Austedo

Name: Austedo

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Pregnancy

Pregnancy

There are no adequate data on the developmental risk in pregnant women

Animal studies

  • 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

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

What is deutetrabenazine?

Deutetrabenazine reduces the amount of certain chemicals in the body that are overly active in people with Huntington's disease.

Deutetrabenazine is used to treat involuntary muscle movements (chorea) caused by Huntington's disease.

Deutetrabenazine is not a cure for Huntington's disease or other causes of involuntary movement.

Deutetrabenazine may also be used for purposes not listed in this medication guide.

Cautions for Austedo

Contraindications

  • Suicidal, or untreated/inadequately treated depression in patients with Huntington’s disease.1

  • Hepatic impairment.1

  • Taking reserpine, MAO inhibitors, tetrabenazine (Xenazine), or valbenazine.1

Warnings/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). Deutetrabenazine may increase the risk for suicidality in patients with Huntington’s disease.1

In a 12-week, double-blind, placebo-controlled trial, suicidal ideation was reported by 2% of patients treated with deutetrabenazine, compared to no patients on placebo; no suicide attempts and no completed suicides were reported. Depression was reported by 4% of patients treated with deutetrabenazine.1

When considering the use of deutetrabenazine, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with deutetrabenazine should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with deutetrabenazine.1

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with deutetrabenazine, 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.1

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 deutetrabenazine, may cause a worsening in mood, cognition, rigidity, and functional capacity.1

Prescribers should periodically reevaluate the need for deutetrabenazine 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 deutetrabenazine.1

Prolongation of QT Interval

Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the corrected QT (QTc) interval.1

A clinically relevant QT prolongation may occur in some patients treated with deutetrabenazine who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor.1

For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary.1

The use of deutetrabenazine in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongations.1

For patients requiring deutetrabenazine doses greater than 24 mg per day who are using deutetrabenazine with other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications that are known to prolong QTc.1

Deutetrabenazine 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.1

Neuroleptic Malignant Syndrome

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 deutetrabenazine, 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.1

The management of NMS should include (1) immediate discontinuation of deutetrabenazine; (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.1

Recurrence of NMS has been reported with resumption of drug therapy. If treatment with deutetrabenazine is needed after recovery from NMS, patients should be monitored for signs of recurrence.1

Akathisia, Agitation, and Restlessness

Deutetrabenazine may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia.1

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 deutetrabenazine, compared to 2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with deutetrabenazine and 1% of patients on placebo experienced these events.1

Patients receiving deutetrabenazine 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 deutetrabenazine, the deutetrabenazine dose should be reduced; some patients may require discontinuation of therapy.1

Parkinsonism in Patients with Huntington’s Disease

Deutetrabenazine may cause parkinsonism in patients with Huntington’s disease.1

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 deutetrabenazine, the deutetrabenazine dose should be reduced; some patients may require discontinuation of therapy.1

Sedation and Somnolence

Sedation is a common dose-limiting adverse reaction of deutetrabenazine. In a 12-week, double-blind, placebo-controlled trial examining patients with Huntington’s disease, 11% of deutetrabenazine-treated patients reported somnolence compared with 4% of patients on placebo and 9% of deutetrabenazine-treated patients reported fatigue compared with 4% of placebo-treated patients.1

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 deutetrabenazine and know how the drug affects them.1

Hyperprolactinemia

Serum prolactin levels were not evaluated in the deutetrabenazine 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.1

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if deutetrabenazine 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.1

Chronic increase in serum prolactin levels (although not evaluated in the deutetrabenazine 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 deutetrabenazine.1

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 deutetrabenazine 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.1

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.1

Specific Populations

Pregnancy

Risk Summary: There are no adequate data on the developmental risk associated with the use of deutetrabenazine 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. 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.1

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.1

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.1

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for deutetrabenazine and any potential adverse effects on the breastfed infant from deutetrabenazine or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.1

Geriatric Use

Clinical studies of deutetrabenazine 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.1

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 deutetrabenazine in patients with hepatic impairment is contraindicated.1

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 deutetrabenazine should not exceed 36 mg (maximum single dose of 18 mg).1

Common Adverse Effects

Most common adverse reactions (>8% of deutetrabenazine-treated patients with Huntington’s disease and greater than placebo): somnolence, diarrhea, dry mouth, and fatigue.1

