`
`
`
`
`
` • Administer with food (2.1)
`
`
`
`
`
`
` • Swallow tablets whole; do not chew, crush, or break (2.1)
`
`
`
`
`
`
` If switching patients from tetrabenazine, discontinue tetrabenazine and
`
`•
` initiate AUSTEDO the following day. See full prescribing information for
`
`
`
`
` recommended conversion table (2.2)
` • Maximum recommended dosage of AUSTEDO in poor CYP2D6
`
`
` metabolizers is 36 mg per day (i.e., 18 mg twice daily) (2.4, 8.7)
`
`
`
`
` _____________
` DOSAGE FORMS AND STRENGTHS______________
`
`
`
`
`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 (XENAZINE®), or valbenazine
`
`
`
`
`
`
`(4, 7.3, 7.4, 7.7)
`
`
`
`
`_______________WARNINGS AND PRECAUTIONS _______________
`
`
`
`
`• 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 (5.3)
`
`
`
`• 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 is 36 mg per day (18 mg twice daily) (2.3, 7.1)
`
`
`
`
`
`• Alcohol or other sedating drugs: May have additive sedation and
`
`somnolence (7.6)
` ______________
` _______________
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`Revised: 08/2017
`
`
`
` Initial
`
` Dose
` 6 mg/day
`
`
`
`
`
` Recommended
`
` Dose
` 6 mg– 48 mg/day
`
`
`
`
`
`Maximum
`
` Dose
` 48 mg/day
`
`
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
` AUSTEDO safely and effectively. See full prescribing information for
`
`
`
`
` AUSTEDO.
`
`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 (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 is contraindicated in patients who are suicidal, and in
`
`patients with untreated or inadequately treated depression (4, 5.1)
`
` _________________
` _________________
`RECENT MAJOR CHANGES
`
`
`
`
`
`
`
`
`
`
`08/2017
`Boxed Warning
`
`
`
`
`
`
`
`
`
`08/2017
`Indications and Usage (1)
`
`
`
`
`
`
`
`Dosage and Administration (2.1)
`08/2017
`
`
`
`
`
`
`
`
`
`08/2017
`Contraindications (4)
`
`
`
`
`
`
`Warnings and Precautions (5.1, 5.2, 5.3, 5.5, 5.7)
`08/2017
`
` _________________
`
`__________________INDICATIONS AND USAGE
`
`
`
`
`AUSTEDO is a vesicular monoamine transporter 2 (VMAT2) inhibitor
`
`
`indicated for the treatment of:
`
`
`
`• Chorea associated with Huntington’s disease (1)
`
`
`
`
`• Tardive dyskinesia in adults (1)
`
`
`
`
`_______________DOSAGE AND ADMINISTRATION ______________
`
`
`
`
` Chorea associated with
`
` Huntington’s disease
` 12 mg/day
`
`
`
`
`
`
`
`
` 12 mg– 48 mg/day
` 48 mg/day
` Tardive dyskinesia
`
` • 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 (24 mg twice daily) (2.1)
`
`
`
` • Administer total daily dosages of 12 mg or above in two divided doses
`
`
`
`
` (2.1)
` • For patients at risk for QT prolongation, assess the QT interval before and
`
`
`
`
`
`
` after increasing the total dosage above 24 mg per day (2.1)
`
`
`
`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 (XENAZINE®) to
`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
`
`
`
`
`
`Reference ID: 4273761
`
`1
`
`
`
`5.4 Neuroleptic Malignant Syndrome (NMS)
`5.5 Akathisia, Agitation, and Restlessness
`
`
`
`
`
`5.6
`Parkinsonism in Patients with Huntington's Disease
`
`
`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
`
`
`7.2 Drugs that Cause QTc Prolongation
`
`
`
`
`7.3 Reserpine
`
`7.4 Monoamine Oxidase Inhibitors (MAOIs)
`
`7.5 Neuroleptic Drugs
`
`
`7.6 Alcohol or Other Sedating Drugs
`
`
`7.7 Concomitant Tetrabenazine or Valbenazine
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.4
`Pediatric Use
`
`
`
`
`6
`
`7
`
`
`8
`
`

