HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
` AUSTEDO XR or AUSTEDO safely and effectively. See full prescribing
`
`
`
`
`
` information for AUSTEDO XR and AUSTEDO.
`
`
`
`AUSTEDO® XR (deutetrabenazine) extended-release tablets, for oral use
`
`
`
`
`
`
`AUSTEDO® (deutetrabenazine) tablets, for oral use
`Initial U.S. Approval: 2017
`
`
`
`
`
`
`
`
`
` WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS
` WITH HUNTINGTON’S DISEASE
`
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`• Increases the risk of depression and suicidal thoughts and behavior
`
`(suicidality) in patients with Huntington’s disease (5.1)
`
`
`• Balance risks of depression and suicidality with the clinical need for
`
`
`
`
`treatment of chorea when considering the use of AUSTEDO XR or
`
`AUSTEDO (5.1)
`
`
`• Monitor patients for the emergence or worsening of depression,
`
`
`
`suicidality, or unusual changes in behavior (5.1)
`
`
`
`• Inform patients, caregivers, and families of the risk of depression and
`
`
`
`suicidality and instruct to report behaviors of concern promptly to
`
`the treating physician (5.1)
`
`• Exercise caution when treating patients with a history of depression
`
`
`
`or prior suicide attempts or ideation (5.1)
`
`
`
`
`• AUSTEDO XR and AUSTEDO are contraindicated in patients who
`
`
`are suicidal, and in patients with untreated or inadequately treated
`depression (4, 5.1)
`
`
`
`
`
`_________________
`_________________
`RECENT MAJOR CHANGES
`AUSTEDO XR (added throughout the Prescribing Information)
`2/2023
`
`
`5/2022
`Dosage and Administration (2.1)
`
`
`
`
`
`
`
`
`Dosage and Administration (2.1, 2.2)
`2/2023
`
`
`
`
`
`
`
`
`
`
`
` __________________INDICATIONS AND USAGE
`
`
`_________________
`AUSTEDO XR and AUSTEDO are vesicular monoamine transporter 2
`
`
`
`
`(VMAT2) inhibitors indicated in adults for the treatment of:
`
`
`
`
`
`• Chorea associated with Huntington’s disease (1)
`
`
`
`
`• Tardive dyskinesia (1)
`
`
`
`
`_______________DOSAGE AND ADMINISTRATION ______________
`
`
`
`
`
`
`
`
`
` AUSTEDO XR
`
`
`
`
`
` AUSTEDO
`
`
`•
`
`
`
`
`
`
`
`
` If switching patients from tetrabenazine, discontinue tetrabenazine and
`
` initiate AUSTEDO XR or AUSTEDO the following day. See full
`
`
`
` prescribing information for recommended conversion table (2.2)
`
`
`
` • Maximum recommended dosage of AUSTEDO XR or AUSTEDO in
`
`
`
`
` poor CYP2D6 metabolizers is 36 mg per day (2.4, 8.7)
`
`
`
`
`
`
`
`______________
`_____________
`
`
`
`DOSAGE FORMS AND STRENGTHS
`Extended-release tablets: 6 mg, 12 mg, and 24 mg (3)
`
`
`
`
`Tablets: 6 mg, 9 mg, and 12 mg (3)
`
`
`
`
`
`___________________ CONTRAINDICATIONS ___________________
`
`
`
`• Suicidal, or untreated/inadequately treated depression in patients with
`
`
`
`
`
`
`Huntington’s disease (4, 5.1)
`
`
`• Hepatic impairment (4, 8.6, 12.3)
`
`
`
`• Taking reserpine, MAOIs, tetrabenazine, or valbenazine (4, 7.2, 7.3, 7.6)
`
`
`
`
`
`
`
`_______________WARNINGS AND PRECAUTIONS _______________
`
`
`
`• 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)
`
`
`___________________ ADVERSE REACTIONS ___________________
`
`
`
`Most common adverse reactions (>8% of AUSTEDO-treated patients with
`
`
`
`Huntington’s disease and greater than placebo): somnolence, diarrhea, dry
`
`
`
`
`
`mouth, and fatigue (6.1)
`
`
`
`
`Most common adverse reactions (that occurred in 4% of AUSTEDO-treated
`
`
`
`
`
`patients with tardive dyskinesia and greater than placebo): nasopharyngitis
`
`
`
`
`
`
`and insomnia (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Teva
`
`
`Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`
`
`___________________ DRUG INTERACTIONS____________________
`
`
`• 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)
`
`
`_______________
`______________
`
`
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
` Recommended
`
`
` Starting Dosage
`
`
` 12 mg once daily
`
`
`
` (12 mg per day)
`
`
`
`
`
` 6 mg twice daily
`
` (12 mg per day)
`
`
`
`
`
`
`
`
`
`
`
`
` • Titrate at weekly intervals by 6 mg per day based on reduction of chorea
`
` or tardive dyskinesia, and tolerability, up to a maximum recommended
`
`
`
` daily dosage of 48 mg (2.1)
`
`
`
` • Administer AUSTEDO XR with or without food in once-daily doses (2.1)
`
`
`
`
`
`
` • Administer AUSTEDO with food and administer total daily dosages of 12
`
`
`
`
` mg or above in two divided doses (2.1)
`
`
`
`
` • Swallow tablets whole; do not chew, crush, or break (2.1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 2/2023
`
`
`
`
`
`Reference ID: 5128727
`
`1
`
`
`
`

