Valbenazine

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# Overview
Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that is FDA approved for the treatment of adults with tardive dyskinesia.   Common adverse reactions include somnolence.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Valbenazine is indicated for the treatment of adults with tardive dyskinesia.
- The initial dose for valbenazine is 40 mg once daily. After one week, increase the dose to the recommended dose of 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients.
- Administer valbenazine orally with or without food.
- The recommended dose for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) is valbenazine 40 mg once daily.
- Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers.
Coadministration with Strong CYP3A4 Inducers
- Concomitant use of strong CYP3A4 inducers with valbenazine is not recommended.
Coadministration with Strong CYP3A4 Inhibitors
- Reduce valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP3A4 inhibitor.
- Consider reducing valbenazine dose based on tolerability when valbenazine is coadministered with a strong CYP2D6 inhibitor.
- Valbenazine capsules are available in the following strengths:
- 40 mg capsules with a white opaque body and purple cap, printed with VBZ and 40 in black ink.
- 80 mg capsules with a purple opaque body and cap, printed with VBZ and 80 in black ink.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding valbenazine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Valbenazine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding valbenazine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None.

# Warnings
- Valbenazine can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by valbenazine.
- Valbenazine may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. In patients taking a strong CYP2D6 or CYP3A4 inhibitor, or who are CYP2D6 poor metabolizers, valbenazine concentrations may be higher and QT prolongation clinically significant. For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary. For patients taking a strong CYP3A4 inhibitor, reduce the dose of valbenazine to 40 mg once daily. Valbenazine should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval.  For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of valbenazine was evaluated in 3 placebo-controlled studies, each 6 weeks in duration (fixed dose, dose escalation, dose reduction), including 445 patients. Patients were 26 to 84 years of age with moderate to severe tardive dyskinesia and had concurrent diagnoses of mood disorder (27%) or schizophrenia/ schizoaffective disorder (72%). The mean age was 56 years. Patients were 57% Caucasian, 39% African-American, and 4% other. With respect to ethnicity, 28% were Hispanic or Latino. All subjects continued previous stable regimens of antipsychotics; 85% and 27% of subjects, respectively, were taking atypical and typical antipsychotic medications at study entry.
Adverse Reactions Leading to Discontinuation of Treatment
- A total of 3% of valbenazine treated patients and 2% of placebo-treated patients discontinued because of adverse reactions.
Common Adverse Reactions
- Adverse reactions that occurred in the 3 placebo-controlled studies at an incidence of 2% and greater than placebo are presented in Table 1.
Other Adverse Reactions Observed During the Premarketing Evaluation of Valbenazine
- Other adverse reactions of 1% incidence and greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.
- Endocrine Disorders: blood glucose increased.
- General Disorders: weight increased.
- Infectious Disorders: respiratory infections.
- Neurologic Disorders: drooling, dyskinesia, extrapyramidal symptoms (non-akathisia).
- Psychiatric Disorders: anxiety, insomnia.
- During controlled trials, there was a dose-related increase in prolactin. Additionally, there was a dose-related increase in alkaline phosphatase and bilirubin, suggesting a potential risk for cholestasis.

## Postmarketing Experience
There is limited information regarding Valbenazine Postmarketing Experience in the drug label.