`

`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`8.7
`Poor CYP2D6 Metabolizers
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`10
`
`11
`
`12
`
`13
`
`
`
`
`
`16
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Chorea Associated with Huntington's Disease
`
`
`
`14.2 Tardive Dyskinesia
`
`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: 4273761
`
`2
`
`
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
` 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 for the treatment of:
`
`
` chorea associated with Huntington’s disease [see Clinical Studies (14.1)]
`
`
`
`•
` tardive dyskinesia in adults [see Clinical Studies (14.2)]
`
`
`
`•
`
`
`
`
`
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
` Dosing Information
`
`
` 2.1
`
`
`
`
` 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 dose of
`
`
`
` AUSTEDO is 6 mg administered orally once daily for patients with Huntington’s disease and 12
`
`
`
` mg per day (6 mg twice daily) for patients with tardive dyskinesia.
`
`
`
`
`
` • The dose of AUSTEDO may be increased at weekly intervals in increments of 6 mg
`
`
`
` per day to a maximum recommended daily dosage of 48 mg.
`
`
`
`
` • 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.
`
`
`
`
`
` • For patients at risk for QT prolongation, assess the QT interval before and after
`
`
`
`
` increasing total AUSTEDO dosage above 24 mg per day [see Warnings and
`
`
`
`
`
`
`
` Precautions (5.3) and Drug Interactions (7.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4273761
`
`3
`
`
`
`
`

`

`
`
`
` Switching Patients from Tetrabenazine (XENAZINE®) to AUSTEDO
` 2.2
`
`
`
` 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
` 12.5 mg
`
`
` 25 mg
` 37.5 mg
`
`
` 50 mg
` 62.5 mg
`
`
` 75 mg
`
` 87.5 mg
`
` 100 mg
`
`
` Initial regimen of
`
` AUSTEDO
`
` 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
`
`
`
`
`
`
` 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)].
`
`
` Dosage Adjustment in Poor CYP2D6 Metabolizers
` 2.4
` 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.
`
`
`
`
`
`
`
`Reference ID: 4273761
`
`
`
` 4
`
`
`
`

`

`
` • 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 (7.3)].
`
`
`• 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 (7.4)].
` • Taking tetrabenazine (XENAZINE®) or valbenazine [see Drug Interactions (7.7)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
`
` 5
`
` Depression and Suicidality in Patients with Huntington’s Disease
`
`
`
` 5.1
` 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.
`
`
`
`
`
`
`Reference ID: 4273761
`
`5
`
`
`
`
`
`

`

`
`
` 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.
`
`
`
` QTc Prolongation
` 5.3
` Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the
`
`
`
` corrected QT (QTc) interval.
`
`
`
`A clinically relevant QT prolongation may occur in some patients treated with AUSTEDO who
`
`are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor [see Clinical
`
`Pharmacology (12.2, 12.3)].
`
`
`For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose
`
`
`
`
`reduction may be necessary [see Dosage and Administration (2.3, 2.4)]. The use of AUSTEDO
`
`
`in combination with other drugs that are known to prolong QTc may result in clinically
`
`
`significant QT prolongations [see Drug Interactions (7.2)].
`
`
`
`
`
`
`
`For patients requiring AUSTEDO doses greater than 24 mg per day who are using AUSTEDO
`
`with other drugs known to prolong QTc, assess the QTc interval before and after increasing the
`
`
`dose of AUSTEDO or other medications that are known to prolong QTc.
`
`
`AUSTEDO should also 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
`
`
`
`
`
`
`
`
`
`Reference ID: 4273761
`
`6
`
`
`
`
`
`

`

`
`
`
`
`
`
`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.
`
` Akathisia, Agitation, and Restlessness
`
`
`
`
`
` 5.5
`
` 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.
`
`
`
` Parkinsonism in Patients with Huntington’s Disease
` 5.6
`
` AUSTEDO may cause parkinsonism in patients with Huntington’s disease.
`
` Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it
`
` may be difficult to distinguish between this potential drug-induced adverse reaction and
`progression of the underlying disease process. Drug-induced parkinsonism has the potential to
`
`cause more functional disability than untreated chorea for some patients with Huntington’s
`
`
`disease. 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.
`
`
`
`
`
`Reference ID: 4273761
`
`
`
` 7
`
`
`
`

`

`
`
` Hyperprolactinemia
` 5.8
`
`
` 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.
` 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 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6
`
`
` ADVERSE REACTIONS
` 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)]
`
`
` • 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 in Patients with Huntington’s disease [see Warnings and Precautions
`
`
`
`
`
`
` (5.6)]
` • Sedation and Somnolence [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4273761
`
`
`
` 8
`
`
`
`