Most common adverse reactions (that occurred in 4% of deutetrabenazine-treated patients with tardive dyskinesia and greater than placebo): nasopharyngitis and insomnia.1

Before Using Austedo

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of deutetrabenazine in the pediatric population. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of deutetrabenazine have not been performed in the geriatric population, no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving deutetrabenazine.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Amifampridine
  • Amisulpride
  • Bepridil
  • Cisapride
  • Dronedarone
  • Furazolidone
  • Iproniazid
  • Isocarboxazid
  • Linezolid
  • Mesoridazine
  • Methylene Blue
  • Moclobemide
  • Nialamide
  • Phenelzine
  • Pimozide
  • Piperaquine
  • Procarbazine
  • Rasagiline
  • Reserpine
  • Safinamide
  • Saquinavir
  • Selegiline
  • Sparfloxacin
  • Terfenadine
  • Tetrabenazine
  • Thioridazine
  • Tranylcypromine
  • Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Alfuzosin
  • Amiodarone
  • Amitriptyline
  • Anagrelide
  • Apomorphine
  • Aripiprazole
  • Arsenic Trioxide
  • Asenapine
  • Astemizole
  • Atazanavir
  • Azithromycin
  • Bedaquiline
  • Bupropion
  • Buserelin
  • Chloroquine
  • Chlorpromazine
  • Ciprofloxacin
  • Citalopram
  • Clarithromycin
  • Clomipramine
  • Clozapine
  • Crizotinib
  • Cyclobenzaprine
  • Dabrafenib
  • Dasatinib
  • Degarelix
  • Delamanid
  • Desipramine
  • Deslorelin
  • Disopyramide
  • Dofetilide
  • Dolasetron
  • Domperidone
  • Donepezil
  • Doxepin
  • Droperidol
  • Ebastine
  • Efavirenz
  • Eribulin
  • Erythromycin
  • Escitalopram
  • Famotidine
  • Felbamate
  • Fingolimod
  • Flecainide
  • Fluconazole
  • Fluoxetine
  • Formoterol
  • Foscarnet
  • Fosphenytoin
  • Galantamine
  • Gatifloxacin
  • Gemifloxacin
  • Gonadorelin
  • Goserelin
  • Granisetron
  • Halofantrine
  • Haloperidol
  • Histrelin
  • Hydroquinidine
  • Hydroxychloroquine
  • Hydroxyzine
  • Ibutilide
  • Iloperidone
  • Imipramine
  • Itraconazole
  • Ivabradine
  • Ketoconazole
  • Lapatinib
  • Leuprolide
  • Levofloxacin
  • Lumefantrine
  • Mefloquine
  • Methadone
  • Methotrimeprazine
  • Metronidazole
  • Mifepristone
  • Mizolastine
  • Moricizine
  • Moxifloxacin
  • Nafarelin
  • Nelfinavir
  • Nilotinib
  • Norfloxacin
  • Octreotide
  • Ofloxacin
  • Olanzapine
  • Ondansetron
  • Paliperidone
  • Panobinostat
  • Papaverine
  • Paroxetine
  • Pasireotide
  • Pazopanib
  • Pentamidine
  • Perphenazine
  • Pimavanserin
  • Pipamperone
  • Pitolisant
  • Posaconazole
  • Probucol
  • Procainamide
  • Prochlorperazine
  • Promethazine
  • Propafenone
  • Protriptyline
  • Quetiapine
  • Quinidine
  • Quinine
  • Ranolazine
  • Risperidone
  • Ritonavir
  • Sertindole
  • Sevoflurane
  • Sodium Phosphate
  • Sodium Phosphate, Dibasic
  • Sodium Phosphate, Monobasic
  • Solifenacin
  • Sorafenib
  • Sotalol
  • Sulpiride
  • Sultopride
  • Sunitinib
  • Tacrolimus
  • Tamoxifen
  • Telaprevir
  • Telavancin
  • Telithromycin
  • Terbinafine
  • Tizanidine
  • Tolterodine
  • Toremifene
  • Trazodone
  • Trimipramine
  • Triptorelin
  • Vandetanib
  • Vardenafil
  • Vemurafenib
  • Venlafaxine
  • Vilanterol
  • Vinflunine
  • Voriconazole
  • Vorinostat
  • Zotepine
  • Zuclopenthixol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Akathisia (a movement disorder), including agitation and restlessness, history of or
  • Depression, history of or
  • Heart rhythm problems (eg, QT prolongation), history of or
  • Suicidal thoughts or behavior—Use with caution. May make these conditions worse.
  • Bradycardia (slow heartbeat) or
  • Breast cancer, history of—Use with caution. May increase risk of serious side effects.
  • Depression, untreated or
  • Liver disease or
  • Suicidal thoughts or behavior, active—Should not be used in patients with these conditions.