# Drug Interactions
- Drugs Having Clinically Important Interactions with Valbenazine
- Drugs Having No Clinically Important Interactions with Valbenazine
- Dosage adjustment for valbenazine is not necessary when used in combination with substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 based on in vitro study results.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- The limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m2. Advise a pregnant woman of the potential risk to a fetus.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively.
- Valbenazine was administered orally to pregnant rats during the period of organogenesis at 1, 5, and 15 mg/kg/day, which are approximately 0.1, 0.6, and 2 times the MRHD of 80 mg/day based on mg/m2 body surface area. Valbenazine produced a significant decrease in maternal body weight gain at 0.6 and 2 times the MRHD of 80 mg/day based on mg/m2. No adverse embryo fetal effects were produced when valbenazine was administered at doses up to 2 times the MRHD of 80 mg/day based on mg/m2.
- Valbenazine was administered orally to pregnant rabbits during the period of organogenesis at 20, 50, and 100 mg/kg/day, which are approximately 5, 12, and 24 times the MRHD of 80 mg/day based on mg/m2. No malformations were observed at doses up to 24 times the MRHD of 80 mg/day based on mg/m2. However, valbenazine produced a delay in fetal development (decreased fetal weights and delayed ossification) at 24 times the MRHD of 80 mg/day based on mg/m2, likely secondary to maternal toxicity (decreased food intake and loss in body weight).
- Valbenazine was administered orally to pregnant rats during the period of organogenesis through lactation (day 7 of gestation through day 20 postpartum) at 1, 3, and 10 mg/kg/day, which are approximately 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine produced an increase in the incidence of stillbirths and postnatal pup mortality at 0.4 and 1.2 times the MRHD of 80 mg/day based on mg/m2.  Valbenazine did not affect neurobehavioral function including learning and memory and had no effect on sexual maturation at doses <1 times the MRHD of 80 mg/day based on mg/m2 (because of death in the majority of the high dose group (1.2 times the MRHD), these parameters were not assessed in this group).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valbenazine in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Valbenazine during labor and delivery.

### Nursing Mothers
- There is no information regarding the presence of valbenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Valbenazine and its metabolites have been detected in rat milk at concentrations higher than in plasma following oral administration of valbenazine at doses 0.1 to 1.2 times the MRHD based on mg/m2. Based on animal findings of increased perinatal mortality in exposed fetuses and pups, advise a woman not to breastfeed during treatment with valbenazine and for 5 days after the final dose.

### Pediatric Use
- Safety and effectiveness of valbenazine have not been established in pediatric patients.

### Geriatic Use
- No dose adjustment is required for elderly patients. In 3 randomized, placebo-controlled studies of valbenazine, 16% were 65 years and older. The safety and effectiveness were similar in patients older than 65 years compared to younger patients.

### Gender
There is no FDA guidance on the use of Valbenazine with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Valbenazine with respect to specific racial populations.

### Renal Impairment
- Dosage adjustment is not necessary for patients with mild to moderate renal impairment (creatinine clearance 30 to 90 mL/min). Valbenazine does not undergo primary renal clearance. Valbenazine is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min).

### Hepatic Impairment
- Dosage reduction of valbenazine is recommended for patients with moderate or severe hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Valbenazine in women of reproductive potentials and males.

### Immunocompromised Patients
- Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers. Increased exposure (Cmax and AUC) to valbenazines active metabolite is anticipated in CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions.

# Administration and Monitoring

### Administration
- The initial dose for valbenazine is 40 mg once daily. After one week, increase the dose to the recommended dose of 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients.
- Administer valbenazine orally with or without food.

### Monitoring
- Decrease in severity of tardive dyskinesia symptoms is indicative of efficacy.
- QT interval: Patients at increased risk of prolonged QT interval, prior to increasing dose.

# IV Compatibility
There is limited information regarding the compatibility of Valbenazine and IV administrations.

# Overdosage
- The pre-marketing clinical trials involving valbenazine in approximately 850 subjects do not provide information regarding symptoms with overdose.
- No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).

# Pharmacology

## Mechanism of Action
- 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), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.

## Structure

## Pharmacodynamics
- Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 M). Valbenazine is converted to the active metabolite --dihydrotetrabenazine (--HTBZ).
- --HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and --HTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors.
- Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6 poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean QT prolongation of 11.7 msec (14.7 msec upper bound of double-sided 90% CI) as compared to otherwise healthy volunteers given valbenazine, who had a mean QT prolongation of 6.7 msec (8.4 msec).