`

`
`
`
`
` • 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.
`
`
`
` Patients with Huntington’s Disease
`
` Study 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 2.
`
`
`Table 2: 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
`
`
`
`
`
`
`
`Adverse Reaction
`
`
`
` AUSTEDO
`
` Placebo
`
`
` (N = 45)
` (N = 45)
`
`
` %
` %
`
`
`
`
`
` Somnolence
`
`
`
` Diarrhea
`
`
`
` Dry mouth
`
`
`
` Fatigue
`
`
`
` Urinary tract infection
`
`
`
` Insomnia
`
`
`
` Anxiety
`
`
`
` Constipation
`
`
`
` Contusion
`
`
`
` 11
`
`
`
` 9
`
`
`
` 9
`
`
`
` 9
`
`
`
` 7
`
`
`
` 7
`
`
`
` 4
`
`
`
` 4
`
`
`
` 4
`
`
`
` 4
`
`
`
` 0
`
`
`
` 7
`
`
`
` 4
`
`
`
` 2
`
`
`
` 4
`
`
`
` 2
`
`
`
` 2
`
`
`
` 2
`
`
`
`
`
`
`
` 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%).
`
`
` Agitation led to discontinuation in 2% of patients treated with AUSTEDO in Study 1.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4273761
`
`
`
` 9
`
`
`
`

`

` 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). 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 3.
`
`
`
`
`
`
`
`
`
` Table 3: Adverse Reactions in 2 Placebo-Controlled Tardive Dyskinesia Studies (Study 1
` and Study 2) of 12-week Treatment on AUSTEDO Reported in at Least 2% of Patients and
`
`
`
`
`
` Greater than Placebo
`
`
`
`
` Preferred Term
`
`
`Nasopharyngitis
`
`Insomnia
`
`Depression/ Dysthymic disorder
`
`Akathisia/Agitation/Restlessness
`
`
` AUSTEDO
`
` (N=279)
`
` (%)
`
`4
`
`4
`
`2
`
`2
`
`
` Placebo
`
` (N=131)
`
` (%)
`
`2
`
`1
`
`1
`
`1
`
` 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.
`
`
`
` DRUG INTERACTIONS
`
`
` 7
`
` Strong CYP2D6 Inhibitors
`
`
` 7.1
`A reduction in AUSTEDO dose may be necessary when adding a strong CYP2D6 inhibitor in
`
` patients maintained on a stable dose of 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 should not exceed 36 mg per day, and the maximum single
`
`
`dose of AUSTEDO should not exceed 18 mg in patients taking strong CYP2D6 inhibitors [see
`
`Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`Reference ID: 4273761
`
`10
`
`
`
`
`
`

`

`
`
`
`
` 7.2
`
`
` Drugs that Cause QTc Prolongation
`
`
` Tetrabenazine, a closely related VMAT2 inhibitor, may cause an increase in the corrected QT
`
` (QTc) interval. Clinically relevant QT prolongation may also occur with AUSTEDO [see
`
`
`
` Warnings and Precautions (5.3), Clinical Pharmacology (12.2)].
`
`
`
` For patients requiring AUSTEDO doses above 24 mg per day, who are using AUSTEDO in
`
` combination with other drugs known to prolong QTc, assess the QTc interval before and after
`
`
`
` increasing the dose of AUSTEDO or other medications that are known to prolong QTc. Drugs
`
`known to prolong QTc include antipsychotic medications (e.g., chlorpromazine, haloperidol,
`thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine,
`procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications.
`
`
`
`
`
` 7.3
` 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 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. AUSTEDO and reserpine should not be used concomitantly [see Contraindications
`
`
` (4)].
` Monoamine Oxidase Inhibitors (MAOIs)
`
`
` 7.4
`
` AUSTEDO is contraindicated in patients taking MAOIs. AUSTEDO should not be used in
` combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI
`
`
`
`
`
` [see Contraindications (4)].
`
`
` 7.5
` Neuroleptic Drugs
`
` The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of
` AUSTEDO and dopamine antagonists or antipsychotics.
`
`
`
`
` 7.6
` 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)].
`
`
`
`
` 7.7
` Concomitant Tetrabenazine or Valbenazine
` AUSTEDO is contraindicated in patients currently taking tetrabenazine or valbenazine.
`
`
`
` AUSTEDO may be initiated the day following discontinuation of tetrabenazine [see Dosage and
`
` Administration (2.2)].
`
`
`
`
`
`Reference ID: 4273761
`
`
`
` 11
`
`
`
`
`

`

`
`
`
`
` 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 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 2-4% and 15-20%, respectively. The
`
`
`background risk of major birth defects and miscarriage for the indicated population is unknown.
`
`Data
`
`Animal Data
`
`Oral administration of deutetrabenazine (5, 10, or 30 mg/kg/day) or tetrabenazine (30
`
`mg/kg/day) to pregnant rats during organogenesis had no clear effect on embryofetal
`
`development. The highest dose tested was 6 times the maximum recommended human dose of
`
`
`48 mg/day, on a body surface area (mg/m2) basis.
`
`
`
` The effects of deutetrabenazine when administered during organogenesis to rabbits or during
`
`
` pregnancy and lactation to rats have not been assessed.
` Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits
`
`
` during the period of organogenesis at oral doses up to 60 mg/kg/day. When tetr