`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 _________________
`Dosage and Administration (2.1)
`
`
`
`
`
`5/2022
` __________________ INDICATIONS AND USAGE _________________
`AUSTEDO is a vesicular monoamine transporter 2 (VMAT2) inhibitor
`indicated in adults for the treatment of:
`• Chorea associated with Huntington’s disease (1)
`• Tardive dyskinesia (1)
` _______________ DOSAGE AND ADMINISTRATION ______________
`• The recommended starting dosage is 12 mg per day (6 mg twice daily)
`(2.1)
`• 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)
`• 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, 7.2, 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 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: 5/2022
`
`
`
`Reference ID: 4978718
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`1
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`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.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH
`HUNTINGTON'S DISEASE
`
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2
`Switching Patients from Tetrabenazine (XENAZINE®) to
`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
`
` 1
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`6
`7
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`Reference ID: 4978718
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`2
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`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)].
`
`INDICATIONS AND USAGE
`1
`AUSTEDO® is indicated in adults for the treatment of:
`• chorea associated with Huntington’s disease [see Clinical Studies (14.1)]
`tardive dyskinesia [see Clinical Studies (14.2)]
`•
`
`DOSAGE AND ADMINISTRATION
`2
`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 dosage of
`AUSTEDO is 12 mg per day (6 mg twice daily) for patients with Huntington’s disease or tardive
`dyskinesia.
`• The dose of AUSTEDO may be increased at weekly intervals in increments of 6 mg
`per day based on reduction of chorea or tardive dyskinesia and tolerability, up to a
`maximum recommended daily dosage of 48 mg [see Clinical Trials 14.1, 14.2)].
`• Administer total daily dosages of 12 mg or above in two divided doses.
`• Administer AUSTEDO with food [see Clinical Pharmacology (12.3)].
`• Swallow AUSTEDO whole. Do not chew, crush, or break tablets.
`
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`Reference ID: 4978718
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`3
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`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.
`
`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.
`
`
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`Reference ID: 4978718
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`4
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`• 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.
`
`CONTRAINDICATIONS
`4
`AUSTEDO is contraindicated in patients:
`• With Huntington’s disease who are suicidal, or have untreated or inadequately treated
`depression [see Warnings and Precautions (5.1)].
`• With hepatic impairment [see Use in Specific Populations (8.6), Clinical
`Pharmacology (12.3)].
`• Taking reserpine. At least 20 days should elapse after stopping reserpine before
`starting AUSTEDO [see Drug Interactions (7.2)].
`• Taking monoamine oxidase inhibitors (MAOIs). AUSTEDO should not be used in
`combination with an MAOI, or within 14 days of discontinuing therapy with an
`MAOI [see Drug Interactions (7.3)].
`• Taking tetrabenazine (XENAZINE®) or valbenazine [see Drug Interactions (7.6)].
`
`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.
`
`
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`Reference ID: 4978718
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`5.2
`
`Clinical Worsening and Adverse Events in Patients with
`Huntington’s Disease
`Huntington’s disease is a progressive disorder characterized by changes in mood, cognition,
`chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including AUSTEDO,
`may cause a worsening in mood, cognition, rigidity, and functional capacity.
`Prescribers should periodically re-evaluate the need for AUSTEDO in their patients by assessing
`the effect on chorea and possible adverse effects, including sedation/somnolence, depression and
`suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. It may be difficult to
`distinguish between adverse reactions and progression of the underlying disease; decreasing the
`dose or stopping the drug may help the clinician to distinguish between the two possibilities. In
`some patients, the underlying chorea itself may improve over time, decreasing the need for
`AUSTEDO.
`5.3
`QTc Prolongation
`AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically
`significant when AUSTEDO is administered within the recommended dosage range [see Clinical
`Pharmacology (12.2)].
`AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with
`a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence
`of torsade de pointes and/or sudden death in association with the use of drugs that prolong the
`QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant
`use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of
`the QT interval.
`5.4
`Neuroleptic Malignant Syndrome (NMS)
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
`(NMS) has been reported in association with drugs that reduce dopaminergic transmission.
`While NMS has not been observed in patients receiving AUSTEDO, it has been observed in
`patients receiving tetrabenazine (a closely related VMAT2 inhibitor). Clinicians should be
`alerted to the signs and symptoms associated with NMS. Clinical manifestations of NMS are
`hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability
`(irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional
`signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute
`renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g.,
`pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders
`can present with similar signs and symptoms. Other important considerations in the differential
`diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
`nervous system pathology.
`The management of NMS should include (1) immediate discontinuation of AUSTEDO; (2)
`intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant
`serious medical problems for which specific treatments are available. There is no general
`agreement about specific pharmacological treatment regimens for NMS.
`
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`Reference ID: 4978718
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`Recurrence of NMS has been reported with resumption of drug therapy. If treatment with
`AUSTEDO is needed after recovery from NMS, patients should be monitored for signs of
`recurrence.
`5.5
`Akathisia, Agitation, and Restlessness
`AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with
`Huntington’s disease and tardive dyskinesia.
`In a 12-week, double-blind, placebo-controlled trial in Huntington’s disease patients, akathisia,
`agitation, or restlessness was reported by 4% of patients treated with AUSTEDO, compared to
`2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with
`AUSTEDO and 1% of patients on placebo experienced these events.
