Ingrezza Valbenazine Molina Clinical Policy

Subject: Ingrezza (valbenazine) Original Effective Date: 3/8/2018

Policy Number: MCP-306 Revision Date(s):

Review Date: 3/8/2018 MCPC Approval Date: 3/8/2018

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

This policy addresses the coverage of Ingrezza (valbenazine) for the treatment of adult patients with tardive dyskinesia (TD) when appropriate criteria are met.

The intent of the Ingrezza (valbenazine) 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.

~ 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.

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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. (Gharabawi GM, et al. 2005; cited by ICER 2017)

~ Valbenazine, a selective inhibitor of VMAT-2, is the first drug approved by the FDA for the treatment of TD. There were no FDA approved therapies before the recent approval of two VMAT2 inhibitors: Ingrezza (valbenazine) and Austedo (deutetrabenazine). --Appendix 2: VMAT2 Inhibitors

The mechanism of action of valbenazine in the treatment of TD is unknown, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. Valbenazine is a selective inhibitor of human VMAT-2, but has no appreciable binding affinity for VMAT-1. VMAT-2 is a presynaptic protein that regulates monoamine uptake (e.g., dopamine) from the cytoplasm to the synaptic vesicle for storage and release. Inhibition of VMAT-2 modulates dopaminergic transmission, potentially resulting in a reduction in synaptic dopamine levels and improvement in TD symptoms

~ The FDA approval was based on results from the KINECT 3 study, which was a phase III randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trial. • The efficacy of Ingrezza was shown in a clinical trial of 234 participants that compared Ingrezza to placebo. The trial enrolled subjects with schizophrenia, schizoaffective disorder, or a mood disorder and moderate or severe TD. Subjects were randomly to treatment with valbenazine 80 mg once daily, valbenazine 40 mg once daily, or placebo in a 1:1:1 ratio for six weeks. All the patients were put on once-daily 40mg or once-daily 80mg of Ingrezza through week 48 upon completion of six-week placebo-controlled dosing. • The AIMS was the primary efficacy measure for the assessment of TD severity. The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6. • The results of the study demonstrated that the patients treated with Ingrezza 80mg once-daily dose met the primary endpoint of change-from-baseline in AIMS at week six compared to placebo. • The change from baseline in the AIMS total dyskinesia score in the 80 mg valbenazine group was statistically significantly different from the change in the placebo group. Valbenazine reduced the AIMS score by 3.2 points compared to 0.1 points for placebo-treated patients following six weeks of treatment. The treatment difference between valbenazine and placebo was 3.1 points. • The study also revealed that patients treated with Ingrezza 80mg/day achieved higher AIMS response compared to placebo. At week six, approximately 40% of the patients that received the Ingrezza 80mg/day dose had a 50% improvement in AIMS dyskinesia score compared to 8.7% in placebo-administered patients. ® Valbenazine 40 mg, was associated with a 1.9 point decrease in AIMS score, while valbenazine 80 mg, was associated with a 3.2 point decrease in AIMS score, and compared with 0.1 point decrease for placebo (P < .05 for valbenazine, 40 mg, P < .001 for valbenazine, 80 mg).

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® This difference for the 40-mg dosage did not meet the pre-specified analysis endpoints; however, for the 80-mg valbenazine dosage, the effect size for this difference (Cohen’s d) was large 0.90. There also were statistically significant differences between 40 mg and 80 mg at weeks 2, 4, and 6 in the intent-to-treat population. Of the 79 participants, 43 taking the 80-mg dosage completed a 48-week extension. Efficacy was sustained in this group; however, when valbenazine was discontinued at Week 48, AIMS scores returned to baseline after 4 weeks. • The treatment difference in this trial was considered statistically significant; however, the minimal clinically important difference for the change in AIMS score has not been established partially due to the lack of comparability between multiple versions of the AIMS used in previous studies in TD. It is unknown if the change in score observed in this study improves function or quality of life in patients with tardive dyskinesia.

~ Adverse Reactions The most common adverse effects observed with valbenazine (both dosage groups combined) vs. placebo were somnolence (5.3% vs. 3.9%), akathisia (3.3% vs. 1.3%), and dry mouth (3.3% vs. 1.3%). Suicidal ideation was the most common AE in the placebo group (5.3% vs. 2.6% in both valbenazine groups combined).