How is this medicine (Austedo) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take Austedo with food.
  • Swallow whole. Do not chew, break, or crush.
  • To gain the most benefit, do not miss doses.
  • Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
  • If you have trouble swallowing, talk with your doctor.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it, with food.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
  • If you miss 7 days of Austedo, call your doctor to find out what to do.

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)].

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 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

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.

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)

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)].

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 [see Warnings and Precautions (5.7)].

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)].

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.

Austedo 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.

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.

Clinical Studies

Chorea Associated with Huntington’s Disease

Double-Blind, Placebo-Controlled Study

The efficacy of Austedo as a treatment for chorea associated with Huntington's disease was established primarily in Study 1, a randomized, double-blind, placebo-controlled, multi-center trial conducted in 90 ambulatory patients with manifest chorea associated with Huntington’s disease. The diagnosis of Huntington’s disease was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including an 8-week dose titration period and a 4-week maintenance period, followed by a 1-week washout. Patients were not blinded to discontinuation. Austedo was started at 6 mg per day and titrated upward, at weekly intervals, in 6 mg increments until satisfactory treatment of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. The primary efficacy endpoint was the Total Maximal Chorea Score, an item of the Unified Huntington's Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28.

Of the 90 patients enrolled, 87 patients completed the study. The mean age was 54 (range 23 to 74). Patients were 56% male and 92% Caucasian. The mean dose after titration was 40 mg per day. Table 4 and Figure 1 summarize the effects of Austedo on chorea based on the Total Maximal Chorea Score. Total Maximal Chorea Scores for patients receiving Austedo improved by approximately 4.4 units from baseline to the maintenance period (average of Week 9 and Week 12), compared to approximately 1.9 units in the placebo group. The treatment effect of -2.5 units was statistically significant (p<0.0001). The Maintenance Endpoint is the mean of the Total Maximal Chorea Scores for the Week 9 and Week 12 visits. At the Week 13 follow-up visit (1 week after discontinuation of the study medication), the Total Maximal Chorea Scores of patients who had received Austedo returned to baseline (Figure 1).

Table 4: Change from Baseline to Maintenance Therapy in Total Maximal Chorea (TMC) Score in Patients with Huntington’s Disease Treated with Austedo in Study 1
Motor Endpoint Austedo
N = 45
Placebo
N = 45
p value
* TMC is a subscale of the Unified Huntington’s Disease Rating Scale (UHDRS) † Primary efficacy endpoint

Change in Total Chorea Score* from Baseline to Maintenance Therapy†

-4.4

-1.9

<0.0001

Figure 1: Total Maximal Chorea Score Over Time in Study 1

Figure 2: Distribution of the Change in Total Maximal Chorea Scores in Study 1

Figure 2 shows the distribution of values for the change in Total Maximal Chorea Score in Study 1. Negative values indicate a reduction in chorea and positive numbers indicate an increase in chorea.

A patient-rated global impression of change assessed how patients rated their overall Huntington’s disease symptoms. Fifty-one percent of patients treated with Austedo rated their symptoms as “Much Improved” or “Very Much Improved” at the end of treatment, compared to 20% of placebo-treated patients.

In a physician-rated clinical global impression of change, 42% percent of patients treated with Austedo rated their symptoms as “Much Improved” or “Very Much Improved” at the end of treatment compared to 13% of placebo-treated patients.

Tardive Dyskinesia

The efficacy of Austedo in the treatment for tardive dyskinesia was established in two 12‑week, randomized, double-blind, placebo-controlled, multi-center trials conducted in 335 adult ambulatory patients with tardive dyskinesia caused by use of dopamine receptor antagonists. Patients had a history of using a dopamine receptor antagonist (antipsychotics, metoclopramide) for at least 3 months (or 1 month in patients 60 years of age and older). Concurrent diagnoses included schizophrenia/schizoaffective disorder (62%) and mood disorder (33%). With respect to concurrent antipsychotic use, 64% of patients were receiving atypical antipsychotics, 12% were receiving typical or combination antipsychotics, and 24% were not receiving antipsychotics.

