Austedo: Package Insert and Label Information

AUSTEDO- deutetrabenazine tablet, coated
AUSTEDO- deutetrabenazine
Teva Neuroscience, Inc.

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of AUSTEDO must balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behaviors of concern promptly to the treating physician.

Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington’s disease. AUSTEDO is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4) and Warnings and Precautions (5.1 )].

1 INDICATIONS AND USAGE

AUSTEDO® is indicated in adults for the treatment of:

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

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

The dose of AUSTEDO is determined individually for each patient based on reduction of chorea or tardive dyskinesia and tolerability. When first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor), the recommended starting dosage of AUSTEDO is 12 mg per day (6 mg twice daily) for patients with Huntington’s disease or tardive dyskinesia.

  • The dose of AUSTEDO may be increased at weekly intervals in increments of 6 mg per day based on reduction of chorea or tardive dyskinesia and tolerability, up to a maximum recommended daily dosage of 48 mg [see Clinical Trials 14.1, 14.2)].
  • Administer total daily dosages of 12 mg or above in two divided doses.
  • Administer AUSTEDO with food [see Clinical Pharmacology (12.3)].
  • Swallow AUSTEDO whole. Do not chew, crush, or break tablets.

2.2 Switching Patients from Tetrabenazine (XENAZINE®) to AUSTEDO

Discontinue tetrabenazine (XENAZINE®) and initiate AUSTEDO the following day. The recommended initial dosing regimen of AUSTEDO in patients switching from tetrabenazine (XENAZINE®) to AUSTEDO is shown in Table 1.

Table 1: Recommended Initial Dosing Regimen when Switching from Tetrabenazine (XENAZINE®) to AUSTEDO
Current tetrabenazine daily dosage Initial regimen ofAUSTEDO

12.5 mg

6 mg once daily

25 mg

6 mg twice daily

37.5 mg

9 mg twice daily

50 mg

12 mg twice daily

62.5 mg

15 mg twice daily

75 mg

18 mg twice daily

87.5 mg

21 mg twice daily

100 mg

24 mg twice daily

After patients are switched to AUSTEDO, the dose may be adjusted at weekly intervals [see Dosage and Administration (2.1)].

2.3 Dosage Adjustment with Strong CYP2D6 Inhibitors

In patients receiving strong CYP2D6 inhibitors (e.g., quinidine, antidepressants such as paroxetine, fluoxetine, and bupropion), the total daily dosage of AUSTEDO should not exceed 36 mg (maximum single dose of 18 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers

In patients who are poor CYP2D6 metabolizers, the total daily dosage of AUSTEDO should not exceed 36 mg (maximum single dose of 18 mg) [see Use in Specific Populations (8.7)].

2.5 Discontinuation and Interruption of Treatment

Treatment with AUSTEDO can be discontinued without tapering. Following treatment interruption of greater than one week, AUSTEDO therapy should be re-titrated when resumed. For treatment interruption of less than one week, treatment can be resumed at the previous maintenance dose without titration.

3 DOSAGE FORMS AND STRENGTHS

AUSTEDO tablets are available in the following strengths:

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

4 CONTRAINDICATIONS

AUSTEDO is contraindicated in patients:

  • With Huntington’s disease who are suicidal, or have untreated or inadequately treated depression [see Warnings and Precautions (5.1)].
  • With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
  • Taking reserpine. At least 20 days should elapse after stopping reserpine before starting AUSTEDO [see Drug Interactions (7.2 )].
  • Taking monoamine oxidase inhibitors (MAOIs). 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 )].
  • Taking tetrabenazine (XENAZINE®) or valbenazine [see Drug Interactions (7.6)].

5 WARNINGS AND PRECAUTIONS

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

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with 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, may cause a worsening in mood, cognition, rigidity, and functional capacity.

Prescribers should periodically re-evaluate the need for 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.

5.3 QTc Prolongation

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

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, 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; (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 is needed after recovery from NMS, patients should be monitored for signs of recurrence.

5.5 Akathisia, Agitation, and Restlessness

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 Huntington’s disease patients, 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 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, the AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.

5.6 Parkinsonism

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, the 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. 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 and know how the drug affects them.

5.8 Hyperprolactinemia

Serum prolactin levels were not evaluated in the 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 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 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.

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 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)].

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