AUSTEDO® (deutetrabenazine) tablets

AUSTEDO® (deutetrabenazine) tablets

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AUSTEDO® (deutetrabenazine) tablets

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 white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.

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.

Indications and usage

AUSTEDO is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of:

  • Chorea associated with Huntington’s disease
  • Tardive dyskinesia in adults

Mechanism of Action

The precise mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington’s disease 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 (αdihydrotetrabenazine [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.

Dosage and administration

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
  • 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

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)

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)

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.

Contraindications

AUSTEDO is contraindicated in patients:

  • With Huntington’s disease who are suicidal, or have untreated or inadequately treated depression
  • With hepatic impairment.
  • Taking reserpine. At least 20 days should elapse after stopping reserpine before starting AUSTEDO.
  • 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.
  • Taking tetrabenazine (XENAZINE®) or valbenazine

Warnings and precautions

Depression and Suicidality in Patients with Huntington’s Disease:

Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality). AUSTEDO may increase the risk for suicidality in patients with Huntington’s disease.

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.

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:

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

For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary.

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.

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.

Akathisia, Agitation, and Restlessness:

AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia.

Parkinsonism:

AUSTEDO may cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors.

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.

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Sedation and Somnolence:

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.

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.

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

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.

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.

Most common adverse reactions (that occurred in 4% of AUSTEDO-treated patients with tardive dyskinesia and greater than placebo): nasopharyngitis and insomnia.

Drug interactions

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.

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. 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.

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.

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.

Neuroleptic Drugs: The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO and dopamine antagonists or antipsychotics.

Alcohol or Other Sedating Drugs: Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Concomitant Tetrabenazine or Valbenazine: AUSTEDO is contraindicated in patients currently taking tetrabenazine or valbenazine. AUSTEDO may be initiated the day following discontinuation of tetrabenazine.

Use in specific populations

Pregnancy: There are no adequate data on the developmental risk associated with the use of AUSTEDO in pregnant women.

Lactation: 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.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

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 reactions, the use of AUSTEDO in patients with hepatic impairment is contraindicated.

Poor CYP2D6 Metabolizers: 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).

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.

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