`

`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH
`
`
` HUNTINGTON'S DISEASE
`
`
`1
`
`2
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`
`Switching Patients from Tetrabenazine to AUSTEDO XR or
`2.2
`
`
`
`
`AUSTEDO
`
`2.3 Dosage Adjustment with Strong CYP2D6 Inhibitors
`
`
`
`2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers
`
`
`
`
`
`
`2.5 Discontinuation and Interruption of Treatment
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Depression and Suicidality in Patients with Huntington's Disease
`
`
`
`
`5.2 Clinical Worsening and Adverse Events in Patients with
`
`
`
`
`
`Huntington's Disease
`5.3 QTc Prolongation
`
`
`
`
`5.4 Neuroleptic Malignant Syndrome (NMS)
`5.5 Akathisia, Agitation, and Restlessness
`
`
`
`
`
`5.6
`Parkinsonism
`
`5.7
`Sedation and Somnolence
`
`
`
`5.8 Hyperprolactinemia
`
`
`5.9 Binding to Melanin-Containing Tissues
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`DRUG INTERACTIONS
`
`7.1 Strong CYP2D6 Inhibitors
`
`
`
`6
`
`7
`
`
`
`
`8
`
`
`
`7.2 Reserpine
`
`7.3 Monoamine Oxidase Inhibitors (MAOIs)
`
`7.4 Neuroleptic Drugs
`
`
`7.5 Alcohol or Other Sedating Drugs
`
`
`7.6 Concomitant Tetrabenazine or Valbenazine
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2 Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`8.7
`Poor CYP2D6 Metabolizers
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`
`14.1 Chorea Associated with Huntington's Disease
`
`
`
`14.2 Tardive Dyskinesia
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`16.2 Storage
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`listed.
`
`
`
`
`Reference ID: 5128727
`
`2
`
`
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH
`
` HUNTINGTON’S DISEASE
`
`
` AUSTEDO XR and 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 XR or 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 XR and AUSTEDO are 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® XR and AUSTEDO® are 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 XR and AUSTEDO is determined individually for each patient based on
`
`
`
`
`
`reduction of chorea or tardive dyskinesia and tolerability. Table 1 displays the recommended
`
`
`dosage and important administration instructions of AUSTEDO XR and AUSTEDO when first
`
`
`
`prescribed to patients who are not being switched from tetrabenazine (a related VMAT2
`inhibitor).
`
`
`
`
`
`Reference ID: 5128727
`
`3
`
`
`
`

`

`
`
` Table 1:
`
`
`
`
`
`
`
` Recommended Dosage and Important Administration Instructions for
`
` AUSTEDO XR and AUSTEDO
`
`
`AUSTEDO XR
`
`extended-release tablet
`
`
`AUSTEDO
`
`tablet
`
`Recommended Starting Dosage
`
`
`
`12 mg once daily
`
`
`(12 mg per day)
`
`
`6 mg twice daily
`
`
`(12 mg per day)
`
`Recommended Dose Titration
`
`
`
`Important Administration Instructions
`
`
`Switching Between AUSTEDO and
`
`AUSTEDO XR
`
`
`
`
`The dosage of AUSTEDO XR or 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 AUSTEDO XR with
`
`
`• Administer AUSTEDO with
`or without food [see Clinical
`food [see Clinical
`
`
`
`Pharmacology (12.3)].
`
`Pharmacology (12.3)].
`
`
`
`• Swallow AUSTEDO XR whole.
`
`
`
`• Swallow AUSTEDO whole. Do
`
`Do not chew, crush, or break
`not chew, crush, or break
`tablets.
`
`tablets.
`
`
`
`• Administer AUSTEDO XR
`
`
`• Administer AUSTEDO total
`
`once daily.
`
`
`daily dosages of 12 mg or above
`
`in two divided doses.
`When switching between AUSTEDO tablets (twice daily) and
`
`AUSTEDO XR extended-release tablets (once daily), switch to the
`
`same total daily dosage.
`
`
` 2.2
`
`
`
`
`
`
`
`
`
`
`
`
`
` Switching Patients from Tetrabenazine to AUSTEDO XR or
`
`
` AUSTEDO
`
`
`
`
` Discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. The
`
` recommended initial dosing regimen of AUSTEDO XR or AUSTEDO in patients switching
`
`
` from tetrabenazine to AUSTEDO XR or AUSTEDO is shown in Table 2.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5128727
`
`
`4
`
`
`
`

