AHFS Class:

• Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors 28:56

Generic Name(s):

• Valbenazine Tosylate

Valbenazine tosylate, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent.1,6,7,8

Tardive Dyskinesia

Valbenazine tosylate is used for the treatment of tardive dyskinesia in adults.1,3,4,5

Efficacy of valbenazine in the management tardive dyskinesia was established primarily in a randomized, double-blind, phase 3 study (KINECT 3), which consisted of an initial 6-week placebo-controlled phase followed by a 42-week extension phase.1,3 A total of 234 adults with moderate or severe tardive dyskinesia and a diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder were included in the study.1,3 Among the study population, 66% of patients had schizophrenia or schizoaffective disorder, and 34% had a mood disorder; 70% of patients were concurrently receiving atypical antipsychotics, 14% were receiving first-generation or combination antipsychotic therapy, and 16% were not receiving any antipsychotic therapy.1,3 Patients considered to be at risk for suicidal or violent behavior and those with unstable psychiatric symptoms were excluded from the study.1,3 Patients were initially randomized to receive valbenazine (40 or 80 mg once daily) or placebo for 6 weeks.1,3 Following the 6-week, placebo-controlled phase, patients receiving placebo were re-randomized to receive valbenazine 40 or 80 mg once daily in a 42-week extension phase followed by a 4-week washout period.1,5 Patients originally randomized to valbenazine continued to receive the drug at the randomized dosage.1 The primary measure of efficacy was evaluated using the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score, which assesses the severity of involuntary movements across body regions.1,3,5

From baseline to week 6, the mean AIMS dyskinesia total score substantially improved in patients receiving valbenazine 80 mg daily compared with patients receiving placebo.1,3,5 Patients receiving the 40-mg dosage of valbenazine also experienced an improvement in AIMS dyskinesia total score; however, the difference was not statistically significant compared with placebo.1,3,5 Improvement in mean AIMS dyskinesia total score was observed by week 2 and maintained throughout the 42-week extension period.1,3,4,5 No substantial difference in mean Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) score was observed between either valbenazine dosage group and placebo at week 6.3,5 Following discontinuance of therapy, mean AIMS dyskinesia total scores in both dosage groups returned toward baseline values during the 4-week washout period.1,4,5

The efficacy of a valbenazine 60-mg dose was evaluated using modeling and simulation.1 The predicted mean change from baseline in the AIMS dyskinesia total score at week 6 for valbenazine 60 mg once daily in patients with tardive dyskinesia is within the efficacy range for valbenazine 40 mg and 80 mg once daily.1

Chorea Associated with Huntington's Disease

Valbenazine tosylate is used for the treatment of chorea associated with Huntington's disease (HD) in adults.1 Huntington's disease is a hereditary neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms which begin subtly and progress over many years, usually leading to death.105 Patients with Huntington's disease experience movement disorders including involuntary movements (chorea) that result in reduced manual dexterity, slurred speech, swallowing difficulties, imbalance, and falls.105

Efficacy of valbenazine for this condition was established primarily in a randomized, double-blind, placebo-controlled study (KINECT-HD) consisting of a 12-week treatment period followed by a 2-week drug-free period in 128 patients with chorea associated with Huntington's disease.1,11 The mean age of patients was 54 years; 46% were male and 96% were white.1 Valbenazine was started at a dosage of 40 mg daily and increased every 2 weeks in 20-mg increments up to a maximum of 80 mg daily.1 At the end of the 12-week treatment period, over 80% of patients were receiving the 80 mg daily dosage.1

The primary measure of efficacy was the mean change from baseline to the end of the treatment period (average of week 10 and week 12) in the Total Maximal Chorea score of the Unified Huntington's Disease Rating Scale (UHDRS).1 The score is rated from 0 to 4 (0 representing no chorea) for 7 different parts of the body, with a total score ranging from 0 to 28.1

Total Maximal Chorea scores in patients receiving valbenazine improved by 4.6 units (least-squares mean change) from baseline to the end of the treatment period compared to 1.4 units in the placebo group; the difference was statistically significant.1,11 Following discontinuance of therapy, the Total Maximal Chorea scores of patients who had received valbenazine returned to baseline.1

Clinicians rated 43% of patients treated with valbenazine as “much improved” or “very much improved” on a clinician-rated global impression of change scale, while only 13% of patients who received placebo received these ratings.1 A patient-rated global impression of change scale was also used to assess how patients rated their overall chorea symptoms; 53% of patients treated with valbenazine rated their symptoms as “much improved” or “very much improved” compared with 26% of patients who received placebo.1 Additional study is needed to determine long-term safety and effectiveness of valbenazine throughout the disease course of patients with Huntington's disease-related chorea.11