~ CLINICAL PRACTICE GUIDELINES © 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.

© The AAN published guidelines on the treatment of tardive syndromes in 2013, however valbenazine (Ingrezza) 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.

~ Valbenazine has demonstrated clinical improvement in tardive dyskinesia, occurring in some patients within 2 weeks of starting therapy; however, mean AIMS dyskinesia total score returned toward baseline after discontinuation of valbenazine therapy. Clinical information regarding valbenazine is limited because it has been evaluated as a "breakthrough" therapy.

~ The long-term benefits and risks of valbenazine remain to be determined as more data are needed to determine the long-term efficacy and safety of valbenazine, and to learn whether it offers any advantage over tetrabenazine.

CLASSIFICATION: Central Monoamine-Depleting Agent; Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor

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FDA INDICATIONS

~ Tardive dyskinesia Treatment of tardive dyskinesia in adults Valbenazine was granted priority review, accelerated approval, breakthrough therapy designation by the FDA.

Available as: Capsules: 40 mg, 80 mg

FDA Approved: April 11, 2017

Black Box Warnings: There are no Black Box Warnings at this time

REMS: No REMS is required for valbenazine at the time of this writing

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RECOMMENDATIONS/COVERAGE CRITERIA

Ingrezza (valbenazine) may be authorized for members who meet ALL of the following criteria [ALL]

1. � Prescriber specialty [ONE]

¶ Prescribed by, or in consultation with, a board-certified psychiatrist or neurologist OR physician experienced in the treatment of Tardive Dyskinesia. 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 [ONE]

¶ 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 tardive dyskinesia 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. 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 ® Reference: AIMS greater than or equal to 10 criteria: A Phase 3 Study of NBI-98854 for the Treatment of Tardive Dyskinesia (KINECT 3) https://clinicaltrials.gov/ct2/show/results/NCT02274558?term=NBI-98854-1304&rank=2 ® Though there is currently no validated measure that reflects the impact of TD on a patient's quality of life, the AIMS has been used in clinical and research settings to assess the general severity of symptoms and the impact of treatment. (Gharabawi GM, et al. 2005; cited by ICER 2017) ® The key secondary endpoint of mean Clinical Global Impression of Change - Tardive Dyskinesia (CGI-TD) score was used by site investigators to rate the overall change in TD from baseline at Week 6. CGI-TD scores ranged from 1 (very much improved) to 7 (very much worse). The mean CGI-TD score did not reach statistical significance for either valbenazine dosage group when compared to placebo (p = 0.056 and p = 0.074 for valbenazine 80 mg and 40 mg, respectively).

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3. � Age/Gender/Restrictions [ALL]

¶ 18 years of age or older ® Safety and efficacy of valbenazine have not been established in pediatric patients. ® The FDA has waived the regulatory requirement (Pediatric Research Equity Act [21 U.S.C. 355c]) for pediatric studies because the necessary studies would be impossible or highly impracticable. Reference: Unger EF. NDA approval letter: Ingrezza (valbenazine NDA 209241). Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/209241Orig1s000ltr.pdf. Published April 11, 2017.

¶ No prior medical history of, or significant risk for: suicidal ideation, violent behavior, or unstable psychiatric symptoms. Documentation required.

4. � Conventional Therapy/Concurrent Therapy/Other Requirements [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

û Prescriber has reduced the dose or discontinued medication(s) known to cause tardive dyskinesia [Refer to Appendix 1] OR Prescriber has 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 (Tarsy, D. Tardive dyskinesia: Prevention and treatment. In: UpToDate).

û At least ONE (1) medication used to reduce tardive dyskinesia symptoms [i.e. benzodiazepines (clonazepam) [Refer to Appendix 1] *Off-label use of various pharmacologic options encompasses the standard treatment approach for controlling symptoms of tardive dyskinesia severe enough to warrant treatment.

