Austedo Tablet, Coated

AUSTEDO XR^® and AUSTEDO^® are indicated in adults for the treatment of:

1. chorea associated with Huntington’s disease [see Clinical Studies (14.1)]
2. tardive dyskinesia [see Clinical Studies (14.2)]

AUSTEDO XR and AUSTEDO are contraindicated in patients:

1. With Huntington’s disease who are suicidal, or have untreated or inadequately treated depression [see Warnings and Precautions (5.1)].
2. With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
3. Taking reserpine. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO [see Drug Interactions (7.2 )].
4. Taking monoamine oxidase inhibitors (MAOIs). AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3 )].
5. Taking tetrabenazine or valbenazine [see Drug Interactions (7.6)].

Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including AUSTEDO XR and AUSTEDO, may cause a worsening in mood, cognition, rigidity, and functional capacity.

Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects, including sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician to distinguish between the two possibilities. In some patients, the underlying chorea itself may improve over time, decreasing the need for AUSTEDO XR or AUSTEDO.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

1. Depression and Suicidality in Patients with Huntington’s disease [see Warnings and Precautions (5.1)]
2. QTc Prolongation [see Warnings and Precautions (5.3)]
3. Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)]
4. Akathisia, Agitation, and Restlessness [see Warnings and Precautions (5.5)]
5. Parkinsonism [see Warnings and Precautions (5.6)]
6. Sedation and Somnolence [see Warnings and Precautions (5.7)]
7. Hyperprolactinemia [see Warnings and Precautions (5.8)]
8. Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.9)]

• QT Prolongation: Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval (5.3)

• Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs (5.4)

• Akathisia, agitation, restlessness, and parkinsonism: Reduce dose or discontinue if this occurs (5.5, 5.6)

• Sedation/somnolence: May impair the patient’s ability to drive or operate complex machinery (5.7) 5.1 Depression and Suicidality in Patients with Huntington’s Disease

Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality). AUSTEDO XR and AUSTEDO may increase the risk for suicidality in patients with Huntington’s disease.

In a 12-week, double-blind, placebo-controlled trial, suicidal ideation was reported by 2% of patients treated with AUSTEDO, compared to no patients on placebo; no suicide attempts and no completed suicides were reported. Depression was reported by 4% of patients treated with AUSTEDO.

When considering the use of AUSTEDO XR or AUSTEDO, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with AUSTEDO XR or AUSTEDO should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with AUSTEDO XR or AUSTEDO.

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with AUSTEDO XR and AUSTEDO, and should be instructed to report behaviors of concern promptly to the treating physician. Patients with Huntington’s disease who express suicidal ideation should be evaluated immediately. 5.2 Clinical Worsening and Adverse Events in Patients with Huntington’s Disease

Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including AUSTEDO XR and AUSTEDO, may cause a worsening in mood, cognition, rigidity, and functional capacity.

Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects, including sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician to distinguish between the two possibilities. In some patients, the underlying chorea itself may improve over time, decreasing the need for AUSTEDO XR or AUSTEDO. 5.3 QTc Prolongation

AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range [see Clinical Pharmacology (12.2)].

AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. 5.4 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. While NMS has not been observed in patients receiving AUSTEDO XR or AUSTEDO, it has been observed in patients receiving tetrabenazine (a closely related VMAT2 inhibitor). 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 creatinine 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 AUSTEDO XR and AUSTEDO; (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 AUSTEDO XR or AUSTEDO is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5.5 Akathisia, Agitation, and Restlessness

AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia.

In a 12-week, double-blind, placebo-controlled trial in patients with Huntington’s disease, akathisia, agitation, or restlessness was reported by 4% of patients treated with AUSTEDO, compared to 2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with AUSTEDO and 1% of patients on placebo experienced these events.

Patients receiving AUSTEDO XR or AUSTEDO should be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia during treatment with AUSTEDO XR or AUSTEDO, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.6 Parkinsonism

AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors.

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 cases of parkinsonism in patients treated with AUSTEDO for tardive dyskinesia have been reported. Signs and symptoms in reported cases have included bradykinesia, gait disturbances, which led to falls in some cases, and the emergence or worsening of tremor. In most cases, the development of parkinsonism occurred within the first two weeks after starting or increasing the dose of AUSTEDO. In cases in which follow-up clinical information was available, parkinsonism was reported to resolve following discontinuation of AUSTEDO therapy.

