 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 (4, 5.2)
`Hepatic impairment (4, 8.6, 12.3)
`Taking MAOIs, reserpine, or tetrabenazine (XENAZINE®) (4, 7.2, 7.3,
`7.7)
`
`
`
`
`
`
`
`
`
`
` _______________
` _______________
`WARNINGS AND PRECAUTIONS
`
`Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs
`(5.3, 7.4)
`Akathisia, agitation, restlessness, and parkinsonism: Reduce dose or
`discontinue if this occurs (5.4, 5.5)
`Sedation/somnolence: May impair the patient’s ability to drive or
`operate complex machinery (5.6)
`
`
`
`
` ___________________
`
` ___________________
`
`
`ADVERSE REACTIONS
`Most common adverse reactions (>8% of AUSTEDO-treated patients and
`greater than placebo) were: somnolence, diarrhea, dry mouth, and fatigue (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 (7.5)
`
`
` ______________
`
` _______________
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 4/2017
`
`8
`
`7.3 Monoamine Oxidase Inhibitors (MAOIs)
`7.4 Neuroleptic Drugs
`7.5 Alcohol or Other Sedating Drugs
`7.6 Drugs that Cause QTc Prolongation
`7.7
`Tetrabenazine
`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
`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.
`
`
`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
`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 (5.2)
`• Balance risks of depression and suicidality with the clinical need for
`treatment of chorea when considering the use of AUSTEDO (5.2)
`• Monitor patients for the emergence or worsening of depression, suicidality,
`or unusual changes in behavior (5.2)
`• Inform patients, caregivers and families of the risk of depression and
`suicidality and instruct to report behaviors of concern promptly to the
`treating physician (5.2)
`• Exercise caution when treating patients with a history of depression or prior
`suicide attempts or ideation (5.2)
`• AUSTEDO is contraindicated in patients who are suicidal, and in patients
`with untreated or inadequately treated depression (4, 5.2)
`
`
`
`
`
` __________________
` _________________
`INDICATIONS AND USAGE
`AUSTEDO is a vesicular monoamine transporter 2 (VMAT2) inhibitor
`indicated for the treatment of chorea associated with Huntington’s disease (1)
`
` _______________
` ______________
`DOSAGE AND ADMINISTRATION
`The starting dose is 6 mg once daily. Titrate up at weekly intervals by
`6 mg per day to a tolerated dose that reduces chorea, 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)
`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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: DEPRESSION AND SUICIDALITY
`
` 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 Clinical Worsening and Adverse Events
`5.2 Depression and Suicidality
`5.3 Neuroleptic Malignant Syndrome (NMS)
`5.4 Akathisia, Agitation, and Restlessness
`5.5
`Parkinsonism
`5.6
`Sedation and Somnolence
`5.7 QTc Prolongation
`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 Reserpine
`
`6
`
`7
`
`
`
`
`
`Reference ID: 4078379
`
`1
`
`
`
`

`

`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: DEPRESSION AND SUICIDALITY
`
`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 (5.2)].
`
`1
`
`INDICATIONS AND USAGE
`
`AUSTEDO™ is indicated for the treatment of chorea associated with Huntington’s disease.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Dosing Information
`
`The dose of AUSTEDO is determined individually for each patient based on reduction of chorea
`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.
`
` 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.
`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.
`
`
`
`
`
`Reference ID: 4078379
`
`2
`
`
`
`

`

`
`
`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)].
`
`
`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.
`
`DOSAGE FORMS AND STRENGTHS
`
` 3
`
`
`
`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.
`
`
`
`Reference ID: 4078379
`
`3
`
`
`
`

`

`
`
`4
`
`CONTRAINDICATIONS
`
`AUSTEDO is contraindicated in patients:
`
` Who are suicidal, or in patients with untreated or inadequately treated depression [see
`Warnings and Precautions (5.2)].
`
` With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology
`(12.3)].
`
` 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 (7.3)].
`
` Taking reserpine. At least 20 days should elapse after stopping reserpine before starting
`AUSTEDO [see Drug Interactions (7.2)].
`
` Taking tetrabenazine (XENAZINE®) [see Drug Interactions (7.7)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Clinical Worsening and Adverse Events
`
`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.
`
`5.2
`
`Depression and Suicidality
`
`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.
`
`
`
`Reference ID: 4078379
`
`4
`
`
`
`

`

`
`
`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.
`
`5.3
`
`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 [see
`Drug Interactions (7.4)]. 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.
`
`5.4
`
`Akathisia, Agitation, and Restlessness
`
`AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with
`Huntington’s disease. In a 12-week, double-blind, placebo-controlled trial, akathisia, agitation, or
`restlessness was reported by 4% of patients treated with AUSTEDO, compared to 2% of patients
`on placebo.
`
`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.
`
`5.5
`
`Parkinsonism
`
`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
`
`
`
`Reference ID: 4078379
`
`5
`
`
`
`

