INGREZZA Capsule Ref.[110006] Active ingredients: Valbenazine

5.1 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. VMAT2 inhibitors, including INGREZZA and INGREZZA SPRINKLE, can increase the risk for suicidal ideation and behaviors in patients with Huntington’s disease.

In a 14-week, double-blind, placebo-controlled trial [see Clinical Studies (14.2)], depression or depressed mood was reported in 4.7% of patients taking INGREZZA compared to 1.6% of patients who received placebo, and no patients taking INGREZZA reported suicidal ideation or behavior compared to 1 patient (1.6%) who received placebo. Patients with significant risk for suicidal behavior or with unstable psychiatric symptoms were excluded from this trial. Suicidal ideation (9 subjects; 7.2%) and suicide attempts (3 subjects; 2.4%) were reported in the longer open-label extension trial (N=125).

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

5.2 Hypersensitivity Reactions

Hypersensitivity reactions, including cases of angioedema involving the larynx, glottis, lips, and eyelids, have been reported in the postmarketing setting in patients after taking the first or subsequent doses of INGREZZA [see Adverse Reactions (6.2)]. A case of angioedema involving the lips and face, with rash and shortness of breath was reported in a patient with Huntington’s disease taking INGREZZA during a clinical study. Urticaria and rash were also reported during a clinical study in patients with Huntington’s disease. Angioedema associated with laryngeal edema can be fatal. If any of these reactions occur, discontinue INGREZZA or INGREZZA SPRINKLE.

5.3 Somnolence and Sedation

INGREZZA and INGREZZA SPRINKLE can cause somnolence and sedation, which was the most common adverse reaction in placebo-controlled trials with INGREZZA [see Adverse Reactions (6.1)]. 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 INGREZZA or INGREZZA SPRINKLE.

5.4 QT Prolongation

INGREZZA and INGREZZA SPRINKLE 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, INGREZZA and INGREZZA SPRINKLE concentrations may be higher and QT prolongation clinically significant [see Clinical Pharmacology (12.2)]. 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 INGREZZA or INGREZZA SPRINKLE to 40 mg once daily [see Dosage and Administration (2.4, 2.5)]. INGREZZA and INGREZZA SPRINKLE 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.

5.5 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. In the postmarketing setting, NMS has been reported in patients taking VMAT2 inhibitors, including INGREZZA. Clinicians should be alerted to the signs and symptoms associated with NMS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include (1) immediate discontinuation of INGREZZA or INGREZZA SPRINKLE; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

Recurrence of NMS has been reported with resumption of drug therapy. If treatment with INGREZZA or INGREZZA SPRINKLE is needed after recovery from NMS, patients should be monitored for signs of recurrence.

5.6 Parkinsonism

INGREZZA and INGREZZA SPRINKLE may cause parkinsonism. Parkinsonism has also been observed with other VMAT2 inhibitors. In the 3 placebo-controlled clinical studies in patients with tardive dyskinesia, the incidence of parkinson-like adverse events was 3% of patients treated with INGREZZA and <1% of placebo-treated patients.

In a placebo-controlled clinical study in patients with chorea associated with Huntington’s disease, the incidence of parkinson-like adverse events was 4.7% in patients treated with INGREZZA and 0% in placebo-treated patients. 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. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease.

Postmarketing safety reports have described parkinson-like symptoms in patients taking INGREZZA for tardive dyskinesia, some of which were severe and required hospitalization. In most cases, severe parkinsonism occurred within the first two weeks after starting or increasing the dose of INGREZZA. Associated symptoms have included falls, gait disturbances, tremor, drooling and hypokinesia. In cases in which follow-up clinical information was available, parkinson-like symptoms were reported to resolve following discontinuation of INGREZZA therapy.

Reduce the dose or discontinue INGREZZA or INGREZZA SPRINKLE treatment in patients who develop clinically significant parkinson-like signs or symptoms.

The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:

• Depression and Suicidal Ideation and Behavior in Patients with Huntington’s Disease [see Boxed Warning and Warnings and Precautions (5.1)]
• Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.2)]
• Somnolence and Sedation [see Warnings and Precautions (5.3)]
• QT Prolongation [see Warnings and Precautions (5.4)]
• Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.5)]
• Parkinsonism [see Warnings and Precautions (5.6)]

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 INGREZZA SPRINKLE has been established from adequate and well-controlled studies of INGREZZA [see Clinical Studies (14)]. Below is a display of the adverse reactions of INGREZZA in these adequate and well-controlled studies.

Tardive Dyskinesia

Variable and Fixed Dose Placebo-Controlled Trial Experience

The safety of INGREZZA 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 INGREZZA-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 INGREZZA

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 INGREZZA 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 INGREZZA-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:

The following adverse reactions have been identified during post-approval use of INGREZZA 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)

7.1 Drugs Having Clinically Important Interactions with INGREZZA and INGREZZA SPRINKLE

Table 3. Clinically Significant Drug Interactions with INGREZZA and INGREZZA SPRINKLE:

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).

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.

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

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)].

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)].

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)].

8.6 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 (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 [see Clinical Pharmacology (12.3, 12.5)].