Valbenazine

The recommended dosage for patients receiving strong CYP3A4 inhibitors is 40 mg once daily.

Concomitant use of valbenazine with strong CYP3A4 inhibitors increased the exposure (C and AUC) to valbenazine and its active metabolite compared with the use of valbenazine alone. Increased exposure of valbenazine and its active metabolite may increase the risk of exposure-related adverse reactions.

The recommended dosage for patients receiving strong CYP2D6 inhibitors is valbenazine 40 mg once daily.

Concomitant use of valbenazine with strong CYP2D6 inhibitors increased the exposure (C and AUC) to valbenazine’s active metabolite compared with the use of valbenazine alone.

Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions.

The recommended dosage for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) is 40 mg once daily.

Patients with moderate to severe hepatic impairment had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function.

Concomitant use of valbenazine with digoxin increased digoxin levels because of inhibition of intestinal P-glycoprotein (P-gp).

Digoxin concentrations should be monitored when co-administering valbenazine with digoxin. Increased digoxin exposure may increase the risk of exposure-related adverse reactions. Dosage adjustment of digoxin may be necessary.

The recommended dosage for known CYP2D6 poor metabolizers is 40 mg once daily.

Increased exposure (C_max and AUC) to valbenazine’s active metabolite was observed in CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions.

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 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

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.

Carcinogenesis

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.

Mutagenesis

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.

Impairment of fertility

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 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 has been established from adequate and well-controlled studies of valbenazine. Below is a display of the adverse reactions of valbenazine in these adequate and well-controlled studies.

Tardive Dyskinesia

Variable and Fixed Dose Placebo-Controlled Trial Experience

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.

Table 1. Adverse Reactions in 3 Placebo-Controlled Studies of 6-week Treatment Duration Reported at ≥2% and >Placebo – Tardive Dyskinesia:

¹ Within each adverse reaction category, the observed adverse reactions are listed in order of decreasing frequency.

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 the tardive dyskinesia controlled trials, there was a dose-related increase in prolactin. Additionally, in these trials there was a dose-related increase in alkaline phosphatase and bilirubin, suggesting a potential risk for cholestasis.

Chorea Associated with Huntington’s Disease

The safety of valbenazine was evaluated in a 14-week placebo-controlled study including 127 patients with chorea associated with Huntington’s disease. Patients were 25 to 75 years of age. The mean age was 54 years. Patients were 96% Caucasian, 1% African-American, 1% Asian, and 2% Other. With respect to ethnicity, 6% were Hispanic or Latino.

Adverse Reactions Leading to Discontinuation of Treatment

A total of 8% of valbenazine-treated patients and 6% of placebo-treated patients discontinued because of adverse reactions.

Common Adverse Reactions

Adverse reactions that occurred in the placebo-controlled study at an incidence of ≥4% and greater than placebo are presented in Table 2.

Table 2. Adverse Reactions in the Placebo-Controlled Study of 12-week Treatment Duration Reported at ≥4% and >Placebo – Chorea Associated with Huntington’s Disease:

Postmarketing experience

The following adverse reactions have been identified during post-approval use of valbenazine that are not included in other sections of labeling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: hypersensitivity reactions (including allergic dermatitis and pruritis)