Policy: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors Reference Number: TCHP.PHAR.181 Effective Date: 07.01.18 Last Review Date: 04.09.20 Line of Business: Oregon Health Plan Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Goal(s): Promote safe use of VMAT2 inhibitors in adult patients. Promote use that is consistent with medical evidence and product labeling. Length of Authorization: Initial: Up to 2 months Renewal: Up to 12 months Requires PA: All VMAT2 inhibitors Covered Alternatives: Current Trillium Preferred Drug List listed at: o https://www.trilliumohp.com/providers/helpful-links.html I. Initial Approval Criteria A. Huntington’s Disease (must meet all): 1. Diagnosis of chorea associated with Huntington’s disease; 2. Baseline total maximal chorea score of 8 or higher; 3. Age ≥ 18 years; 4. Patient is determined to not have uncontrolled depression or be at risk of violent or suicidal behavior; 5. Patient is not at risk for a prolonged QT interval; 6. Request is for one of the following (a or b): a. Request is for tetrabenazine; b. Request is for deutetrabenazine and patient has had failure of tetrabenazine at up to 100 mg/day, unless contraindicated or clinically significant adverse effects are experienced 7. At the time of request, tetrabenazine or valbenazine is not prescribed concomitantly; 8. Dose does not exceed the FDA-approved maximum recommended dose. Approval duration: 2 months B. Tardive Dyskinesia (must meet all): 1. Diagnosis of moderate to severe tardive dyskinesia secondary to a centrally acting dopamine receptor blocking agent (DRBA); *See Appendix D; if the offending agent is not included in Appendix D, the status of the agent as a centrally acting DRBA as well as its association with tardive dyskinesia should be confirmed. 2. Prescribed by or in consultation with a psychiatrist or neurologist; 3. Age ≥ 18 years; 4. Request is for one of the following (a or b): Page 1 of 6 a. Request is for deutetrabenazine; b. Request is for valbenazine; 5. Patient is not at risk for a prolonged QT interval; 6. Dose does not exceed the FDA-approved maximum recommended dose. Approval duration: 2 months C. Other diagnoses/indications 1. Refer to the off-label use policy for the relevant line of business if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized): CP.PMN.53 for Medicaid. II. Continued Therapy A. Huntington’s Disease (must meet all): 1. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; 2. Patient is responding positively to therapy as documented by evidence of improvement in total maximal chorea score of at least 2 points from baseline; 3. Metal status of the patient is stable and there is no risk of uncontrolled depression or risk of violent or suicidal behavior; 4. If request is for a dose increase, new dose does not exceed the FDA-approved maximum recommended dose. Approval duration: 12 months B. Tardive Dyskinesia (must meet all): 5. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; 6. Patient is responding positively to therapy as documented by evidence of improvement by a reduction in AIMS dyskinesia score (Items 1-7) by at least 50%; 7. Metal status of the patient is stable and there is no risk of uncontrolled depression or risk of violent or suicidal behavior; 8. If request is for a dose increase, new dose does not exceed the FDA-approved maximum recommended dose. Approval duration: 12 months C. Other diagnoses/indications (must meet 1 or 2): 1. Currently receiving medication via Centene benefit and documentation supports positive response to therapy. Approval duration: Duration of request or 6 months (whichever is less); or 2. Refer to the off-label use policy for the relevant line of business if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized): CP.CPA.09 for commercial, HIM.PHAR.21 for health insurance marketplace, and CP.PMN.53 for Medicaid. III. Appendices/General Information: Appendix A: General Information: Ingrezza should not be used concurrently with other VMAT2 inhibitors such as tetrabenazine or deutetrabenazine as this is considered duplicate therapy. Page 2 of 6 Xenazine is contraindicated in patients: o Who are actively suicidal, or who have depression which is untreated or undertreated; o Taking monoamine oxidase inhibitors (MAOIs). Xenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI; o Taking reserpine. At least 20 days should elapse after stopping reserpine before starting Xenazine Medication-induced movement disorders, including tardive dyskinesia, are organized in the DSM V as follows: neuroleptic-induced parkinsonism/other