General

Pretreatment Screening

• In patients with Huntington's disease, balance risk of depression and suicidal ideation and behavior with the clinical need for treatment of chorea when considering use of valbenazine.1
• Evaluate baseline liver function.1

Patient Monitoring

• Monitor for hypersensitivity reactions such as rash, urticaria, and angioedema (e.g., swelling of the face, lips, and mouth).1
• Monitor QT interval if clinically indicated.1 For patients at increased risk of QT prolongation, assess the QT interval before increasing dosage.1
• Monitor for signs or symptoms of parkinsonism.1

Administration

Valbenazine tosylate capsules are administered orally once daily without regard to food.1

Store valbenazine capsules at 15-30°C.1

Dosage

Dosage of valbenazine tosylate is expressed in terms of valbenazine.1

Tardive Dyskinesia

For the treatment of tardive dyskinesia in adults, the recommended initial dosage of valbenazine is 40 mg once daily.1 After 1 week, dosage should be increased to the recommended dosage of 80 mg once daily.1 A dosage of 40 or 60 mg once daily may be considered depending on response and tolerability.1

Continued valbenazine therapy appears to be necessary in patients with tardive dyskinesia; in clinical studies, symptoms recurred following discontinuance of the drug.4

In the principal efficacy study for the management of tardive dyskinesia, patients who had received antipsychotic agents continued to receive the antipsychotic treatment regimen they had been stabilized on during valbenazine therapy.3

Chorea Associated with Huntington's Disease

For the management of chorea associated with Huntington's disease in adults, the recommended initial dosage of valbenazine is 40 mg once daily.1 The dosage should be increased in 20 mg increments every 2 weeks to the recommended dosage of 80 mg once daily.1 A dosage of 40 or 60 mg once daily may be considered depending on response and tolerability.1

Continued valbenazine therapy appears to be necessary in patients with chorea associated with Huntington's disease; in clinical studies, symptoms recurred following discontinuance of the drug.1

Special Populations

Hepatic Impairment

In patients with moderate or severe hepatic impairment (Child-Pugh score of 7-15), the recommended dosage of valbenazine is 40 mg once daily.1 The manufacturer makes no specific dosage recommendations for patients with mild hepatic impairment.1

Renal Impairment

Dosage adjustment is not necessary in patients with mild, moderate, or severe renal impairment.1

Geriatric Patients

The manufacturer states that no dosage adjustment is necessary in geriatric patients.1

Pharmacogenomics and Poor CYP2D6 Metabolizers

Dosage adjustment of valbenazine is recommended in patients who are known to be poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6.1

In patients who are known poor metabolizers of CYP2D6, the recommended dosage of valbenazine is 40 mg once daily.1

Patients Receiving Concomitant Therapy

Dosage adjustment of valbenazine is recommended in patients receiving concomitant therapy with a strong CYP3A4 and/or CYP2D6 inhibitor.1

If valbenazine is used concurrently with a strong CYP2D6 inhibitor, the recommended dosage is valbenazine 40 mg once daily.1

If valbenazine is used concurrently with a strong CYP3A4 inhibitor, the recommended dosage is 40 mg once daily.1

Concomitant use of valbenazine and strong CYP3A4 inducers is not recommended.1

Contraindications

• History of hypersensitivity to valbenazine or any of its components.1 Rash, urticaria, and angioedema have been reported.1

Warnings/Precautions

Depression and Suicidal Ideation and Behavior in Patients with Huntington's Disease

Patients with Huntington's disease are at increased risk for depression and suicidal ideation or behaviors.1 VMAT2 inhibitors, including valbenazine, can increase the risk for suicidal ideation and behaviors.1 A boxed warning about this risk is included in the prescribing information for the drug.1

In a 14-week controlled clinical trial, depression or depressed mood was reported in 4.7% of patients taking valbenazine compared to 1.6% of patients who received placebo; no patients taking valbenazine reported suicidal ideation or behavior compared to one patient who received placebo.1 Patients with significant risk for suicidal behavior or with unstable psychiatric symptoms were excluded from this trial.1 Suicidal ideation (7.2%) and suicide attempts (2.4%) were reported in a longer open-label extension of this trial.1