## Pharmacokinetics
- Valbenazine and its active metabolite (--HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose).
- Following oral administration, the time to reach maximum valbenazine plasma concentration (tmax) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. --HTBZ gradually forms and reaches Cmax 4 to 8 hours after administration of valbenazine.
- Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. --HTBZ Cmax and AUC are unaffected.
- The plasma protein binding of valbenazine and --HTBZ are greater than 99% and approximately 64%, respectively. The mean steady state volume of distribution of valbenazine is 92 L.
- Nonclinical data in Long-Evans rats show that valbenazine can bind to melanin-containing structures of the eye such as the uveal tract. The relevance of this observation to clinical use of valbenazine is unknown.
- Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr. Valbenazine and --HTBZ have half-lives of 15 to 22 hours.
Metabolism
- Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite (--HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. --HTBZ appears to be further metabolized in part by CYP2D6.
- The results of in vitro studies suggest that valbenazine and --HTBZ are unlikely to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5, or induce CYP1A2, CYP2B6 or CYP3A4/5 at clinically relevant concentrations.
- The results of in vitro studies suggest that valbenazine and --HTBZ are unlikely to inhibit the transporters (BCRP, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3) at clinically relevant concentrations.
Excretion
- Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively.  Less than 2% was excreted as unchanged valbenazine or --HTBZ in either urine or feces.
- Exposures of valbenazine in patients with hepatic impairment are summarized in Figure 1.
- The effects of ketoconazole and rifampin on the exposure of valbenazine are summarized in Figure 2.
- The effects of valbenazine on the exposure of other coadministered drugs are summarized in Figure 3.

## Nonclinical Toxicology
- Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m2.
- Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30 and 75 mg/kg/day, which are 0.6, 1.9 and 4.6 times the MRHD of 80 mg/day based on mg/m2.
- Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.
- In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2, respectively. Valbenazine delayed mating in both sexes, which led to lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions and post-implantation loss) at any dose.

# Clinical Studies
- A randomized, double-blind, placebo-controlled trial of valbenazine was conducted in patients with moderate to severe tardive dyskinesia as determined by clinical observation. Patients had underlying schizophrenia, schizoaffective disorder, or a mood disorder. Individuals at significant risk for suicidal or violent behavior and individuals with unstable psychiatric symptoms were excluded.
- The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. 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 thus range from 0 to 28, with a decrease in score indicating improvement. The AIMS was scored by central raters who interpreted the videos blinded to subject identification, treatment assignment, and visit number.
- The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6. The change from baseline for two fixed doses of valbenazine (40 mg or 80 mg) was compared to placebo. At the end of Week 6, subjects initially assigned to placebo were re-randomized to receive valbenazine 40 mg or 80 mg. Subjects originally randomized to valbenazine continued valbenazine at their randomized dose. Follow-up was continued through Week 48 on the assigned drug, followed by a 4-week period off-drug (subjects were not blind to withdrawal).
- A total of 234 subjects were enrolled, with 29 (12%) discontinuing prior to completion of the placebo-controlled period. Mean age was 56 (range 26 to 84). Patients were 54% male and 46% female. Patients were 57% Caucasian, 38% African-American, and 5% other. Concurrent diagnoses included schizophrenia/schizoaffective disorder (66%) and mood disorder (34%). With respect to concurrent antipsychotic use, 70% of subjects were receiving atypical antipsychotics, 14% were receiving typical or combination antipsychotics, and 16% were not receiving antipsychotics.
- Results are presented in Table 3, with the distribution of responses shown in Figure 4.  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. Subgroup analyses by gender, age, racial subgroup, underlying psychiatric diagnostic category, and concomitant antipsychotic medication did not suggest any clear evidence of differential responsiveness.
- The mean changes in the AIMS dyskinesia total score by visit are shown in Figure 5. Among subjects remaining in the study at the end of the 48-week treatment (N=123 ), following discontinuation of valbenazine, the mean AIMS dyskinesia total score appeared to return toward baseline (there was no formal hypothesis testing for the change following discontinuation).

# How Supplied
- Valbenazine capsules are available as:
- 40 mg Capsule: White opaque body with a purple cap, printed with VBZ and 40 in black ink.
- Bottle of 30: NDC 70370-1040-1
- Bottle of 90: NDC 70370-1040-2
- 80 mg Capsule: Purple opaque body and cap, printed with VBZ and 80 in black ink.
- Bottle of 30: NDC 70370-1080-1

## Storage
- Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Inform patients that valbenazine may cause somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to valbenazine, they should be careful or avoid doing activities that require them to be alert, such as driving a car or operating machinery.
- Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations. Advise patients to inform physicians that they are taking valbenazine before any new drug is taken.
- Advise a pregnant patient of the potential risk to a fetus.
- Advise a woman not to breastfeed during treatment with valbenazine and for 5 days after the final dose.

# Precautions with Alcohol
Alcohol-Valbenazine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Ingrezza

# Look-Alike Drug Names
There is limited information regarding Valbenazine Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price