`

`
`
`disease. If a patient develops parkinsonism during treatment with AUSTEDO, the AUSTEDO
`dose should be reduced; some patients may require discontinuation of therapy.
`
`5.6
`
`Sedation and Somnolence
`
`Sedation is a common dose-limiting adverse reaction of AUSTEDO. In a 12-week, double-blind,
`placebo-controlled trial, 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.
`
`5.7
`
`QTc Prolongation
`
`Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the
`corrected QT (QTc) interval [see Clinical Pharmacology (12.2)].
`
`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)].
`
`The use of AUSTEDO should be avoided in combination with other drugs that are known to
`prolong QTc [see Drug Interactions (7.6)].
`
`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.
`
`5.8
`
`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.
`
`
`
`Reference ID: 4078379
`
`6
`
`
`
`

`

`
`
`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)].
`
`6
`
`ADVERSE REACTIONS
`
`The following serious adverse reactions are discussed in greater detail in other sections of the
`labeling:
`
` Depression and Suicidality [see Warnings and Precautions (5.2)]
`
` Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.3)]
`
` Akathisia, Agitation, and Restlessness [see Warnings and Precautions (5.4)]
`
` Parkinsonism [see Warnings and Precautions (5.5)]
`
` Sedation and Somnolence [see Warnings and Precautions (5.6)]
`
` QTc Prolongation [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.
`
`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.
`
`
`
`
`
`
`
`Reference ID: 4078379
`
`7
`
`
`
`

`

`
`
`Table 2. Adverse Reactions in Study 1 Experienced by at Least 4% of Patients on
`AUSTEDO and with a Greater Incidence than on Placebo
`
` Adverse Reaction
`
`
`
`Somnolence
`
`Diarrhea
`
`Dry mouth
`
`Fatigue
`
`Urinary tract infection
`
`Insomnia
`
`Anxiety
`
`Constipation
`
`Contusion
`
`AUSTEDO
`(N = 45)
`%
`
`Placebo
`(N = 45)
`%
`
`
`
`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.
`
`7
`
`DRUG INTERACTIONS
`
`7.1
`
`Strong CYP2D6 Inhibitors
`
`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)].
`
`7.2
`
`Reserpine
`
`Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers
`should wait for chorea 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)].
`
`
`
`Reference ID: 4078379
`
`8
`
`
`
`

`

`
`
`7.3
`
`Monoamine Oxidase Inhibitors (MAOIs)
`
`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)].
`
`7.4
`
`Neuroleptic Drugs
`
`The risk for parkinsonism, NMS, and akathisia may be increased by concomitant use of
`AUSTEDO and 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 (5.6)].
`
`
`7.6
`
`Drugs that Cause QTc Prolongation
`
`Tetrabenazine, a closely related VMAT2 inhibitor, causes a small increase in the corrected QT
`(QTc) interval. Clinically relevant QT prolongation may also occur with AUSTEDO [see
`Warnings and Precautions (5.7), Clinical Pharmacology (12.2)].
`
`The use of AUSTEDO should be avoided in combination with other drugs that are known to
`prolong QTc, including 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 or any other
`medications known to prolong the QTc interval.
`
`7.7
`
`Tetrabenazine
`
`AUSTEDO is contraindicated in patients currently taking tetrabenazine. AUSTEDO may be
`initiated the day following discontinuation of tetrabenazine [see Dosage and Administration
`(2.2)].
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`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.
`
`
`
`Reference ID: 4078379
`
`9
`
`
`
`

`

`
`
`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 tetrabenazine was
`administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of
`organogenesis through the lactation period, an increase in stillbirths and offspring postnatal
`mortality was observed at 15 and 30 mg/kg/day, and delayed pup maturation was observed at all
`doses.
`
`8.2
`
`Lactation
`
`Risk Summary
`
`There are no data on the presence of deutetrabenazine or its metabolites in human milk, the
`effects on the breastfed infant, or the effects of the drug on milk production.
`
`The developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for AUSTEDO and any potential adverse effects on the breastfed infant
`from AUSTEDO or from the underlying maternal condition.
`
`8.4
`
`Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use
`
`8.5
`
`Clinical studies of AUSTEDO did not include sufficient numbers of subjects aged 65 and over to
`determine whether they respond differently from younger subjects. Other reported clinical
`experience has not identified differences in responses between the elderly and younger patients.
`In general, dose selection for an elderly patient should be cautious, usually starting at the low end
`of the dosing range, reflecting the greater frequency of hepatic, renal, and cardiac dysfunction,
`and of concomitant disease or other drug therapy.
`
`8.6
`
`Hepatic Impairment
`
`The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary
`metabolites has not been studied; however, in a clinical study conducted with tetrabenazine, a
`closely related VMAT2 inhibitor, there was a large increase in exposure to tetrabenazine and its
`active metabolites in patients with hepatic impairment. The clinical significance of this increased
`exposure has not been assessed, but because of concerns for a greater risk for serious adverse
`
`
`
`Reference ID: 4078379
`
`10
`
`
`
`

