VALBENAZINE: 23,191 Adverse Event Reports & Safety Profile

INGREZZA and INGREZZA SPRINKLE contains valbenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, present as valbenazine tosylate salt, with the chemical name, L-Valine, ( 2R,3R ,11b R )-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2 H -benzo[ a ]quinolizin-2-yl ester, 4-methylbenzenesulfonate (1:2). Valbenazine tosylate is slightly soluble in water. Its molecular formula is C 38 H 54 N 2 O 10 S 2 , and its molecular weight is 762.97 g/mol (ditosylate salt) with the following structure: The molecular formula of valbenazine free base is C 24 H 38 N 2 O 4 and its molecular weight is 418.57. INGREZZA is intended for oral administration only. Each capsule contains 73 mg, 109 mg or 146 mg of valbenazine tosylate equivalent to 40 mg, 60 mg or 80 mg of valbenazine free base, respectively. The capsules contain the following inactive ingredients: hypromellose, isomalt, magnesium stearate, pregelatinized starch, and silicified microcrystalline cellulose. The capsule shells contain candurin silver fine, FD&C Blue#1, FD&C Red#40, and gelatin. INGREZZA SPRINKLE is intended for oral administration. Each capsule contains granules consisting of 73 mg, 109 mg or 146 mg of valbenazine tosylate equivalent to 40 mg, 60 mg or 80 mg of valbenazine free base, respectively. The oral granules contain the following inactive ingredients: silicified microcrystalline cellulose, isomalt, pregelatinized maize starch, hypromellose, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc in hard gelatin capsules (contains gelatin and candurin silver fine). INGREZZA contains valbenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, present as valbenazine tosylate salt, with the chemical name, L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester, 4-methylbenzenesulfonate (1:2). Valbenazine tosylate is slightly soluble in water. Its molecular formula is C38H54N2O10S2, and its molecular weight is 762.97 g/mol (ditosylate salt) with the following structure:

AND USAGE INGREZZA and INGREZZA SPRINKLE are indicated for the treatment of adults with: - tardive dyskinesia [see Clinical Studies ( 14.1 )] . - chorea associated with Huntington’s disease [see Clinical Studies ( 14.2 )] . INGREZZA and INGREZZA SPRINKLE are vesicular monoamine transporter 2 (VMAT2) inhibitors indicated for the treatment of adults with: - tardive dyskinesia. ( 1 ) - chorea associated with Huntington’s disease. ( 1 )

AND ADMINISTRATION Tardive dyskinesia: The initial dosage is 40 mg once daily. After one week, increase the dose to the recommended dosage of 80 mg once daily. ( 2.1 ) Chorea associated with Huntington’s disease: The initial dosage is 40 mg once daily. Increase the dose in 20 mg increments every two weeks to the recommended dosage of 80 mg once daily. ( 2.1 ) 40 mg or 60 mg once daily may be considered depending on response and tolerability. ( 2.1 ) Can be taken with or without food. ( 2.2 ) INGREZZA SPRINKLE may be opened and sprinkled over soft food (do not use milk or drinking water). INGREZZA SPRINKLE may be swallowed whole with water. Do not crush or chew. ( 2.2 ) The recommended dosage for patients with moderate or severe hepatic impairment is 40 mg once daily. ( 2.3 ) The recommended dosage for known CYP2D6 poor metabolizers is 40 mg once daily. ( 2.4 )

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 )].

INGREZZA and INGREZZA SPRINKLE are contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA or INGREZZA SPRINKLE. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported with use of INGREZZA [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )]. Known hypersensitivity to valbenazine or any components of INGREZZA or INGREZZA SPRINKLE. ( 4 )

REACTIONS 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 )] Most common adverse reaction (≥5% and twice the rate of placebo): - Tardive dyskinesia: somnolence. ( 6.1 ) - Chorea associated with Huntington’s disease: somnolence/lethargy/sedation, urticaria, rash, insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Neurocrine Biosciences, Inc. at 877-641-3461 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 INGREZZA SPRINKLE has been established from adequate and well-controlled studies of INGREZZA <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . 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 Adverse Reaction 1 INGREZZA (n=262) % Placebo (n=183) % General Disorders Somnolence (somnolence, fatigue, sedation) 10.9

4.2 Nervous System Disorders Anticholinergic effects 5.4 4.9 (dry mouth, constipation, disturbance in attention, vision blurred, urinary retention) Balance disorders/fall (fall, gait disturbance, dizziness, balance disorder) 4.1

2.2 Headache 3.4

2.7 Akathisia (akathisia, restlessness) 2.7

0.5 Gastrointestinal Disorders Vomiting 2.6

0.6 Nausea 2.3

2.1 Musculoskeletal Disorders Arthralgia 2.3 0.5 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 Adverse Reaction INGREZZA (n=64) % Placebo (n=63) % Nervous System Disorders Somnolence, lethargy, sedation 18.8

3.2 Akathisia 6.3

4.8 General Disorders and Administration Site Conditions Fatigue 14.1

9.5 Skin and Subcutaneous Tissue Disorders Urticaria 9.4 0 Rash 7.8 0 Gastrointestinal Disorders Diarrhea 4.7

1.6 Nausea 4.7 0 Psychiatric Disorders Insomnia, middle insomnia 6.3

1.6 Depression, depressed mood 4.7

1.6 Musculoskeletal D isorders Back pain 4.7 0

6.2 Postmarketing Experience 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)

AND PRECAUTIONS Depression and suicidal ideation and behavior in patients with Huntington’s disease. ( 5.1 ) Hypersensitivity, including angioedema may occur. Discontinue if this occurs. ( 5.2 ) Somnolence/sedation: May impair patient’s ability to drive or operate hazardous machinery. ( 5.3 ) QT Prolongation: May cause an increase in QT interval. Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. ( 5.4 )

Neuroleptic Malignant

Syndrome (NMS): Discontinue if this occurs. ( 5.5 ) Parkinsonism: Cases of parkinson-like symptoms, some of which were severe, have been reported in the postmarketing period. Reduce the dose or discontinue INGREZZA or INGREZZA SPRINKLE treatment in patients who develop clinically significant parkinson-like signs or symptoms. ( 5.6 )

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> , 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 , 2.5 )]</span>. 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 &lt;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.

INTERACTIONS 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.