`

`
`
`
`
` Recommended Initial Dosing Regimen when Switching from Tetrabenazine
`
`
`
` to AUSTEDO XR or AUSTEDO
`Current tetrabenazine
` Initial regimen of
`
`
`
`
` daily dosage
` AUSTEDO XR
` extended-release tablet
`
` 6 mg once daily
`
` 12 mg once daily
`
` 18 mg once daily
`
` 24 mg once daily
`
` 30 mg once daily
`
` 36 mg once daily
`
` 42 mg once daily
`
` 48 mg once daily
`
`
`
` Table 2:
`
`
`
`
`
`
`
`
`
`
`
` Initial regimen of
`
` AUSTEDO
`
` tablet
`
` 6 mg once daily
`
` 6 mg twice daily
`
` 9 mg twice daily
` 12 mg twice daily
`
`
` 15 mg twice daily
`
` 18 mg twice daily
`
` 21 mg twice daily
`
` 24 mg twice daily
`
`
` 12.5 mg
`
` 25 mg
`
` 37.5 mg
`
` 50 mg
`
` 62.5 mg
`
` 75 mg
`
` 87.5 mg
`
` 100 mg
`
`
`
`
`After patients are switched to AUSTEDO XR or 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, the total daily dosage of AUSTEDO XR or
`
`
` AUSTEDO should not exceed 36 mg [see Drug Interactions (7.1) and Clinical Pharmacology
`
` (12.3)].
` Dosage Adjustment in Poor CYP2D6 Metabolizers
`
`
`
` 2.4
`
`
` 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)].
`
`
`
` 2.5
` Discontinuation and Interruption of Treatment
` Treatment with AUSTEDO XR or AUSTEDO can be discontinued without tapering. Following
`
`
`
`
`
` treatment interruption of greater than one week, AUSTEDO XR or 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.
`
`
`
` DOSAGE FORMS AND STRENGTHS
` 3
`
`
` AUSTEDO XR extended-release tablets are available in the following strengths:
`
`
` • The 6 mg extended-release tablets are round, grey-coated tablets, with “Q6” printed
`
` in black ink on one side.
` • The 12 mg extended-release tablets are round, blue-coated tablets, with “Q12” printed
`
` in black ink on one side.
` • The 24 mg extended-release tablets are round, purple-coated tablets, with “Q24”
`
` printed in black ink on one side.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5128727
`
`
`
` 5
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` 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 XR and AUSTEDO are 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 XR or AUSTEDO [see Drug Interactions (7.2)].
`
` • 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)].
`
`
`
`
`
`• Taking tetrabenazine 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 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.
`
`
`
`
`Reference ID: 5128727
`
`6
`
`
`
`
`

`

`
`
`
`
`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.
`
`
`
` QTc Prolongation
`
`
` 5.3
`
`
`
` 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.
`
`
`
`
`
`
`
`Reference ID: 5128727
`
`7
`
`
`
`
`

`

`
`
`
`
`
`
` 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.
` Parkinsonism
`
`
` 5.6
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5128727
`
`
`8
`
`
`
`

`

`
`
` 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.
`
` Hyperprolactinemia
`
`
` 5.8
` 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.
`
`
` Binding to Melanin-Containing Tissues
` 5.9
` 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)].
`
`
`
`
`
`
`
`
`
` ADVERSE REACTIONS
` 6
`
`
`
` The following serious adverse reactions are discussed in greater detail in other sections of the
`
` labeling:
` • Depression and Suicidality in Patients with Huntington’s disease [see Warnings and
`
`
` Precautions (5.1)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5128727
`
`
`
` 9
`
`
`
`

