine compared with 24% treated with placebo (P = ). Poor baseline Functional Impact Scale scores predicted a favorable chorea response (85% vs 46%; P = 0.005), as did low baseline Stroop Page 14 of 23

15 Color-Naming scores (77% vs 48%; P = 0.043). No baseline variables predicted the final dosage or the occurrence of somnolence, insomnia, or fatigue. Although tetrabenazine-treated patients exhibited greater motor improvement, greater improvement in cognitive assessment and functional assessment on the UHDRS was observed in the placebo-treated patients, prompting an FDA advisory committee review. References: Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006; 66(3): Frank S for the Huntington Study Group/TETRA-HD Investigators. Tetrabenazine as anti-chorea therapy in Huntington disease: an open-label continuation study. BMC Neurol. 2009; 9: 62. DOI: / CLINICAL PRACTICE GUIDELINES NOTE: Deutetrabenazine (Austedo) and valbenazine (Ingrezza) have not been addressed in clinical practice guidelines as of this writing in January 2018 TARDIVE DYSKINESIA AMERICAN ACADEMY OF NEUROLOGY (AAN) Evidence-Based Guideline: Treatment of Tardive Syndromes: Report of the Guideline Development Subcommittee of the American Academy of Neurology (Bhidayasiri et al 2013) The AAN guidelines were originally published in 2013 and reaffirmed by the AAN on July 16, 2016 AAN guideline states that treatments for tardive dyskinesia caused by prolonged use of dopamine receptor blocking agents include amantadine, clonazepam, ginkgo biloba extract, or tetrabenazine; switching from a first-generation antipsychotic to a second-generation antipsychotic may lower the risk of tardive dyskinesia. The AAN does not provide any Level A recommendations for the treatment of tardive syndromes; however, it does list ginkgo biloba extract and clonazepam as Level B recommendations. Level A recommendations (recommendation must be done; high confidence in the evidence with high benefit and low risk) None Level B recommendations (recommendation should be done based on benefit/risk profile) Ginkgo biloba extract (EGb-761) for schizophrenia only Clonazepam, for short-term use Level C recommendations (recommendation may or might be done; lowest recommendation level considered useful within the scope of practice) Amantadine for short-term use Tetrabenazine Level U (available evidence is insufficient to support or refute efficacy of an intervention) Withdrawal of DRBAs Switching from typical to atypical antipsychotics Acetazolamide plus thiamine Typical antipsychotics Atypical antipsychotics Electroconvulsive therapy Reserpine or α-methyldopa Bromocriptine Anticholinergic agents (other than galantamine) Biperiden discontinuation Antioxidants (vitamin E, vitamin B6, melatonin, selegiline, yi-gan san) Page 15 of 23

16 Baclofen Levetiracetam Nifedipine Buspirone Botulinum toxin Pallidal deep-brain stimulation Potential interventions assessed included discontinuing dopamine receptor antagonists, switching from first generation to second generation antipsychotics, pharmacological medications, chemodenervation with botulinum toxin (BoNT), and surgical therapy, such as pallidal deep brain stimulation (DBS). Data were insufficient to support or refute TD treatment by discontinuation of a dopamine receptor antagonist, switching from first generation to second generation antipsychotics, botulinum toxin, or pallidal deep brain stimulation (DBS) therapies. Data are insufficient to support or refute the use of acetazolamide, anticholinergic drugs, baclofen, bromocriptine, buspirone, levetiracetam, nifedipine, selegiline, and vitamin B 6. Diltiazem probably does not reduce tardive dyskinesia and should not be considered as treatment. Galantamine is possibly ineffective. HAYES At the time of this writing in March 2018, a Hayes Directory report addressing the management of Tardive Dyskinesia and Huntington Disease is not available. Page 16 of 23

17 DEFINITIONS Chorea: a rapid, involuntary, non-repetitive movement involving the face, trunk, and limbs. Huntington s Disease: an inherited progressive neurodegenerative disorder characterized by chorea, psychiatric problems, and dementia. APPENDIX Appendix 1: Centrally-Acting Dopamine Receptor Blocking Agents (Neuroleptics) Drugs that most commonly cause TD are older antipsychotic agents such as haloperidol, chlorpromazine, and thioridazine; other drugs that may be associated with TD include antidepressants (amitriptyline, fluoxetine, phenelzine, sertraline, and trazodone), anti-parkinson s drugs (levodopa), epilepsy drugs (phenobarbital and phenytoin), and metoclopramide. NOTE: Table below is a reference only and may not all-inclusive of every causative agent. If the suspected/causative agent is not listed below, confirm the status of the agent as a centrally acting DRBA and its association with tardive dyskinesia. PHARMACOLOGIC CLASS First-Generation (Typical) Antipsychotics THERAPEUTIC CLASS Antiemetic Agents Tricyclic Antidepressants Phenothiazine Butryophenone Substituted benzamide Dibenzazepine Diphenylbutylpiperidine Quinolone Dibenzazepine Piperazine Dibenzodiazephine Benzisoxazole Benzisothiazole Thienobenzodiazepine Pyrimidinone Chlorpromazine Fluphenazine Perphenazine Thioridazine Thiothixene Trifluoperazine Haloperidol Chlorpromazine Perphenazine Prochlorperazine Promethazine (First generation H1 antagonist) Thiethylperazine Droperidol Haloperidol (Off-label use) Metoclopromide Trimethobenzamide Loxapine Pimozide Second-Generation (atypical) Antipsychotics Aripiprazole, brexpiprazole Asenapine Cariprazine Clozapine, quetiapine Iloperidone Lurasidone, ziprasidone Olanzapine Paliperidone, risperidone Amoxapine (a dibenzoxapine that shares properties with phenothiazines) Page 17 of 23

