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ph-1152

Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-1152

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.

POLICY REVIEW CYCLE

Effective Date	Date of Origin
7/1/2023	10/1/2021

FDA APPROVED INDICATIONS AND DOSAGE

Agent(s)	FDA Indication(s)	Notes	Ref#
Austedo^® (deutetrabenazine) Tablet	Treatment of chorea associated with Huntington’s disease Treatment of tardive dyskinesia in adults		1
Ingrezza^® (valbenazine) Capsule	Treatment of adults with tardive dyskinesia		2
Xenazine^® (tetrabenazine) Tablet	Treatment of chorea associated with Huntington’s disease	Generic equivalent available	3

See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

Huntington's disease

Huntington’s Disease (HD) is an autosomal dominant hereditary neurodegenerative disorder caused by an expansion of a repeating CAG triplet series in the huntingtin gene on chromosome 4, which results in a protein with an abnormally long polyglutamine sequence. The huntingtin gene directs the cell to make huntingtin protein, whose functions within the cell are largely unknown. Huntingtin gene contains a repeating sequence of three base-pairs, called a “triplet repeat” or “trinucleotide repeat.” An excess number of CAG repeats in the gene results in a protein containing an excess number of glutamine units. The huntingtin protein appears to be produced in equal quantities, whether it has a normal or excess number of glutamines, but the abnormally elongated protein appears to be processed aberrantly within the neurons, so that its fragments tend to accumulate over time into intranuclear inclusions.(6)

Movement-associated symptoms are a core feature of HD. Chorea is the most recognized motor symptom, but there are a number of additional movement disorders that can occur. More than 90% of people affected by HD have chorea, which is characterized by involuntary movements which are often sudden, irregular and purposeless or semi-purposeful. The movements are often more prominent in the extremities early in the disease, but may eventually include facial grimacing, eyelid elevation, neck, shoulder, trunk, and leg movements as the disease progresses. Chorea typically increases in frequency and amplitude over time and may peak about 10 years after disease onset. In some people chorea plateaus and lessens, while others have inexorable worsening as they enter late stage HD.(6)

Treating chorea is an important part of HD management. The pathophysiology and neurochemical bases of HD are not completely understood. Dopamine and glutamate transmission and interactions are affected. The FDA approved agents target these neurotransmitters and receptors.(4) Tetrabenazine and deutetrabenazine act by depleting monoamines (e.g., dopamine, serotonin, and norepinephrine) from nerve terminals. Tetrabenazine and the major metabolites of deutetrabenazine are centrally-acting dopamine depleting agents that works by reversibly inhibiting vesicular monoamine transporter 2 (VMAT2), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. The mechanism of action of valbenazine in the treatment of tardive dyskinesia is unknown, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2).(1,3)

The American Academy of Neurology guidelines for the treatment of chorea in HD recommend tetrabenazine, if the chorea requires treatment. Other agents also shown to be effective in varying degrees for the treatment of chorea include amantadine or riluzole. Adverse events should be discussed and monitored especially the increased risk of depression/suicidality and parkinsonism with the treatment of tetrabenazine.(4)

Tardive dyskinesia

Tardive syndromes are persistent abnormal involuntary movement disorders caused by sustained exposure to antipsychotic medication, the most common of which are tardive dyskinesia, tardive dystonia, and tardive akathisia. They begin later in treatment than acute dystonia, akathisia, or medication-induced parkinsonism and they persist and may even increase, despite reduction in dose or discontinuation of the antipsychotic medication. Tardive dyskinesia has been reported after exposure to any of the available antipsychotic medications. It occurs at a rate of approximately 4-8% per year in adult patients treated with first generation antipsychotics. Evaluation of the risk of tardive dyskinesia is complicated by the fact that dyskinetic movements may be observed with a reduction in antipsychotic medication dose. Fluctuations in symptoms are also common and may be influenced by factors such as psychosocial stressors. Regular assessment of patients for tardive syndromes through clinical examination or through the use of a structured evaluative tool can aid in identification and monitoring, such as the Abnormal Involuntary Movement Scale (AIMS). It should be noted that there is no specific score threshold that suggests a need for intervention, although ranges of scores are noted to correspond with mild, moderate, and severe symptoms. If no other contributing etiology is identified and moderate or severe or disabling tardive dyskinesia persists, treatment is recommended with a VMAT2 inhibitors. A lower dose of antipsychotic medication can be considered. The potential for benefit needs to be weighed against the potential side effects of these medications. A change in antipsychotic therapy to a lower potency medication and particularly to clozapine may also be associated with a reduction in tardive dyskinesia. Again, however, the potential benefits of changing medication should be considered in light of the possibility of symptom recurrence.(7)

Safety(1,3)

Austedo is contraindicated in patients:

with Huntington’s disease who are suicidal, or have untreated or inadequately treated depression
with hepatic impairment
taking reserpine. At least 20 days should elapse after stopping reserpine before starting Austedo
taking monoamine oxidase inhibitors (MAOIs). Austedo should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI
taking tetrabenazine (Xenazine) or valbenazine (Ingrezza)