`

`
`
`reactions, the use of AUSTEDO in patients with hepatic impairment is contraindicated [see
`Contraindications (4), Clinical Pharmacology (12.3)].
`
`Poor CYP2D6 Metabolizers
`
`8.7
`
`Although the pharmacokinetics of deutetrabenazine and its metabolites have not been
`systematically evaluated in patients who do not express the drug metabolizing enzyme, it is
`likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking a strong
`CYP2D6 inhibitor (approximately 3-fold). In patients who are CYP2D6 poor metabolizers, the
`daily dose of AUSTEDO should not exceed 36 mg (maximum single dose of 18 mg) [see
`Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
`
`10
`
`OVERDOSAGE
`
`Overdoses ranging from 100 mg to 1 g have been reported in the literature with tetrabenazine, a
`closely related VMAT2 inhibitor. The following adverse reactions occurred with overdosing:
`acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension,
`confusion, diarrhea, hallucinations, rubor, and tremor.
`
`Treatment should consist of those general measures employed in the management of overdosage
`with any central nervous system-active drug. General supportive and symptomatic measures are
`recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the
`possibility of multiple drug involvement should always be considered. The physician should
`consider contacting a poison control center on the treatment of any overdose. Telephone numbers
`for certified poison control centers are listed on the American Association of Poison Control
`Centers website www.aapcc.org.
`
`11
`
`DESCRIPTION
`
`AUSTEDO (deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor for
`oral administration. The molecular weight of deutetrabenazine is 323.46; the pKa is 6.31.
`Deutetrabenazine is a hexahydro-dimethoxybenzoquinolizine derivative and has the following
`chemical name: (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-
`2H-benzo[a]quinolizin-2-one.
`
`The molecular formula for deutetrabenazine is C19H21D6NO3. Deutetrabenazine is a racemic
`mixture containing the following structures:
`
`Deutetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in
`water and soluble in ethanol.
`
`
`
`
`
`Reference ID: 4078379
`
`11
`
`
`
`RR - Deutetrabenazine
`
`SS - Deutetrabenazine
`
`

`

`
`
`AUSTEDO tablets contain 6 mg, 9 mg, or 12 mg deutetrabenazine, and the following inactive
`ingredients: ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole,
`butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose,
`polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene
`glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain
`FD&C red #40 lake. The 12 mg tablets also contain FD&C yellow #6 lake.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`The precise mechanism by which AUSTEDO (deutetrabenazine) exerts its anti-chorea effects is
`unknown but is believed to be related to its effect as a reversible depletor of monoamines (such
`as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The major
`circulating metabolites (α-dihydrotetrabenazine [HTBZ] and β-HTBZ) of deutetrabenazine, are
`reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic
`vesicles and depletion of monoamine stores.
`
`12.2
`
`Pharmacodynamics
`
`Cardiac Electrophysiology
`
`The effect of a single 12-mg or 24-mg dose of AUSTEDO on the QT interval was studied in a
`randomized, double-blind, placebo-controlled crossover study in healthy male and female
`subjects with moxifloxacin as a positive control. At 24 mg, AUSTEDO caused an approximately
`4.5 msec mean increase in QTc (90% CI: 2.4, 6.5 msec). Effects at higher exposures to
`AUSTEDO or its metabolites have not been evaluated.
`
`The effect of a single 25-mg or 50-mg dose of tetrabenazine, a closely related VMAT2 inhibitor,
`on the QT interval was studied in a randomized, double-blind, placebo-controlled crossover
`study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg,
`tetrabenazine caused an approximately 8 msec mean increase in QTc (90% CI: 5.0, 10.4 msec).
`Effects at higher exposures to either tetrabenazine or its metabolites have not been evaluated [see
`Warnings and Precautions (5.7) and Drug Interactions (7.6)].
`
`Melanin Binding
`
`Deutetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in
`pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still
`detected in eye and fur at 35 days following dosing [see Warnings and Precautions (5.9)].
`
`12.3
`
`Pharmacokinetics
`
`After oral dosing up to 25 mg, plasma concentrations of deutetrabenazine are generally below
`the limit of detection because of the extensive h