When considering the use of valbenazine, the risk of suicidal ideation and behaviors must be balanced against the need for chorea treatment.1 All patients treated with valbenazine should be observed for new or worsening depression and suicidal ideation or behaviors.1 If any of these reactions occur and do not resolve, consider discontinuing treatment with valbenazine.1

Hypersensitivity Reactions

Hypersensitivity reactions, including cases of angioedema involving the larynx, glottis, lips, and eyelids, have been reported in the postmarketing setting in patients receiving valbenazine.1 Urticaria and rash were also reported during a clinical study in patients with Huntington's disease.1 If any of these reactions occur, discontinue treatment with valbenazine.1

Somnolence and Sedation

Valbenazine can cause somnolence and sedation and may impair cognitive and/or physical abilities required to perform potentially hazardous tasks such as driving or operating machinery.1 Patients should not perform such tasks until they know how the drug will affect them.1 In placebo-controlled trials of valbenazine, somnolence (including fatigue and sedation) was the most commonly reported adverse event.1

Prolongation of QT Interval

Valbenazine therapy may prolong the QT interval; however, the degree of QT-interval prolongation is not clinically important at drug concentrations expected with recommended dosing.1 Higher than expected plasma concentrations of valbenazine and/or its active metabolite and clinically important QT-interval prolongation may occur in poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 and in patients concurrently receiving a strong CYP2D6 or CYP3A4 inhibitor.1 Dosage adjustments are recommended in these patients.1

Valbenazine should be avoided in patients with congenital long QT syndrome or cardiac arrhythmias associated with a prolonged QT interval.1 In patients at increased risk of QT-interval prolongation, the QT interval should be assessed prior to increasing the dosage of valbenazine.1

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic malignant syndrome (NMS), a potentially fatal condition, has been reported in association with drugs that reduce dopaminergic transmission such as VMAT2 inhibitors.1 Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia); additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure.1 The diagnosis of NMS can be complicated; other serious medical illnesses (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms.1

Management of NMS should include immediate discontinuation of valbenazine, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems for which specific treatments are available.1 There is no general agreement about specific pharmacological treatment regimens for NMS.1

Recurrence of NMS has been reported with resumption of drug therapy; therefore, if treatment with valbenazine is needed after recovery from NMS, patients should be monitored for signs of recurrence.1

Parkinsonism

Valbenazine may cause parkinsonism.1 Parkinsonism has also been observed with other VMAT2 inhibitors.1 The incidence of parkinsonism in placebo-controlled trials of patients with tardive dyskinesia was 3% in patients receiving valbenazine and <1% in placebo-treated patients.1 In a placebo-controlled study in patients with chorea associated with Huntington's disease, the incidence of parkinson-like adverse events was 4.7% in patients treated with valbenazine and 0% in placebo-treated patients.1

Because rigidity can develop as part of the underlying disease process in Huntington's disease, it may be difficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntington's disease.1 Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington's disease.1

Postmarketing cases of parkinsonism in patients with tardive dyskinesia treated with valbenazine have been reported, some of which were severe and required hospitalization.1 In most cases, severe parkinsonism occurred within the first 2 weeks after starting or increasing the dosage of valbenazine.1 Symptoms have included falls, gait disturbances, tremor, drooling, and hypokinesia.1 Available data suggest that parkinson-like symptoms resolve following discontinuation of valbenazine.1

Reduce the dosage or discontinue therapy in patients who develop clinically significant parkinson-like signs or symptoms during valbenazine therapy.1

Specific Populations

Pregnancy

There is insufficient data regarding valbenazine use in pregnant women to inform a drug-associated risk.1 Reproduction studies in animals revealed no malformations when valbenazine was administered orally during the period of organogenesis in rats and rabbits at dosages up to 1.8 and 24 times the maximum recommended human dosage, respectively.1 However, increased stillbirths and reduced postnatal pup survival were observed when the drug was administered to pregnant rats during organogenesis and lactation at dosages less than the maximum recommended human dosage.1 Pregnant women should be advised of the potential risk to the fetus.1

Lactation

Valbenazine and its metabolites are distributed into milk in rats at concentrations higher than those in maternal plasma; it is not known whether the drug and/or its metabolites distribute into human milk.1 The effects of valbenazine on breast-fed infants and on milk production also are not known.1 Because increased perinatal mortality has been observed in exposed fetuses and pups in animal studies, the manufacturer recommends that women not breast-feed while receiving valbenazine and for 5 days after discontinuance of the drug.1