Ingrezza is contraindication in patients:

with a history of hypersensitivity to valbenazine or any components of Ingrezza

Xenazine is contraindicated in patients:

who are actively suicidal, or in patients with untreated or inadequately treated depression
with hepatic impairment
taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.
taking reserpine. At least 20 days should elapse after stopping reserpine before starting Xenazine.
taking deutetrabenazine or valbenazine

REFERENCES

Number	Reference
1	Austedo prescribing information. Teva. May 2022.
2	Ingrezza prescribing information. Neurocrine Biosciences, Inc. April 2021.
3	Xenazine Prescribing Information. Lundbeck/Valeant. November 2019.
4	Armstrong MJ, Miyasaki MJ. Evidence-based guideline: Pharmacologic treatment of Chorea in Huntington disease. Neurology 2012; 79:597-603. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413759/pdf/znl597.pdf
5	Institute for Clinical and Economic Review (ICER). Vesicular Monoamine Transporter 2 Inhibitors for Tardive Dyskinesia: Effectiveness and Value. Final Evidence Report. December 22, 2017. Available at: https://icer-review.org/wp-content/uploads/2017/04/NECEPAC_TD_FINAL_REPORT_122217.pdf
6	Nance, M., MD, Paulsen, J. S., PhD, Rosenblatt, A., MD, & Wheelock, V., MD. (2011). A Physician’s Guide to the Management of Huntington’s Disease (3rd edition) (Third ed.). New York, NY: Huntington’s Disease Society of America. Available at: http://hdsa.org/wp-content/uploads/2015/03/PhysiciansGuide_3rd-Edition.pdf.
7	Keepers GA, Fochtmann LJ, Anzia JM et al. The American Psychiatric Associations Practice Guideline for the Treatment of Patients with Schizophrenia (Pre-release edition) Avaliable at: https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/Clinical%20Practice%20Guidelines/APA-Draft-Schizophrenia-Treatment-Guideline-Dec2019.pdf.

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Available MSC	Final Age Limit	Preferred Status

Austedo ; Austedo patient titration ; Austedo xr	deutetrabenazine tab ; deutetrabenazine tab er ; deutetrabenazine tab titration pack	12 MG ; 24 MG ; 6 & 9 & 12 MG ; 6 MG ; 9 MG	M ; N ; O ; Y	N
Xenazine	tetrabenazine tab	12.5 MG ; 25 MG	M ; N ; O ; Y	O ; Y
Ingrezza	valbenazine tosylate cap ; valbenazine tosylate cap therapy pack	40 & 80 MG ; 40 MG ; 60 MG ; 80 MG	M ; N ; O ; Y	N

POLICY AGENT SUMMARY QUANTITY LIMIT

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	QL Amount	Dose Form	Day Supply	Duration	Addtl QL Info	Allowed Exceptions	Targeted NDCs When Exclusions Exist

Austedo	Deutetrabenazine Tab 12 MG	12 MG	120	Tablets	30	DAYS
Austedo	Deutetrabenazine Tab 6 MG	6 MG	60	Tablets	30	DAYS
Austedo	Deutetrabenazine Tab 9 MG	9 MG	120	Tablets	30	DAYS
Austedo xr	deutetrabenazine tab er	6 MG	30	Tablets	30	DAYS
Austedo xr	deutetrabenazine tab er	12 MG	30	Tablets	30	DAYS
Austedo xr	deutetrabenazine tab er	24 MG	60	Tablets	30	DAYS
Ingrezza	Valbenazine Tosylate Cap	60 MG	30	Capsules	30	DAYS
Ingrezza	Valbenazine Tosylate Cap 40 MG (Base Equiv)	40 MG	30	Capsules	30	DAYS
Ingrezza	Valbenazine Tosylate Cap 80 MG (Base Equiv)	80 MG	30	Capsules	30	DAYS
Ingrezza	Valbenazine Tosylate Cap Therapy Pack 40 MG (7) & 80 MG (21)	40 & 80 MG	28	Capsules	180	DAYS
Xenazine	Tetrabenazine Tab 12.5 MG	12.5 MG	240	Tablets	30	DAYS
Xenazine	Tetrabenazine Tab 25 MG	25 MG	120	Tablets	30	DAYS

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Austedo ; Austedo patient titration ; Austedo xr	deutetrabenazine tab ; deutetrabenazine tab er ; deutetrabenazine tab titration pack	12 MG ; 24 MG ; 6 & 9 & 12 MG ; 6 MG ; 9 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Ingrezza	valbenazine tosylate cap ; valbenazine tosylate cap therapy pack	40 & 80 MG ; 40 MG ; 60 MG ; 80 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Xenazine	tetrabenazine tab	12.5 MG ; 25 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