û tetrabenazine (Xenazine) at up to 100 mg/day [REFER TO MCP-075: Xenazine (tetrabenazine)]

û Austedo (deutetrabenazine): Inadequate response to therapy after at least 12 weeks of treatment on the labeled dose for Tardive Dyskinesia. Documentation required. [REFER TO MCP-307]

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¶ Ingrezza (valbenazine) is not prescribed with nor intended for use in combination with the following therapies: [ANY]

û Other VMAT2 Inhibitors: [ANY] o tetrabenazine (Xenazine) o deutetrabenazine (Austedo)

û MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate)]

û QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents]

Informational Note: ® Concurrent use with other VMAT2 inhibitors such as tetrabenazine or valbenazine is considered duplicate therapy. Deutetrabenazine may enhance the adverse/toxic effect of Valbenazine. Refer to Appendix 2 for VMAT2 Inhibitors and recommended dosages. ® Valbenazine may enhance the adverse/toxic effect of MAOI (monoamine oxidase inhibitors) ® Avoid use in patients with congenital long QT syndrome or arrhythmias associated with prolonged QT interval. For patients at risk of prolonged QT interval, perform EKG before increasing the dosage.

5. � Contraindications*/Exclusions/Discontinuations *There are no contraindications listed in the manufacturer's labeling. Authorization will not be granted if ANY of the following conditions apply [ANY] ¶ Non-FDA approved indications ¶ Younger than 18 years ¶ Hypersensitivity to valbenazine or any component of the formulation [inactive ingredients (mannitol, partially pregelatinized starch, fumed silica, magnesium stearate, gelatin, candurin silver fine, FD&C Red No. 40, and FD&C Blue No. 1)] ¶ Serious untreated or undertreated psychiatric illness, such as depression ¶ A history of significant suicidal thoughts or behavior ¶ Congenital long QT syndrome or with 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. ® Ingrezza may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. Ingrezza should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval ¶ Severe renal impairment (creatinine clearance 30 mL/min or less) NOTE: Members with a history of renal impairment, appropriate labs and/or additional documentation may be requested at the discretion of the Pharmacy/Medical Director. ¶ Moderate or severe hepatic impairment (use reduced dose) 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. ¶ Concomitant therapy with ANY of the following will NOT be authorized: [ANY] û Other VMAT2 inhibitors: Austedo (deutetrabenazine) or tetrabenazine (Xenazine) û MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine(Nardil), tranylcypromine (Parnate)] û QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents] Page 7 of 22

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.

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CONTINUATION OF THERAPY Ingrezza (valbenazine) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL]

1. � Initial Coverage Criteria [ALL]

ß Member currently meets ALL initial coverage criteria

ß 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. Compliance [ALL]

ß Adherence to therapy at least 85% of the time as verified by Prescriber and member’s medication fill history (review Rx history for compliance), including: û Adherent to the prescribed medication regimen û Tolerance to therapy û No severe adverse reactions or drug toxicity

NOTE: 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

NOTE: History of non-compliance or non-adherence as verified by member’s medication fill history or prescription drug profile may result in continuation of therapy request not being authorized. [MOLINA MEDICAL/PHARMACY REVIEWER TO VERIFY]

3. � Labs/Reports/Documentation required [ALL] Ingrezza (valbenazine) therapy may be authorized when therapy has demonstrated efficacy as evidenced by an improvement in disease activity after initial therapy documentation by: [ALL]

¶ Improvement in TD symptoms due to Ingrezza therapy as documented by AIMS score (items 1-7): decrease from baseline by at least 2 points

Informational Note: The change from baseline in the AIMS total dyskinesia score in the 80 mg valbenazine group was statistically significantly different from the change in the placebo group. Valbenazine (Ingrezza) reduced the AIMS score by 3.2 points compared to 0.1 points for placebo-treated patients following six weeks of treatment. The treatment difference between valbenazine (Ingrezza) and placebo was 3.1 points.

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¶ STABLE psychiatric status AND ALL of the following as applicable to member. Documentation required [ALL APPLICABLE] û For members on maintenance medication(s) for schizophrenia or schizoaffective disorder, or mood disorders): Stable medication doses and therapy required. û 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 behavioral health provider is required. o Member is not experiencing suicidal thoughts or behaviors