Pediatric Use

Safety and efficacy of valbenazine in pediatric patients have not been established.1 Tardive dyskinesia rarely occurs in pediatric patients since prolonged antipsychotic therapy usually is needed to cause the condition.5

Geriatric Use

In controlled clinical trials of valbenazine in patients with tardive dyskinesia, 16% of patients were ≥65 years of age.1 Safety and efficacy of valbenazine in these patients were similar to those observed in younger adults.1 In a controlled clinical trial of valbenazine in patients with chorea associated with Huntington's disease, 15% of patients were ≥65 years of a however, this study did not include sufficient numbers of patients ≥65 years of age to determine whether they responded differently from younger patients.1

The manufacturer states that dosage adjustment is not necessary in geriatric patients.1

Hepatic Impairment

In patients with mild hepatic impairment, peak plasma concentrations and AUC of valbenazine and its active metabolite are increased by less than 1.5-fold; the manufacturer makes no specific dosage recommendations for such patients.1,10

Peak plasma concentrations and AUC of valbenazine and its active metabolite are increased by up to 2.5- and 3.4-fold, respectively, in patients with moderate or severe hepatic impairment (Child-Pugh score of 7-15); the recommended dosage of valbenazine is 40 mg once daily in such patients.1,10

Renal Impairment

Valbenazine does not undergo primary renal clearance.1 Dosage adjustment of the drug is not necessary in patients with mild, moderate, or severe renal impairment.1

Pharmacogenomics and Poor CYP2D6 Metabolizers

Because increased exposure (peak plasma concentration and AUC) of valbenazine's active metabolite is expected in patients who are poor metabolizers of CYP2D6 (individuals with two non-functioning alleles), a reduced dosage of 40 mg once daily is recommended.1 Increased exposure of the active metabolite may increase the risk of exposure-related adverse effects.1

In a clinical study of intermediate CYP2D6 metabolizers, AUC of the active metabolite of valbenazine was 22% higher and its peak plasma concentration was 9% lower compared to normal metabolizers; these changes were not considered clinically relevant.1 The effects of ultrarapid metabolizer status on the pharmacokinetics of the active metabolite of valbenzaine have not been studied.1

Common Adverse Effects

The most common adverse reaction (≥5% and twice the rate of placebo) in clinical trials of valbenazine in patients with tardive dyskinesia was somnolence.5

The most common adverse reactions (≥5% and twice the rate of placebo) in clinical trials of valbenazine in patients with chorea associated with Huntington's disease were somnolence/lethargy/sedation, urticaria, rash, and insomnia.3

Valbenazine is metabolized in part by cytochrome P-450 (CYP) isoenzyme 3A4/5; further biotransformation of the active metabolite is mediated in part by CYP2D6.1

In vitro studies indicate that valbenazine and its active metabolite do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4/5, nor induce CYP isoenzymes 1A2, 2B6, or 3A4/5 at clinically relevant concentrations.1

Valbenazine and its active metabolite are unlikely to inhibit breast cancer resistance protein (BCRP), organic anion transporters (OAT) 1 and OAT3, organic cation transporter (OCT) 2, or organic anion transport proteins (OATP) 1B1 and OATP1B3 at clinically relevant concentrations.1 Valbenazine inhibits intestinal P-glycoprotein (P-gp).1,10

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4

Concomitant use of valbenazine with strong inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, ketoconazole) may increase exposure of valbenazine and its active metabolite and increase the risk of adverse effects.1,10 When the strong CYP3A4 inhibitor ketoconazole was administered concomitantly with valbenazine in healthy individuals, exposures of valbenazine and its active metabolite increased approximately twofold.1,10

Valbenazine dosage should be reduced to 40 mg once daily when used concurrently with strong CYP3A4 inhibitors.1,10

Dosage reduction of valbenazine is not necessary when used concomitantly with weak or moderate CYP3A4 inhibitors.10

Inducers of CYP3A4

Concomitant use of valbenazine and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) may decrease exposure of valbenazine and its active metabolite and potentially reduce the drug's efficacy.1 When the strong CYP3A4 inducer rifampin was administered concomitantly with valbenazine in healthy individuals, exposures of valbenazine and its active metabolite were decreased by approximately 70-80%.1,10 Concomitant use of valbenazine and strong CYP3A4 inducers is therefore not recommended.1,10

Inhibitors of CYP2D6

Concomitant use of valbenazine with strong inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, quinidine) may increase the exposure of valbenazine's active metabolite and increase the risk of adverse effects.1 Valbenazine dosage should be reduced to 40 mg once daily when used concurrently with strong CYP2D6 inhibitors.1