medication-induced parkinsonism, neuroleptic malignant syndrome, medication-induced acute dystonia, medication-induced acute akathisia, tardive dyskinesia, tardive dystonia/tardive akathisia, medication-induced postural tremor, other medication-induced movement disorder, antidepressant discontinuation syndrome, and other adverse effects of medication.5 Tardive dyskinesia is a type of movement disorder that occurs secondary to therapy with centrally acting DRBAs (Appendix C).5 Typical therapeutic drug classes containing DRBAs include first- and second-generation antipsychotics, antiemetics, and tri-cyclic antidepressants (Appendix D).5 Other therapeutic drug classes containing agents that have been variously associated with movement disorders are listed below:6-8 o Antiarrhythmics o Central nervous system stimulants o Antibiotics o Dopamine agonists o Anticholinergics o Dopamine depleting agents o Antidepressants o Dopaminergics o Antiepileptics o Glucocorticoids o Antihistamines o Immunosuppressants o Antimanics o Mood stabilizers o Bronchodilators o Muscle relaxants o Calcium channel blockers o Oral contraceptives Appendix B: Contraindications/Boxed Warnings Contraindication(s): o QT prolongation o Neuroleptic Malignant Syndrome (NMS) o Akathisia, agitation, restlessness, and parkinsonism o Sedation/somnolence Boxed warning(s): o Depression and suicidality Appendix C: DSM-V Definition of Tardive Dyskinesia Tardive Dyskinesia (ICD-9 333.85/ICD-10 G24.01) Involuntary athetoid or choreiform movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, diaphragmatic, or trunk muscles) developing in association with the use of a neuroleptic medication for at least a few months. Symptoms may develop after a shorter period of medication use in older persons. In some patients, movements of this type may appear after discontinuation, or after change or reduction in dosage, of neuroleptic medications, in which case the condition is called neuroleptic withdrawal emergent dyskinesia. Because withdrawal emergent Page 3 of 6 dyskinesia is usually time limited, lasting less than 4-8 weeks, dyskinesia that persists beyond this window is considered to be tardive dyskinesia. Appendix D: Centrally Acting Dopamine Receptor Blocking Agents (Neuroleptics)5,6,9,10 Pharmacologic Class Therapeutic Class First-generation Antiemetic agents Tri-cyclic (typical) antidepressants antipsychotics Phenothiazine Chlorpromazine Chlorpromazine Amoxapine† Fluphenazine Perphenazine Perphenazine Prochlorperazine Thioridazine Promethazine* Thiothixene Thiethylperazine Trifluoperazine Butryophenone Haloperidol Droperidol Haloperidol** Substituted benzamide Metoclopromide Trimethobenzamide Dibenzazepine Loxapine Diphenylbutylpiperidine Pimozide Second-generation (atypical) antipsychotics Quinolone Aripiprazole, brexpiprazole Dibenzazepine Asenapine Piperazine Cariprazine Dibenzodiazephine Clozapine, quetiapine Benzisoxazole Iloperidone Benzisothiazole Lurasidone, ziprasidone Thienobenzodiazepine Olanzapine Pyrimidinone Paliperidone, risperidone *First generation H1 antagonist **Off-label use †A dibenzoxapine that shares properties with phenothiazines Appendix E: Dosage and Administration Medication Indication Dosing Regimen Maximum Dose Valbenazine Tardive dyskinesia 40 mg once daily; after a week, increase to 80 mg/day 80 mg if needed Tetrabenazine Chorea associated 12.5 mg PO QD for first week, then 12.5 50 mg/day (max with Huntington’s mg PO BID for second week, then titrate single dose of 25 mg) disease by 12.5 mg weekly thereafter to tolerated dose that reduces chorea; doses of 37.5 mg Extensive or and up to 50 mg/day should be intermediate administered in 3 divided doses per day CYP2D6 metabolizer: 100 mg/day (max single dose of 37.5 mg) Page 4 of 6 Medication Indication Dosing Regimen Maximum Dose Deutetrabenazine Huntington’s 6 mg/day (6 mg once daily) PO; may be 48 mg/day (18 chorea increased weekly by increments of 6 mg/dose and 36 mg/day to a maximum of 48 mg/day mg/day in poor CYP2D6 metabolizers) Tardive dyskinesia 12 mg/day (6 mg twice daily) PO; may be 48 mg/day (18 increased weekly by increments of 6 mg/dose and 36 mg/day to a maximum of 48 mg/day mg/day in poor CYP2D6 metabolizers) Appendix F: Product Availability: Medication Formulation and Strength Valbenazine Capsules: 40 mg, 80 mg Tetrabenazine Tablets: 12.5 mg, 25 mg Deutetrabenazine Tablets: 6 mg, 9 mg, 12 mg IV. References 1. Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors. Oregon Health Plan Current Drug Use Criteria. Available at: http://orpdl.org/drugs/index.php.