Informational Note: ® Valbenazine has not been associated with an increased risk of depression or suicidal ideation to date, but patients at risk for these effects were excluded from clinical trials. ® Pivotal Trial (KINETIC 3) exclusion criteria included clinically significant unstable medical condition within 1 month prior to screening; history of substance or alcohol abuse and risk of suicidal or violent behavior. ® KINETIC 3 trial resulted in withdrawal due to serious adverse events in 5 patients with valbenazine (worsening of schizoaffective disorder, suicide attempt, suicidal ideation, and reactivation of viral hepatitis) and in 2 patients with placebo (worsening of schizoaffective disorder, altered mental status due to exacerbation of chronic obstructive pulmonary disease)

¶ Ingrezza (valbenazine) is not prescribed with nor intended for use in combination with the following therapies: [ANY]

û Other VMAT2 Inhibitors: [ANY] o tetrabenazine (Xenazine) o deutetrabenazine (Austedo)

û MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate)]

û QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents]

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4. � Discontinuation of Treatment [ANY] Discontinue treatment if ANY of the following conditions applies: [ANY] ß Intolerable adverse effects or drug toxicity ß Persistent and uncorrectable problems with adherence to treatment ß Poor response to treatment as evidenced by physical findings and/or clinical symptoms Contraindications*/Exclusions/Discontinuations Authorization for continuation of treatment will not be granted if ANY of the following conditions apply [ANY] *There are no contraindications listed in the manufacturer's labeling. ¶ Non-FDA approved indications ¶ Younger than 18 years ¶ Hypersensitivity to valbenazine or any component of the formulation [inactive ingredients (mannitol, partially pregelatinized starch, fumed silica, magnesium stearate, gelatin, candurin silver fine, FD&C Red No. 40, and FD&C Blue No. 1)] ¶ Serious untreated or undertreated psychiatric illness, such as depression ¶ A history of significant suicidal thoughts or behavior ¶ Congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval ® Ingrezza may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. Ingrezza should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval ¶ Severe renal impairment (creatinine clearance 30 mL/min or less) ¶ Concomitant therapy with ANY of the following will NOT be authorized: [ANY] û Other VMAT2 inhibitors: Austedo (deutetrabenazine) or tetrabenazine (Xenazine) û MAOI (monoamine oxidase inhibitors) [e.g., selegiline (Emsam), isocarboxazid (Marplan), phenelzine(Nardil), tranylcypromine (Parnate)] û QTc-prolonging agents [e.g., antipsychotic agents (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin), class IA and III antiarrhythmic agents]

5. � 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.

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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]

¶ The initial dose of Ingrezza is 40 mg by mouth once daily, with or without food. After 1 week, the dose should be increased to 80 mg once daily. However, patients with moderate or severe hepatic impairment should continue with 40 mg daily, and a dose reduction may be required in patients who are known CYP2D6 poor metabolizers.

2. � Authorization Limit [ALL]

¶ Quantity limit: [ALL] û 80 mg/day û 2 capsules per day

¶ Dispensing limit: Only a 1-month supply may be dispensed at a time

¶ Duration authorization: [ALL] û Initial: 3 months û 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]

¶ Ingrezza (valbenazine) is considered a self-administered medication. Ingrezza (valbenazine) 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.

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COVERAGE EXCLUSIONS

This policy addresses the coverage of Ingrezza (valbenazine) for the treatment of adult patients with tardive dyskinesia when appropriate criteria are met.

The safety and effectiveness of valbenazine (Ingrezza) in conditions other than tardive dyskinesia have not been established.

All other uses of Ingrezza (valbenazine) 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.

SUMMARY OF EVIDENCE/POSITION

TARDIVE DYSKINESIA

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: 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. • 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 dyskinesia is usually time limited, lasting less than 4-8 weeks, dyskinesia that persists beyond this window is considered to be tardive dyskinesia.

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ASSESSING TARDIVE DYSKINESIA (TD) has been complicated by the use of different research criteria and rating scales. We studied concordance between two commonly used scales, the Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS), to study interscale concordance and criteria to define TD.

~ Abnormal Involuntary Movement Scale (AIMS) The most widely used instrument is the Abnormal Involuntary Movement Scale (AIMS) developed by the Psychopharmacology Research Branch of the National Institute of Mental Health (see the image below). Because the AIMS can be readily administered in a few minutes, it is recommended in patients receiving treatment with substances that may cause TD. Administer the AIMS at baseline before the institution of pharmacotherapy to document any movements present, then at least every 3 months thereafter during the course of treatment. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=no dyskinesia; 1=low amplitude, present during some but not most of the exam; 2=low amplitude and present during most of the exam (or moderate amplitude and present during some of the exam); 3=moderate amplitude and present during most of exam; or 4=maximal amplitude and present during most of exam. The AIMS dyskinesia total score (sum of items 1 to 7) could range from 0 to 28, with a decrease in score indicating improvement.