CLIENT SUMMARY – QUANTITY LIMITS

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Austedo	Deutetrabenazine Tab 12 MG	12 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Austedo	Deutetrabenazine Tab 6 MG	6 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Austedo	Deutetrabenazine Tab 9 MG	9 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Austedo xr	deutetrabenazine tab er	24 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Austedo xr	deutetrabenazine tab er	12 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Austedo xr	deutetrabenazine tab er	6 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Ingrezza	Valbenazine Tosylate Cap	60 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Ingrezza	Valbenazine Tosylate Cap 40 MG (Base Equiv)	40 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Ingrezza	Valbenazine Tosylate Cap 80 MG (Base Equiv)	80 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Ingrezza	Valbenazine Tosylate Cap Therapy Pack 40 MG (7) & 80 MG (21)	40 & 80 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Xenazine	Tetrabenazine Tab 12.5 MG	12.5 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Xenazine	Tetrabenazine Tab 25 MG	25 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module

Clinical Criteria for Approval

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

ONE of the following:
1. The requested agent is Ingrezza/valbenazine AND ONE of the following:
  1. The patient has a diagnosis of tardive dyskinesia AND BOTH of the following:
    1. ONE of the following:
      1. The prescriber has reduced the dose or discontinued any medications known to cause tardive dyskinesia (i.e., dopamine receptor blocking agents) OR
      2. The prescriber has provided clinical rationale indicating that a reduced dose or discontinuation of any medications known to cause tardive dyskinesia is not appropriate AND
    2. The prescriber has documented the patient’s baseline Abnormal Involuntary Movement Scale (AIMS) score OR
  2. The patient has another FDA approved indication for the requested agent OR
  3. The patient has another indication that is supported in compendia for the requested agent OR
2. The requested agent is Austedo/deutetrabenazine AND ONE of the following:
  1. The patient has a diagnosis of tardive dyskinesia AND BOTH of the following:
    1. ONE of the following:
      1. The prescriber has reduced the dose or discontinued any medications known to cause tardive dyskinesia (i.e., dopamine receptor blocking agents) OR
      2. The prescriber has provided clinical rationale indicating that a reduced dose or discontinuation of any medications known to cause tardive dyskinesia is not appropriate AND
    2. The prescriber has documented the patient’s baseline Abnormal Involuntary Movement Scale (AIMS) score OR
  2. The patient has a diagnosis of chorea associated with Huntington’s disease OR
  3. The patient has another FDA approved indication for the requested agent OR
  4. The patient has another indication that is supported in compendia for the requested agent OR
3. The requested agent is Xenazine/tetrabenazine and ONE of the following:
  1. The patient has a diagnosis of chorea associated with Huntington’s disease OR
  2. The patient has another FDA approved indication for the requested agent OR
  3. The patient has another indication that is supported in compendia for the requested agent AND
If the request is for one of the following brand agents with an available generic equivalent (listed below), then ONE of the following:

Brand	Generic Equivalent
Xenazine	tetrabenazine

1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
2. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
3. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent AND
ONE of the following:
1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
2. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
The prescriber is a specialist in the area of the patient’s diagnosis (e.g., psychiatrist, neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
The patient will NOT be using the requested agent in combination with another agent included in this prior authorization program AND
The patient does NOT have any FDA labeled contraindications to the requested agent

Compendia Allowed: AHFS, or DrugDex 1 or 2a level of evidence

Length of Approval:

Tardive dyskinesia	3 months
Chorea associated with Huntington’s Disease	12 months
All other indications	12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

The patient has been previously approved for the requested agent through the plan’s Prior Authorization process AND
The prescriber is a specialist in the area of the patient’s diagnosis (e.g., psychiatrist, neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
ONE of the following:
1. The diagnosis is tardive dyskinesia AND the patient has had stabilization or improvement from baseline in Abnormal Involuntary Movement Scale (AIMS) score OR
2. The diagnosis is another FDA approved indication or another indication that is supported in compendia AND the patient has had clinical benefit with the requested agent AND
If the request is for one of the following brand agents with an available generic equivalent (listed below), then ONE of the following:

Brand	Generic Equivalent
Xenazine	tetrabenazine

1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
2. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
3. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent AND
The patient will NOT be using the requested agent in combination with another agent included in this prior authorization program AND
The patient does NOT have any FDA labeled contraindications to the requested agent

Compendia Allowed: AHFS, or DrugDex 1 or 2a level of evidence

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL

Module

Clinical Criteria for Approval

QL with PA

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

The requested quantity (dose) does NOT exceed the program quantity limit OR
ALL of the following:
1. The requested quantity (dose) is greater than the program quantity limit AND
2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit OR
ALL of the following:
1. The requested quantity (dose) is greater than the program quantity limit AND
2. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication AND
3. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval:

Indication	Initial	Renewal
Tardive dyskinesia	3 months	12 months
Chorea associated with Huntington’s Disease	12 months	12 months
All other indications	12 months	12 months

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

_ Commercial _ PS _ Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors Prior Authorization with Quantity Limit _ProgSum_ 7/1/2023

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Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-1152

POLICY REVIEW CYCLE

FDA APPROVED INDICATIONS AND DOSAGE

CLINICAL RATIONALE

REFERENCES

CLIENT SUMMARY – PRIOR AUTHORIZATION

CLIENT SUMMARY – QUANTITY LIMITS