If a patient develops parkinsonism during treatment with AUSTEDO XR or AUSTEDO, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.7 Sedation and Somnolence

Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. In a 12-week, double-blind, placebo-controlled trial examining patients with Huntington’s disease, 11% of AUSTEDO-treated patients reported somnolence compared with 4% of patients on placebo and 9% of AUSTEDO-treated patients reported fatigue compared with 4% of placebo-treated patients.

Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. 5.8 Hyperprolactinemia

Serum prolactin levels were not evaluated in the AUSTEDO XR and AUSTEDO development program. Tetrabenazine, a closely related VMAT2 inhibitor, elevates serum prolactin concentrations in humans. Following administration of 25 mg of tetrabenazine to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent

in vitro, a factor of potential importance if AUSTEDO XR or AUSTEDO is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia, and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown.

Chronic increase in serum prolactin levels (although not evaluated in the AUSTEDO XR, AUSTEDO, or tetrabenazine development programs) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO. 5.9 Binding to Melanin-Containing Tissues

Since deutetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that AUSTEDO XR and AUSTEDO may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.

The clinical relevance of deutetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects

[see Clinical Pharmacology (12.2)].

In patients receiving strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

In patients who are poor CYP2D6 metabolizers, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Use in Specific Populations (8.7)].

AUSTEDO XR extended-release tablets are available in the following strengths:

1. The 6 mg extended-release tablets are round, grey-coated tablets, with “Q6” printed in black ink on one side.
2. The 12 mg extended-release tablets are round, blue-coated tablets, with “Q12” printed in black ink on one side.
3. The 18 mg extended-release tablets are round, light grey-coated tablets, with “Q18” printed in black ink on one side.
4. The 24 mg extended-release tablets are round, purple-coated tablets, with “Q24” printed in black ink on one side.
5. The 30 mg extended-release tablets are round, light orange-coated tablets, with “Q30” printed in black ink on one side.
6. The 36 mg extended-release tablets are round, light purple-coated tablets, with “Q36” printed in black ink on one side.
7. The 42 mg extended-release tablets are round, orange-coated tablets, with “Q42” printed in black ink on one side.
8. The 48 mg extended-release tablets are round, pink-coated tablets, with “Q48” printed in black ink on one side.

AUSTEDO tablets are available in the following strengths:

1. The 6 mg tablets are round, purple-coated tablets, with “SD” over “6” printed in black ink on one side.
2. The 9 mg tablets are round, blue-coated tablets, with “SD” over “9” printed in black ink on one side.
3. The 12 mg tablets are round, beige-coated tablets, with “SD” over “12” printed in black ink on one side.

• Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of AUSTEDO XR or AUSTEDO is 36 mg per day (2.3, 7.1)

• Alcohol or other sedating drugs: May have additive sedation and somnolence (7.5) 7.1 Strong CYP2D6 Inhibitors

A reduction in AUSTEDO XR or AUSTEDO dose may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose of AUSTEDO XR or AUSTEDO. Concomitant use of strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine, bupropion) has been shown to increase the systemic exposure to the active dihydro-metabolites of deutetrabenazine by approximately 3-fold. The daily dose of AUSTEDO XR or AUSTEDO should not exceed 36 mg per day in patients taking strong CYP2D6 inhibitors

[see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 7.2 Reserpine

Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea or dyskinesia to reemerge before administering AUSTEDO XR or AUSTEDO to help reduce the risk of overdosage and major depletion of serotonin and norepinephrine in the central nervous system. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO. AUSTEDO XR and AUSTEDO should not be used concomitantly with reserpine [see Contraindications (4)]. 7.3 Monoamine Oxidase Inhibitors (MAOIs)

AUSTEDO XR and AUSTEDO are contraindicated in patients taking MAOIs. AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Contraindications (4)]. 7.4 Neuroleptic Drugs

The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO XR or AUSTEDO with dopamine antagonists or antipsychotics. 7.5 Alcohol or Other Sedating Drugs

Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence

[see Warnings and Precautions (5.7)]. 7.6 Concomitant Tetrabenazine or Valbenazine

AUSTEDO XR and AUSTEDO are contraindicated in patients currently taking tetrabenazine or valbenazine. AUSTEDO XR or AUSTEDO may be initiated the day following discontinuation of tetrabenazine

[see Dosage and Administration (2.2)].