~ Extrapyramidal Symptom Rating Scale (ESRS) The Extrapyramidal Symptom Rating Scale (ESRS) was developed to assess four types of drug-induced movement disorders (DIMD): Parkinsonism, akathisia, dystonia, and TD. Comprehensive ESRS definitions and basic instructions are given. Factor analysis provided six ESRS factors: 1) hypokinetic Parkinsonism; 2) orofacial dyskinesia; 3) trunk/limb dyskinesia; 4) akathisia; 5) tremor; and 6) tardive dystonia. Two pivotal studies found high inter-rater reliability correlations in both antipsychotic-induced movement disorders and idiopathic Parkinson disease. For inter-rater reliability and certification of raters, >or=80% of item ratings of the complete scale should be +/-1 point of expert ratings and >or=70% of ratings on individual items of each ESRS subscale should be +/-1 point of expert ratings. During a cross-scale comparison, AIMS and ESRS were found to have a 96% (359/374) agreement between TD-defined cases by DSM-IV TD criteria. Two recent international studies using the ESRS included over 3000 patients worldwide and showed an incidence of TD ranging from 10.2% (2000) to 12% (1998). ESRS specificity was investigated through two different approaches, path analyses and ANCOVA PANSS factors changes, which found that ESRS measurement of drug-induced EPS is valid and discriminative from psychiatric symptoms. (Gharabawi GM et al. 2005 PMID: 15913963 DOI: 10.1016/j.schres.2005.03.008)

PIVOTAL TRIAL

KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia (Fernandez HH, et al. 2016) [NCT02274558]

Drug: Valbenazine vs Placebo

Subjects 234 patients 18 to 85 years of age with schizophrenia, schizoaffective disorder, or mood disorder. Patients had moderate to severe neuroleptic-induced tardive dyskinesia for at least 3 months prior to screening. Patients were required to be receiving a stable neuroleptic dose. Exclusion criteria included clinically significant unstable medical condition within 1 month prior to screening; history of substance or alcohol abuse, neuroleptic malignant syndrome, or long QT syndrome or cardiac tachyarrhythmia; risk of suicidal or violent behavior; previous exposure to an investigational drug (within 30 days prior to screening) or to valbenazine; pregnancy or breastfeeding; or known allergy or hypersensitivity to tetrabenazine. Average baseline patient characteristics were as follows: age was 56.1 years, 54.2% were male, 56.4% were white, 38.3% were black, 66.1% had schizophrenia or schizoaffective disorder, 86% were receiving concomitant antipsychotic medications (16.7% typical, 76.7% atypical), and mean baseline Abnormal Involuntary Movements Scale (AIMS) score was 10. The study was completed by 205 (87.6%) patients. Page 14 of 22

Intervention Patients were randomized (1:1:1) to treatment with valbenazine 40 mg, valbenazine 80 mg, or placebo once daily in the morning (between 7 AM and 10 AM) for 6 weeks. The valbenazine 40 mg group received 1 valbenazine 40 mg capsule and 1 placebo capsule; the valbenazine 80 mg group received 1 valbenazine 40 mg capsule and 1 placebo capsule for the first week, then 2 valbenazine 40 mg capsules for the remaining 5 weeks; and the placebo group received 2 placebo capsules. At week 6, placebo subjects were re-randomized to valbenazine 40 mg or 80 mg once daily for the remainder of the study, while patients initially randomized to valbenazine 40 mg or 80 mg remained at their current dose (with subjects re-randomized to valbenazine 80 mg receiving 40 mg for the first week) for the remainder of the study (42 weeks).

Results Primary End Point(s) • Change in severity of tardive dyskinesia symptoms, as assessed by AIMS score least squares (LS) mean change from baseline to week 6, was −0.1 with placebo, −3.2 with valbenazine 80 mg (P<0.001 vs placebo), and −1.9 with valbenazine 40 mg (P=0.002 vs placebo).

