Valbenazine

Dose adjustments due to drug interactions ( 2.4 , 7.1 ): Factors Dose Adjustments for INGREZZA and INGREZZA SPRINKLE Use of MAOIs with INGREZZA or INGREZZA SPRINKLE Avoid concomitant use with MAOIs. Use of strong CYP3A4 inducers with INGREZZA or INGREZZA SPRINKLE Concomitant use is not recommended. Use of strong CYP3A4 inhibitors with INGREZZA or INGREZZA SPRINKLE Recommended dosage is 40 mg once daily. Use of strong CYP2D6 inhibitors with INGREZZA or INGREZZA SPRINKLE Recommended dosage is 40 mg once daily.

7.1 Drugs Having Clinically Important Interactions with INGREZZA and INGREZZA SPRINKLE Table 3: Clinically Significant Drug Interactions with INGREZZA and INGREZZA SPRINKLE Monoamine Oxidase Inhibitors (MAOIs) Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to increased risk of adverse reactions such as serotonin syndrome, or attenuated treatment effect of INGREZZA or INGREZZA SPRINKLE. Prevention or Management: Avoid concomitant use of INGREZZA or INGREZZA SPRINKLE with MAOIs, or within 14 days of discontinuing therapy with an MAOI.

Strong CYP3A4 Inhibitors Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with strong CYP3A4 inhibitors increased the exposure (C max and AUC) to valbenazine and its active metabolite compared with the use of INGREZZA or INGREZZA SPRINKLE alone [see Clinical Pharmacology ( 12.3 )]. Increased exposure of valbenazine and its active metabolite may increase the risk of exposure-related adverse reactions [see Warnings and Precautions ( 5.4 )]. Prevention or Management: Reduce INGREZZA or INGREZZA SPRINKLE dose when INGREZZA or INGREZZA SPRINKLE is coadministered with a strong CYP3A4 inhibitor [see Dosage and Administration ( 2.5 )].

Strong CYP2D6 Inhibitors Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with strong CYP2D6 inhibitors increased the exposure (C max and AUC) to valbenazine’s active metabolite compared with the use of INGREZZA or INGREZZA SPRINKLE alone [see Clinical Pharmacology ( 12.3 , 12.5 )] . Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions [see Warnings and Precautions ( 5.4 )]. Prevention or Management: Reduce INGREZZA or INGREZZA SPRINKLE dose when INGREZZA or INGREZZA SPRINKLE is coadministered with a strong CYP2D6 inhibitor [see Dosage and Administration ( 2.5 )].

Strong CYP3A4 Inducers Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with a strong CYP3A4 inducer decreased the exposure of valbenazine and its active metabolite compared to the use of INGREZZA or INGREZZA SPRINKLE alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy [see Clinical Pharmacology ( 12.3 )]. Prevention or Management: Concomitant use of strong CYP3A4 inducers with INGREZZA or INGREZZA SPRINKLE is not recommended [see Dosage and Administration ( 2.5 )].

Digoxin Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with digoxin increased digoxin levels because of inhibition of intestinal P-glycoprotein (P-gp) [see Clinical Pharmacology ( 12.3 )] . Prevention or Management: Digoxin concentrations should be monitored when co-administering INGREZZA or INGREZZA SPRINKLE with digoxin. Increased digoxin exposure may increase the risk of exposure-related adverse reactions. Dosage adjustment of digoxin may be necessary.

8.1 Pregnancy Risk Summary The limited available data on INGREZZA or INGREZZA SPRINKLE 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/m 2 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/m 2 [see Data ].

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. Data Animal Data 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/m 2 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/m 2 . 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/m 2 . 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/m 2 . No malformations were observed at doses up to 24 times the MRHD of 80 mg/day based on mg/m 2 .

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/m 2 , 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/m 2 . 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/m 2 .…