18 Appendix 2: VMAT2 Inhibitors All 3 agents within this class are vesicular monoamine transporter 2 (VMAT2) inhibitors. Via reversible inhibition at this transporter, these agents decrease uptake of monoamines (e.g., dopamine, norepinephrine, serotonin, histamine) into synaptic vesicles, thus depleting monoamines stores from nerve terminals. The exact benefit of deutetrabenazine (Austedo) and tetrabenazine (Xenazine) in the role of chorea treatment is unknown, but is thought to be related to the monoamine depletion. The exact mechanism by which deutetrabenazine and valbenazine (Ingrezza) exert their effects in the treatment of TD is unknown. VMAT2 Inhibitors Brand Name Recommended Dose FDA Approval Valbenazine Ingrezza 80 mg daily dose April 2017 (TD) Deutetrabenazine Austedo 12mg 48mg/day in two divided dose Tetrabenazine* Xenazine *Not approved for TD, but used off label 12.5mg 100mg/day in two to three divided doses April 2017 (HD) August 2017 (TD) May 2008 (HD) Additional pharmacologic options (e.g. benzodiazepines, anticholinergic drugs) have also been used in clinical practice for many years. [Reference: Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013] Medications used to reduce Tardive Dyskinesia Symptoms Amantadine* Anticholinergics (e.g. trihexyphenidyl, benztropine)* Benzodiazepines (e.g. clonazepam)* Second-generation antipsychotic drugs (e.g. clozapine, quetiapine)* *Not approved for TD, but used off label Page 18 of 23

19 Appendix 3: OFF-LABEL USE: TARDIVE DYSKINESIA Per Micromedex (2018): Tetrabenazine Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence favors efficacy Recommendation: Adult, Class IIb Strength of Evidence: Adult, Category B Summary Effective in 50% or more of patients in several studies Good efficacy in patients unresponsive to prior regimens Adult Oral tetrabenazine in doses up to 200 milligrams (mg) daily has abolished or reduced dyskinetic movements in at least half of patients with tardive dyskinesia, including those unresponsive to prior treatment; many patients continued to receive neuroleptics during tetrabenazine therapy. Efficacy was comparable to that of haloperidol in one small comparison. a) Tetrabenazine 25 mg two to four times daily for one week abolished facial (presumably oral) dyskinesia induced by phenothiazines (chlorpromazine, trifluoperazine) in 3 of 6 elderly patients in a placebo-controlled study. Dyskinesias reappeared within several days of discontinuing therapy. b) In a larger study (n=44), marked reduction in abnormal movements (with excellent functional improvement) was seen in 14% of patients with tardive dyskinesia unresponsive to prior therapy; 57% demonstrated moderate reduction of abnormal movements and good functional improvement. Tetrabenazine was administered for a mean of 21 months. The initial dose was 25 mg daily, with increases by 25 mg daily until 100 mg daily was reached or adverse effects intervened; patients were subsequently titrated based on response (maximum daily dose range, 25 to 200 mg). Reference: Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare) Inc. Updated periodically. Accessed March [Available with subscription]. Summary of Disease: Tardive Dyskinesia (TD) The diagnosis of TD is based upon presence of abnormal, involuntary movements, a history of taking a DRBA for at least three months, and the absence of another condition that may produce such movements. Diagnosis is therefore clinical in nature only, meaning there are no specific tests that can be done to confirm or prove the diagnosis. The severity of TD symptoms and the impact of treatment can be assessed using survey questionnaires, such as the Abnormal Involuntary Movement Scale (AIMS). While the AIMS assesses symptom severity, it is unclear how well it reflects the overall impact of TD on a patient's quality of life. Reference: Institute for Clinical and Economic Review, Final Evidence Report: VMAT2 Inhibitors for Tardive Dyskinesia: Effectiveness and Value Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) According to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), TD develops during exposure to a DRBA for 3 months (or one month in patients 60 years of age) or within four weeks of withdrawal from an oral medication (or within eight weeks of withdrawal from a depot medication). The disorder should persist for at least one month after discontinuation of an offending drug to qualify as TD (Waln and Jankovic 2013). DSM-V Definition of Tardive Dyskinesia Diagnostic and statistical manual of mental disorders, 5th Ed. American Psychiatric Association. Tardive dyskinesia is a type of movement disorder that occurs secondary to therapy with centrally acting DRBAs (Appendix 1) Medication-induced movement disorders, including tardive dyskinesia, are organized in the DSM-V as follows: neurolepticinduced parkinsonism/other medication-induced parkinsonism, neuroleptic malignant syndrome, medication-induced acute dystonia, medication-induced acute akathisia, tardive dyskinesia, tardive dystonia/tardive akathisia, medication-induced Page 19 of 23