`

` • QTc Prolongation [see Warnings and Precautions (5.3)]
`
`
` • Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)]
`
`
`
` • Akathisia, Agitation, and Restlessness [see Warnings and Precautions (5.5)]
`
`
`
` • Parkinsonism [see Warnings and Precautions (5.6)]
`
`
`
` • Sedation and Somnolence [see Warnings and Precautions (5.7)]
`
`
` • Hyperprolactinemia [see Warnings and Precautions (5.8)]
`
`
`
`
` • Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.9)]
`
`
` 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 studies described below were conducted with AUSTEDO tablets; adverse reactions with
`
`AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.
`
`Patients with Huntington’s Disease
`
`
`Study 1 [see Clinical Studies (14.1)] was a randomized, 12-week, placebo-controlled study in
`
`patients with chorea associated with Huntington’s disease. A total of 45 patients received
`
`
`AUSTEDO, and 45 patients received placebo. Patients ranged in age between 23 and 74 years
`
`
`(mean 54 years); 56% were male, and 92% were Caucasian. The most common adverse reactions
`
`
`occurring in greater than 8% of AUSTEDO-treated patients were somnolence, diarrhea, dry
`
`
`mouth, and fatigue. Adverse reactions occurring in 4% or more of patients treated with
`
`AUSTEDO, and with a greater incidence than in patients on placebo, are summarized in Table 3.
`
`
`
`
`
`Table 3:
`Adverse Reactions in Patients with Huntington’s Disease (Study 1)
`
`
`
`
`
`Experienced by at Least 4% of Patients on AUSTEDO and with a Greater
`
`
`Incidence than on Placebo
` AUSTEDO
`Adverse Reaction
`
`
`
` (N = 45)
`
` %
`
` 11
`
` 9
`
` 9
`
` 9
`
` 7
`
` 7
`
` 4
`
` 4
`
` 4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo
`
` (N = 45)
`
` %
`
` 4
`
` 0
`
` 7
`
` 4
`
` 2
`
` 4
`
` 2
`
` 2
`
` 2
`
`
`
`
`
`
`
` Somnolence
`
` Diarrhea
` Dry mouth
`
` Fatigue
` Urinary tract infection
` Insomnia
`
`
` Anxiety
` Constipation
`
` Contusion
`
`
` One or more adverse reactions resulted in a reduction of the dose of study medication in 7% of
`
`
`
`
`
`
`
`
` patients in Study 1. The most common adverse reaction resulting in dose reduction in patients
` receiving AUSTEDO was dizziness (4%).
`
`
`
`
`
`Reference ID: 5128727
`
`10
`
`
`
`

`

`
`
`
`
` Agitation led to discontinuation in 2% of patients treated with AUSTEDO in Study 1.
`
` Patients with Tardive Dyskinesia
`The data described below reflect 410 tardive dyskinesia patients participating in clinical trials.
`AUSTEDO was studied primarily in two 12-week, placebo-controlled trials (fixed dose, dose
`
`
`
`
`escalation) [see Clinical Studies (14.2)]. The population was 18 to 80 years of age, and had
`
`tardive dyskinesia and had concurrent diagnoses of mood disorder (33%) or
`
`schizophrenia/schizoaffective disorder (63%). In these studies, AUSTEDO was administered in
`
`doses ranging from 12-48 mg per day. All patients continued on previous stable regimens of
`
`antipsychotics; 71% and 14% respective atypical and typical antipsychotic medications at study
`
`
`entry.
`
`The most common adverse reactions occurring in greater than 3% of AUSTEDO-treated patients
`
`
`and greater than placebo were nasopharyngitis and insomnia. The adverse reactions occurring in
`
`
`>2% or more patients treated with AUSTEDO (12-48 mg per day) and greater than in placebo
`
`patients in two double-blind, placebo-controlled studies in patients with tardive dyskinesia
`
`
`(Study 1 and Study 2) are summarized in Table 4.
`
`
`Adverse Reactions in 2 Placebo-Controlled Tardive Dyskinesia Studies
`Table 4:
`
`
`
`
`(Study 1 and Study 2) of 12-week Treatment on AUSTEDO Reported in at
`
`
`
`Least 2% of Patients and Greater than Placebo
`
`
` AUSTEDO
`
` Preferred Term
`
`
` (N=279)
`
` (%)
`
` 4
`
` 4
`
` 2
`
` 2
`
`
` Placebo
`
` (N=131)
`
` (%)
`
`2
`
`1
`
`1
`
` 1
`
`
`
` Nasopharyngitis
`
` Insomnia
`
` Depression/ Dysthymic disorder
` Akathisia/Agitation/Restlessness
`
`
` One or more adverse reactions resulted in a reduction of the dose of study medication in 4% of
`
`
`
`
` AUSTEDO-treated patients and in 2% of placebo-treated patients.
`
` 7
`
` DRUG INTERACTIONS
`
` 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)].
`
`
`
`
`
`
`Reference ID: 5128727
`
`11
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`
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`

`

`
`
`
`
`
`
` Reserpine
` 7.2
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
` USE IN SPECIFIC POPULATIONS
` 8
`
`
` Pregnancy
` 8.1
`
`
` Risk Summary
` There are no adequate data on the developmental risk associated with the use of AUSTEDO XR
`
`or AUSTEDO in pregnant women. Administration of deutetrabenazine to rats during
`organogenesis produced no clear adverse effect on embryofetal development. However,
`
`
`administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase
`
`
`in stillbirths and postnatal offspring mortality [see Data].
`
`
`In the U.S. general population, the estimated background risk of major birth defects and
`
`
`
`miscarriage in clinically recognized pregnancies is