Drugs Metabolized by Hepatic Microsomal Enzymes

The manufacturer states that clinically important pharmacokinetic interactions are unlikely and that dosage adjustment of the concurrently administered drug is not necessary when valbenazine is used concurrently with substrates of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4/5.1

No clinically important pharmacokinetic interaction was observed when valbenazine was administered with midazolam (a CYP3A4 substrate).1

Digoxin

Concomitant use of valbenazine and digoxin resulted in approximately twofold and 1.5-fold increases in peak plasma concentration and AUC of digoxin, respectively, because of inhibition of intestinal P-glycoprotein.1 Increased digoxin exposure may increase the risk of exposure-related adverse effects.1 If digoxin and valbenazine are used concomitantly, serum digoxin concentrations should be monitored and digoxin dosage adjusted, if necessary.1

Monoamine Oxidase Inhibitors

Concomitant use of valbenazine and monoamine oxidase (MAO) inhibitors (e.g., isocarboxazid, phenelzine, selegiline, tranylcypromine) may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to an increased risk of adverse reactions such as serotonin syndrome.1 In addition, valbenazine's efficacy may be reduced.1 Use of valbenazine concomitantly with MAO inhibitors or within 14 days of discontinuing therapy with an MAO inhibitor should therefore be avoided.1

Description

Valbenazine tosylate, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent.1,6,7,8 Valbenazine is a valine ester prodrug of (+)-α-dihydrotetrabenazine ([+]-α-HTBZ) and an active metabolite of tetrabenazine.5,6,7,8 Of the 4 tetrabenazine metabolite isomers, (+)-α-HTBZ has the highest binding affinity and selectivity for VMAT2.6

Although the exact mechanism of action of valbenazine in the treatment of tardive dyskinesia and chorea in patients with Huntington's disease has not been fully elucidated, the drug selectively and reversibly inhibits VMAT2, a transporter that regulates the uptake of monoamines (e.g., dopamine, norepinephrine, serotonin, histamine) from the cytoplasm to the synaptic vesicles for storage and release in the CNS.1,6,7 Monoamines not transported into synaptic vesicles are rapidly degraded by monoamine oxidase (MAO), resulting in depleted monoamine stores in nerve terminals.8

Valbenazine and its (+)-α-HTBZ metabolite have no appreciable binding affinity for VMAT1 or for dopaminergic (including D₂), serotonergic (including 5-HT_2B), adrenergic, histaminergic, or muscarinic receptors.1,6

Following oral administration of valbenazine, the drug undergoes ester hydrolysis to form the major active metabolite, (+)-α-HTBZ.1,5,6 Peak plasma concentrations of valbenazine and (+)-α-HTBZ occur in 30-60 minutes and 4-8 hours, respectively.1,10 The absolute oral bioavailability of valbenazine is approximately 49%.1,10 Steady-state plasma concentrations of valbenazine are achieved within 1 week.1 Administration of the capsules with a high-fat meal decreases peak plasma concentrations and AUC of valbenazine by approximately 47 and 13%, respectively; peak plasma concentration and AUC of (+)-α-HTBZ are not substantially affected.1,10 In addition to undergoing ester hydrolysis to the major active metabolite, valbenazine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4/5 to other metabolites, including NBI-136110.1,5,6 The active metabolite of valbenazine is further metabolized in part by CYP2D6.1,5,10 The parent drug and NBI-136110 also inhibit VMAT2 but have approximately 40- to 65-fold lower binding affinity than (+)-α-HTBZ.1,6 Valbenazine is highly bound (greater than 99%) to plasma proteins while its active metabolite is approximately 64% protein bound.1 In rats, valbenazine can bind to melanin-containing structures of the eye such as the uveal tract; the clinical relevance of this finding is not known.1 Following administration of a single radiolabeled dose of valbenazine, approximately 60 and 30% of the dose is recovered in urine and feces, respectively.1,10 Less than 2% of the dose is excreted as unchanged valbenazine or its active metabolite.1 The half-lives of valbenazine and (+)-α-HTBZ are both 15-22 hours.1