`Patients receiving AUSTEDO should be monitored for signs and symptoms of restlessness and
`agitation, as these may be indicators of developing akathisia. If a patient develops akathisia
`during treatment with AUSTEDO, the AUSTEDO dose should be reduced; some patients may
`require discontinuation of therapy.
`5.6
`Parkinsonism
`AUSTEDO may cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia.
`Parkinsonism has also been observed with other VMAT2 inhibitors.
`Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it
`may be difficult to distinguish between potential drug-induced parkinsonism and progression of
`underlying Huntington’s disease. Drug-induced parkinsonism has the potential to cause more
`functional disability than untreated chorea for some patients with Huntington’s disease.
`Postmarketing cases of parkinsonism in patients treated with AUSTEDO for tardive dyskinesia
`have been reported. Signs and symptoms in reported cases have included bradykinesia, gait
`disturbances, which led to falls in some cases, and the emergence or worsening of tremor. In
`most cases, the development of parkinsonism occurred within the first two weeks after starting or
`increasing the dose of AUSTEDO. In cases in which follow-up clinical information was
`available, parkinsonism was reported to resolve following discontinuation of AUSTEDO
`therapy.
`If a patient develops parkinsonism during treatment with AUSTEDO, the AUSTEDO dose
`should be reduced; some patients may require discontinuation of therapy.
`5.7
`Sedation and Somnolence
`Sedation is a common dose-limiting adverse reaction of AUSTEDO. In a 12-week, double-blind,
`placebo-controlled trial examining patients with Huntington’s disease, 11% of AUSTEDO-
`treated patients reported somnolence compared with 4% of patients on placebo and 9% of
`AUSTEDO-treated patients reported fatigue compared with 4% of placebo-treated patients.
`Patients should not perform activities requiring mental alertness to maintain the safety of
`themselves or others, such as operating a motor vehicle or operating hazardous machinery, until
`they are on a maintenance dose of AUSTEDO and know how the drug affects them.
`
`
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`Reference ID: 4978718
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`7
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`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.
`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)].
`
`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)]
`• 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)]
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`• Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.9)]
`Clinical Trials Experience
`6.1
`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
`(N = 45)
`%
`
`Placebo
`(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.
`
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`Reference ID: 4978718
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`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
`AUSTEDO
`(N=279)
`(%)
`4
`4
`2
`2
`
`Nasopharyngitis
`Insomnia
`Depression/ Dysthymic disorder
`Akathisia/Agitation/Restlessness
`
`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)].
`7.2
`Reserpine
`Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers
`should wait for chorea or dyskinesia to reemerge before administering AUSTEDO to help reduce
`
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`Reference ID: 4978718
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`10
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`
`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)
`7.3
`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 of 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 (5.7)].
`7.6
`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)].
`
`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.
`
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`Reference ID: 4978718
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`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.
`Lactation
`8.2
`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
`Tourette syndrome
`The safety and effectiveness of AUSTEDO have not been established in pediatric patients for the
`treatment of Tourette syndrome.
`Efficacy was not demonstrated in two randomized, double-blind, placebo-controlled studies in
`pediatric patients aged 6 to 16 years with Tourette syndrome. One study evaluated fixed doses of
`deutetrabenazine over 8 weeks (NCT03571256); the other evaluated flexible doses of
`deutetrabenazine over 12 weeks (NCT03452943). The studies included a total of 274 pediatric
`patients who received at least one dose of deutetrabenazine or placebo. The primary efficacy
`endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global
`Tic Severity Scale Total Tic Score (YGTSS-TTS). The estimated treatment effect of
`deutetrabenazine on the YGTSS-TTS was not statistically significantly different from placebo in
`either study. The placebo subtracted least squares means difference in YGTSS-TTS from
`baseline to end-of-treatment was -0.7 (95% CI: -4.1, 2.8) in the flexible dose study and -0.8
`(95% CI: -3.9, 2.3) for the primary analysis in the fixed dose study.
`The following adverse reactions were reported in frequencies of at least 5% of pediatric patients
`treated with AUSTEDO and with a greater incidence than in pediatric patients receiving placebo
`(AUSTEDO vs placebo): headache (includes: migraine, migraine with aura, and headache; 13%
`vs 9%), somnolence (includes: sedation, hypersomnia, and somnolence; 11% vs 2%), fatigue
`(8% vs 3%), increased appetite (5% vs <1%), and increased weight (5% vs <1%).
`Chorea associated with Huntington’s disease and Tardive dyskinesia
`The safety and effectiveness of AUSTEDO have not been established in pediatric patients for the
`treatment of chorea associated with Huntington’s disease or for the treatment of tardive
`dyskinesia.
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`Reference ID: 4978718
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`12
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`Juvenile Animal Toxicity Data
`Deutetrabenazine orally administered to juvenile rats from postnatal days 21 through 70 (at 2.5,
`5, or 10 mg/kg/day) resulted in an increased incidence of tremor, hyperactivity, and adverse
`increases in motor activity at ≥5 mg/kg/day, and reduced body weight and food consumption at
`10 mg/kg/day. There was no reproductive or early embryonic toxicity up to the highest dose. All
`drug-related findings were reversible after a drug-free period. The no observed adverse effect
`level (NOAEL) in juvenile rats was 2.5 mg/kg/day. These drug-related findings were similar to
`those observed in adult rats; however, the juvenile rats were more sensitive.
`8.5
`Geriatric Use
`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.