Secondary End Point(s) • Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) mean score at week 6 was 3.2 with placebo, 2.9 with valbenazine 40 mg (P=0.074 vs placebo), and 2.9 with valbenazine 80 mg (P=0.056 vs placebo).

Comments ® The study was conducted at 63 sites. The results from KINECT 3 are favorable and show a potential beneficial effect within 2 weeks of valbenazine treatment, with no alteration in patient psychiatric status. ® Subgroup analyses by race, age, gender, underlying psychiatric diagnostic category, and concomitant antipsychotic medication did not show clear evidence of differential responsiveness. ® Earlier phase 2 studies (e.g., KINECT 2) demonstrated similar results. ® Results of a completed open-label, nonrandomized phase 3 safety and tolerability study (KINECT 4) have not been published. An open-label, rollover, phase 3b extension study conducted in subjects completing KINECT 3 or KINECT 4 provided subjects open-label access to valbenazine until commercial availability of the drug, or up to 72 weeks of treatment; results have not been published. ® Among patients remaining in KINECT 3 at the end of the 48-week treatment (n=123), mean AIMS dyskinesia total score appeared to return toward baseline after discontinuation of valbenazine therapy.

Limitations The majority of the results are from the first 6 weeks of therapy. The longest treatment duration with valbenazine was 48 weeks.

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CLINICAL PRACTICE GUIDELINES NOTE: Deutetrabenazine (Austedo) and valbenazine (Ingrezza) have not been addressed in clinical practice guidelines as of this writing in January 2018

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) ° 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).

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~ 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 B6.

~ 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 January 2018, a Hayes Directory report addressing the management of ‘Tardive Dyskinesia’ is not available.

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DEFINITIONS

N/A �

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.

THERAPEUTIC CLASS PHARMACOLOGIC First- Tricyclic CLASS Generation Antiemetic Agents Antidepressants (Typical)

Chlorpromazine Chlorpromazine Fluphenazine Perphenazine Amoxapine Phenothiazine Perphenazine Prochlorperazine (a dibenzoxapine that shares properties with Thioridazine Promethazine (First generation H1 antagonist) phenothiazines) Thiothixene Thiethylperazine Trifluoperazine

Droperidol Butryophenone Haloperidol Haloperidol (Off-label use)

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

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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) April 2017 (HD) Deutetrabenazine Austedo 12mg – 48mg/day in two divided dose August 2017 (TD) 12.5mg – 100mg/day in two to three divided Tetrabenazine* Xenazine May 2008 (HD) doses *Not approved for TD, but used off label

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 �

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CODING INFORMATION: THE CODES LISTED IN THIS CLINICAL POLICY ARE FOR INFORMATIONAL PURPOSES ONLY. LISTING OF A SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON- COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE AND INCLUSION OR EXCLUSION OF ANY CODES DOES NOT GUARANTEE COVERAGE. PROVIDERS SHOULD REFERENCE THE MOST UP-TO-DATE SOURCES OF PROFESSIONAL CODING GUIDANCE PRIOR TO THE SUBMISSION OF CLAIMS FOR REIMBURSEMENT OF COVERED SERVICES. CPT Description NA

HCPCS Description J8499 Prescription drug, oral, non-chemotherapeutic, Not Otherwise Specified

ICD-10 Description [For dates of service on or after 10/01/2015] G24.01 Drug-induced subacute dyskinesia

*CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

REFERENCES

PACKAGE INSERT, FDA, DRUG COMPENDIA Ingrezza (valbenazine) [prescribing information]. San Diego, CA: Neurocrine Biosciences Inc; October 2017.

Drug Facts and Comparisons. Facts and Comparisons eAnswers [online]. Clinical Drug Information LLC, 2017. Available from Wolters Kluwer Health, Inc. Accessed January 2018. [available with subscription]

DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. 113751, Tardive dyskinesia; [updated 2017 May 18, cited January 2018]; [about 14 screens]. Available from http://www.dynamed.com/login.aspx?direct=true&site=DynaMed&id=113751. Registration and login required.

Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at www.clinicalpharmacology.com. Accessed January 2018. [available with subscription]

Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare) Inc. Updated periodically. http://www.thomsonhc.com. Accessed January 2018. [available with subscription].