Advice to Patients

• Advise patients to read the manufacturer's patient information.1
• Inform patients, their caregivers, and families of the risks of depression, worsening depression, and suicidal ideation and behavior associated with valbenazine, and instruct them to report behaviors of concern promptly to the treating physician.1 Patients with Huntington's disease who express suicidal ideation should be evaluated immediately.1
• Inform patients about the signs and symptoms of hypersensitivity reactions, such as angioedema, including difficulty breathing and swelling of the face, lips, eyelids, tongue, or throat.1 Advise patients to discontinue valbenazine immediately if any of these reactions occur and report to the emergency room if symptoms of angioedema occur.1
• Risk of somnolence and sedation.1,2 Advise patients to exercise caution or avoid engaging in activities requiring mental alertness and coordination such as operating a motor vehicle or other dangerous machinery until the effects of the drug on the individual are known.1,2
• Risk of QT-interval prolongation.1,2 Advise patients to inform clinicians immediately if abnormal heartbeat, palpitations, shortness of breath, feelings of dizziness or faintness, or loss of consciousness occurs.1,2
• Inform patients about a potentially fatal adverse reaction, neuroleptic malignant syndrome (NMS), that has been reported in association with administration of VMAT2 inhibitors, including valbenazine.1 Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS.1
• Risk of parkinsonism.1 Advise patients to consult their clinician if they experience difficulty moving or loss of ability to move muscles voluntarily, tremor, gait disturbances, or drooling.1
• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1,2 Apprise patient of potential risk to the fetus if used during pregnancy.1 Advise women to avoid breast-feeding while receiving valbenazine and for 5 days after discontinuance of the drug.1,2
• Advise patient to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., liver or kidney disease, cardiovascular disease, arrhythmias).1,2Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Neurocrine Biosciences, Inc. Ingrezza^® (valbenazine) capsules prescribing information. San Diego, CA; 2023 Aug.

2. Neurocrine Biosciences, Inc. Ingrezza^® (valbenazine) capsules patient information. San Diego, CA; 2023 Aug.

3. 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; 174:476-84. [PubMed 28320223]

4. Factor S, Comella C, Correll C et al. Efficacy of valbenazine (NBI-98854) in subjects with tardive dyskinesia: results of a long-term study (KINECT 3 Extension) (S56.005). Neurology . 2017; 88 (Suppl S56.005).

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209241Orig1s000: Summary review. From FDA website. [Web]

6. Grigoriadis DE, Smith E, Hoare SRJ et al. Pharmacologic characterization of valbenazine (NBI-98854) and its metabolites. J Pharmacol Exp Ther . 2017; 361:454-61. [PubMed 28404690]

7. Müller T. Valbenazine granted breakthrough drug status for treating tardive dyskinesia. Expert Opin Investig Drugs . 2015; 24:737-42. [PubMed 25809133]

8. Jankovic J. Dopamine depleters in the treatment of hyperkinetic movement disorders. Expert Opin Pharmacother . 2016; 17:2461-70. [PubMed 27819145]

9. Neurocrine Biosciences, Inc. Prescribing Ingrezza® (valbenazine): Path to Ingrezza® Brochure. 2022 Apr. From INBRACE® support program website. [Web]

10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209241Orig1s000: Clinical pharmacology and biopharmaceutics review. From FDA website. [Web]

11. Furr Stimming E, Claassen DO, Kayson E et al. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2023 Jun;22(6):494-504. doi: 10.1016/S1474-4422(23)00127-8. Erratum in: Lancet Neurol. 2023 Sep;22(9):e10. Erratum in: Lancet Neurol. 2023 Sep;22(9):e10. PMID: 37210099.

28. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry . 2004; 161(2 Suppl):1-56.

62. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 3rd ed. American Psychiatric Association Publishing. Washington, DC; 2021. http://psychiatryonline.org/doi/epdf/10.1176/appi.books.9780890424841

100. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (N Y) . 2013; 3

101. Rakesh G, Muzyk A, Szabo ST et al. Tardive dyskinesia: 21st century may bring new treatments to a forgotten disorder. Ann Clin Psychiatry . 2017; 29:108-19. [PubMed 28207919]

102. Margolese HC, Chouinard G, Kolivakis TT et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction. Can J Psychiatry . 2005; 50:541-7. [PubMed 16262110]

103. Margolese HC, Chouinard G, Kolivakis TT et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry . 2005; 50:703-14. [PubMed 16363464]

104. Lerner PP, Miodownik C, Lerner V. Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. Psychiatry Clin Neurosci . 2015; 69:321-34. [PubMed 25556809]

105. Nance M, Paulsen JS, Rosenblatt A et al. A Physician's Guide to the Management of Huntington's Disease, 3rd Edition. Huntington's Disease Society of America. 2011.