Ingrezza

2.1 Recommended Dosage

Tardive Dyskinesia

The initial dosage for INGREZZA and INGREZZA SPRINKLE is 40 mg once daily. After one week, increase the dose to the recommended dosage of 80 mg once daily. A dosage of 40 mg or 60 mg once daily may be considered depending on response and tolerability. 

Chorea Associated with Huntington’s Disease

The initial dosage for INGREZZA and INGREZZA SPRINKLE is 40 mg once daily. Increase the dose in 20 mg increments every two weeks to the recommended dosage of 80 mg once daily. A dosage of 40 mg or 60 mg once daily may be considered depending on response and tolerability.

2.2 Administrative Information

Administer INGREZZA and INGREZZA SPRINKLE orally with or without food [see Clinical Pharmacology ( 12.3)].

Administration Information for INGREZZA SPRINKLE

• Open INGREZZA SPRINKLE and sprinkle the entire contents of the capsule over a bowl containing a small amount (1 tablespoonful) of soft food such as applesauce, yogurt, or pudding. Do not sprinkle the contents of the capsule into milk or drinking water. Stir the contents of the capsule into the soft food with the tablespoon and swallow the drug/food mixture immediately. If necessary, the mixture can be stored for up to 2 hours at room temperature. Discard of any unused portion after 2 hours. Following administration of the drug/food mixture, drink a glass (e.g., 240 mL) of water.

Do not administer INGREZZA SPRINKLE via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction of enteral tubes.

• INGREZZA SPRINKLE may be swallowed whole with water. Do not crush or chew INGREZZA SPRINKLE.

2.3 Dosage Recommendations for Patients with Hepatic Impairment

The recommended dosage for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Use in Specific Populations ( 8.7), Clinical Pharmacology ( 12.3)].

2.4 Dosage Recommendations for Known CYP2D6 Poor Metabolizers

The recommended dosage for known CYP2D6 poor metabolizers is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Use in Specific Populations ( 8.6), Clinical Pharmacology ( 12.3, 12.5)].

2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inducers and Strong CYP3A4 or CYP2D6 Inhibitors

Coadministration with Strong CYP3A4 Inducers

Concomitant use of strong CYP3A4 inducers with INGREZZA or INGREZZA SPRINKLE is not recommended [see Drug Interactions ( 7.1)].

Coadministration with Strong CYP3A4 Inhibitors

The recommended dosage for patients receiving strong CYP3A4 inhibitors is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Drug Interactions ( 7.1)].

Coadministration with Strong CYP2D6 Inhibitors

The recommended dosage for patients receiving strong CYP2D6 inhibitors is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Drug Interactions ( 7.1)].

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/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 [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/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).

8.2 Lactation

Risk Summary

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 INGREZZA or INGREZZA SPRINKLE and for 5 days after the final dose.

8.4 Pediatric Use

Safety and effectiveness of INGREZZA and INGREZZA SPRINKLE have not been established in pediatric patients.

8.5 Geriatric Use

No dose adjustment of INGREZZA or INGREZZA SPRINKLE is required for elderly patients.

Tardive Dyskinesia

In 3 randomized, placebo-controlled studies of INGREZZA in patients with tardive dyskinesia, 16% of patients were 65 years and older. The safety and effectiveness were similar in patients older than 65 years compared to younger patients.

Huntington’s Disease

In the randomized, placebo-controlled study of INGREZZA in 127 patients with chorea associated with Huntington’s disease, 15% were 65 years and older. This study did not include sufficient numbers of subjects aged 65 and older to determine whether they responded differently from younger subjects [see Clinical Studies ( 14.2)].

8.6 CYP2D6 Poor Metabolizers

Dosage reduction of INGREZZA and INGREZZA SPRINKLE is recommended for known CYP2D6 poor metabolizers [see Dosage and Administration ( 2.4)]. Increased exposure (Cmax 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 [see Clinical Pharmacology ( 12.3, 12.5)].

8.7 Hepatic Impairment

Dosage reduction of INGREZZA and INGREZZA SPRINKLE is recommended for patients with moderate or severe hepatic impairment [see Dosage and Administration ( 2.3)]. 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 [see Clinical Pharmacology ( 12.3)].

8.8 Renal Impairment

Dosage adjustment is not necessary for patients with mild, moderate, or severe renal impairment. INGREZZA and INGREZZA SPRINKLE do not undergo primary renal clearance. [see Clinical Pharmacology ( 12.3)].