US National Institutes of Health. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2017 April 14]. Available from: https://www.clinicaltrials.gov/. Accessed on January 2018. Search term: deutetrabenazine.

FDA approves first drug to treat tardive dyskinesia [news release]. FDA’s website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm552418.htm?source=govdelivery&utm_ medium=email&utm_source=govdelivery. Accessed January 2018.

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CLINICAL TRIALS, DEFINITIONS, PEER-REVIEWED PUBLICATIONS

Medication-induced movement disorders and other adverse effects of medication. Diagnostic and statistical manual of mental disorders, 5th Ed. American Psychiatric Association.

Factor SA, Remington G, Comella CL, et al. The effects of valbenazine in participants with tardive dyskinesia: results of the 1-year KINECT 3 extension study. [published online November 14, 2017]. J Clin Psych.[PubMed 29141124]10.4088/JCP.17m11777

G Chouinard, H Margolese. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophrenia Research 76 (2005) 247–265.

Gharabawi GM, Bossie CA, Lasser RA, Turkoz I, Rodriguez S, Chouinard G. Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS): cross-scale comparison in assessing tardive dyskinesia. Schizophrenia research. 2005;77(2-3):119-128.

Hauser RA, Factor SA, Marder SR, et al. KINECT 3: A phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484.[PubMed 28320223]

Neurocrine Biosciences. A phase 3 study of NBI-98854 for the treatment of tardive dyskinesia (KINECT 3). ClinicalTrials.gov website. https://www.clinicaltrials.gov/ct2/show/NCT02274558. Updated October 12, 2016. Accessed January 2018. NLM Identifier: NCT02274558.

Camilleri M. Treatment of gastroparesis. In: UpToDate. Waltham, MA: Walters Kluwer Health; 2017. Available at www.uptodate.com. Accessed January 2018

Suchowersky O, Bouchard M. Overview of chorea. In: UpToDate. Waltham, MA: Walters Kluwer Health; 2017. Available at www.uptodate.com. Accessed January 2018

Tarsy D. Tardive dyskinesia: Etiology and epidemiology. In: UpToDate. Waltham, MA: Walters Kluwer Health; 2017. Available at www.uptodate.com. Accessed January 2018

Tarsy D. Tardive dyskinesia: Clinical features and diagnosis. In: UpToDate. Waltham, MA: Walters Kluwer Health; 2017. Available at www.uptodate.com. Accessed January 2018

Tarsy, D. Tardive dyskinesia: Prevention and treatment. In: UpToDate, Hurtig, H (Ed). UpToDate, Waltham, MA, 2017.

GOVERNMENT AGENCIES, PROFESSIONAL SOCIETIES, AND OTHER AUTHORITATIVE PUBLICATIONS American Academy of Neurology. Summary of evidence-based guideline for patients and their families: Treating and managing tardive syndromes. https://www.aan.com/Guidelines/home/GetGuidelineContent/614. Published 2013. Accessed January 2018. American Academy of Neurology. Summary of evidence-based guideline for clinicians: Treatment of tardive syndromes. https://www.aan.com/Guidelines/home/GetGuidelineContent/613. Published 2013. Accessed January 2018. Bhidayasiri R, Fahn S, Weiner WJ, Gronseth GS, Sullivan KL, Zesiewicz TA; American Academy of Neurology. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2013;81(22):1968]. Neurology. 2013;81(5):463-469.[PubMed 23897874]

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American Psychiatric Association. (2013). Medication-induced movement disorders and other adverse effects of medication. In Diagnostic and statistical manual of mental disorders (5th ed.). Available at: http://dx. doi/full/10.1176/appi.books.9780890425596.MedicationInduced#x45151.2829056. Accessed January 2018.

Institute for Clinical and Economic Review (ICER). Vesicular Monoamine Transporter 2 Inhibitors for Tardive Dyskinesia: Effectiveness and Value. Revised Background and Scope. June 9, 2017. Available at: https://icer- review.org/wp-content/uploads/2017/04/NECEPAC_TD_Final_Scope_06.09.17.pdf Accessed January 2018.

Policy History MCPC Policy Developed 3/8/18 AMR Peer Review Network. 1/29/2018. Board certified in Neurology, Pain Medicine

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