The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=not present; 1=minimal, may be extreme normal (abnormal movements occur infrequently and/or are difficult to detect); 2=mild (abnormal movements occur infrequently and are easy to detect); 3=moderate (abnormal movements occur frequently and are easy to detect) or 4 =severe (abnormal movements occur almost continuously and/or of extreme intensity). The AIMS total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement.

In Study 1, a 12-week, placebo-controlled, fixed-dose trial, adults with tardive dyskinesia were randomized 1:1:1:1 to 12 mg Austedo, 24 mg Austedo, 36 mg Austedo, or placebo. Treatment duration included a 4-week dose escalation period and an 8-week maintenance period followed by a 1-week washout. The dose of Austedo was started at 12 mg per day and increased at weekly intervals in 6 mg/day increments to a dose target of 12 mg, 24 mg or 36 mg per day. The population (n= 222) was 21 to 81 years old (mean 57 years), 48% male, and 79% Caucasian. In Study 1, the AIMS total score for patients receiving Austedo demonstrated statistically significant improvement, from baseline to Week 12, of 3.3 and 3.2 units for the 36 mg and 24 mg arms, respectively, compared with 1.4 units in placebo (Study 1 in Table 5). The improvements on the AIMS total score over the course of the study are displayed in Figure 3. Data did not suggest substantial differences in efficacy across various demographic groups. The treatment response rate distribution, based on magnitude of AIMS total score from baseline to week 12 is displayed in Figure 4.

The mean changes in the AIMS total score by visit are shown in Figure 3.

In Study 2, a 12-week, placebo-controlled, flexible-dose trial, adults with tardive dyskinesia (n=113) received daily doses of placebo or Austedo, starting at 12 mg per day with increases allowed in 6-mg increments at 1-week intervals until satisfactory control of dyskinesia was achieved, until intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. Treatment duration included a 6-week dose titration period and a 6-week maintenance period followed by a 1-week washout. The population was 25 to 75 years old (mean 55 years), 48% male, and 70% Caucasian. Patients were titrated to an optimal dose over 6 weeks. The average dose of Austedo after treatment was 38.3 mg per day. There was no evidence suggesting substantial differences in efficacy across various demographic groups. In Study 2, AIMS total score for patients receiving Austedo demonstrated statistically significant improvement by 3.0 units from baseline to endpoint (Week 12), compared with 1.6 units in the placebo group with a treatment effect of -1.4 units. Table 5 summarizes the effects of Austedo on tardive dyskinesia based on the AIMS.

Table 5: Improvement in AIMS Total Score in Patients Treated with Austedo in Study 1 and Study 2
Study Treatment Group Primary Efficacy Measure: AIMS Total Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Treatment Effect (95% CI)

Study 1

Austedo 36 mg*

(n= 55)

10.1 (3.21)

-3.3 (0.42)

-1.9 (-3.09, -0.79)

Austedo 24 mg

(n= 49)

9.4 (2.93)

-3.2 (0.45)

-1.8 (-3.00, -0.63)

Austedo 12 mg

(n= 60)

9.6 (2.40)

-2.1 (0.42)

-0.7 (-1.84, 0.42)

Placebo (n= 58)

9.5 (2.71)

-1.4 (0.41)

Study 2

Austedo

(12-48 mg/day)*

(n= 56)

9.7 (4.14)

-3.0 (0.45)

-1.4 (-2.6, -0.2)

Placebo (n= 57)

9.6 (3.78)

-1.6 (0.46)

*Dose that was statistically significantly different from placebo after adjusting for multiplicity.

LS Mean = Least-squares mean; SD = Standard deviation; SE = Standard error; CI = 2-sided 95% confidence interval

Figure 3: Least Square Means of Change in AIMS Total Score from Baseline for Austedo Compared to Placebo (Study 1)

SE = Standard error

Figure 4: Percent of Patients with Specified Magnitude of AIMS Total Score Improvement at the End of Week 12 (Study 1)

In Summary

Common side effects of Austedo include: drowsiness. Other side effects include: depression, agitation, akathisia, fatigue, and restlessness. See below for a comprehensive list of adverse effects.

(web3)