Tetrabenazine

Dosage Forms & Strengths

tablet

• 12.5mg
• 25mg

Huntington Disease

Indicated for treatment of chorea associated with Huntington’s disease

Individualize and slowly titrate dosage over several weeks to identify a dose that reduces chorea and is well tolerated

Total daily dose up to 50 mg/day

• 12.5 mg PO qDay initially; after 1 week, the dose should be increased to 12.5 mg q12hr
• Maintenance: Titrate slowly by weekly intervals of 12.5 mg/day to identify dose that reduces chorea and is tolerated
• If daily dose is 37.5 to 50 mg/day, administer in divided doses q8hr
• Not to exceed 25 mg per single dose for total daily dosage between 37.5-50 mg/day

Total Daily dose >50 mg/day

• If >50 mg/day is required, test and genotype to determine if poor or extensive metabolizers of CYP2D6; not to exceed 100 mg/day or 37.5 mg/dose
• Dose maintenance requirements are dependent on CYP2D6 genotype (see Dosage Modifications)

Dosage Modifications

CYP2D6 extensive/intermediate metabolizers

• Extensive metabolizers may require dose >50 mg/day
• If total daily dose >50 mg/day, administer in divided doses q8hr
• Titrate slowly by 12.5 mg/day qWeek to identify dose that reduces chorea and is tolerated
• If >50 mg/day is required, do not to exceed 37.5 mg per single dose or a total daily dose of 100 mg/day

CYP2D6 poor metabolizers

• Not to exceed 25 mg per single dose or a total daily dose of 50 mg/day

Hepatic impairment

• Contraindicated; it is not possible to adjust the dose to ensure safe use

Dosing Considerations

May take with or without food

Dosage interruption >5 days: Retitrate dose when treatment resumed

Dosage interruption <5 days: May resume at previous maintenance dose without titration

Suspend upward dosage titration and reduce dose; discontinue if adverse reaction (intolerable effects such as: akathisia, restlessness, parkinsonism, insomnia, depression, suicidality, anxiety, sedation) does not resolve (may stop without taper)

Treatment discontinuation

• May discontinue without tapering
• Chorea may re-emerge within 12-18 hr after last dose

Tardive Dyskinesia (Off-label)

Investigational (see www.clinicaltrials.gov)

Safety and efficacy not established

Black Box Warnings

Increased risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease

Balance risks of depression and suicidality with the clinical need for control of choreiform movements when considering the use of tetrabenazine

Monitor for emergence or worsening of depression, suicidality, or unusual changes in behavior

Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician

Caution in patients with a history of depression or prior suicide attempts or ideation

Contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression

Contraindications

Hypersensitivity

Hepatic impairment

Patients who are actively suicidal, or who have untreated or inadequately treated depression (see Black Box Warnings)

Coadministration with deutetrabenazine or valbenazine

Concomitant MAO inhibitor or within 14 days of discontinuing MAO inhibitor

Reserpine

• Do not use tetrabenazine and reserpine concomitantly
• Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days
• Caution when switching from reserpine to tetrabenazine; wait for chorea to re-emerge before administering tetrabenazine to avoid overdosage and major CNS depletion of serotonin and norepinephrine
• At least 20 days should elapse after stopping reserpine before starting tetrabenazine

Cautions

Not indicated for treatment of levodopa-induced dyskinetic movements

Should only be used by physicians experienced with treatment of hyperkinetic disorders

May cause depression; consider risk of suicidality; should be balanced against need for treatment of chorea; discontinue at first sign

May induce symptoms of Parkinsonism, including symptoms of tardive dyskinesia; akathisia, restlessness, and agitation may occur; reduce dose or discontinue

Dysphagia, a component of Huntington chorea, may also be caused by dopamine antagonists such as tetrabenazine

Neuroleptic malignant syndrome (NMS) reported; clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia); additional signs include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure

May cause sedation/somnolence; avoid alcohol and other sedative drugs

May prolong QTc interval

May cause orthostatic hypotension

Concomitant use of neuroleptics (eg, haloperidol, chlorpromazine, risperidone, olanzapine) may cause additive effects of QTc prolongation, NMS, and extrapyramidal disorders

Caution with poor CYP2D6 metabolizers or drugs that inhibit CYP2D6 (eg, fluoxetine, paroxetine, quinidine); may markedly increase exposure to tetrabenazine active metabolites (alpha- and beta-HTBZ)

Hyperprolactinemia has resulted from dopaminergic antagonists

Serious side effects have been reported with tetrabenazine. See the “Drug Precautions” section.

Common side effects of tetrabenazine include the following:

• drowsiness
• insomnia
• depression
• restlessness or agitiation
• nausea
• irritability
• dizzinesss

This is not a complete list of tetrabenazine side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
 

Tetrabenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of tetrabenazine must balance the risks of depression and suicidality with the clinical need for control of choreiform movements. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. 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. Tetrabenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have:

• tremors, shaking, restless movement, problems with balance;

• uncontrolled muscle movements in your face (chewing, lip smacking, frowning, tongue movement, blinking or eye movement);

• trouble swallowing;

• fast or pounding heartbeats;

• a light-headed feeling, like you might pass out; or

• severe nervous system reaction--very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats.

Common side effects may include:

• drowsiness, tiredness;

• depressed mood;

• nausea; or

• feeling anxious, agitated, or restless.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Reversibly inhibits uptake of monoamines (e.g., dopamine, norepinephrine, serotonin, histamine) into synaptic vesicles and depletes monoamine stores from nerve terminals.1 2 13 17 18 19 20 21 23 24 25

• Precise mechanism of antichorea effects not established, but appears to be related to drug's ability to reversibly and selectively inhibit vesicular monoamine transporter type 2 (VMAT2) in CNS, thereby decreasing uptake of monoamines into synaptic vesicles and depleting monoamine stores from nerve terminals.1 2 7 8 13 17 18 19 20 21 23 24 25

• Preferentially depletes dopamine; dose required to deplete norepinephrine or serotonin is approximately fivefold higher than that required to deplete dopamine.2 7 17 21 23 Preferential depletion of dopamine in striatum may contribute to antichorea effects.4 13 18 22

• Exhibits weak in vitro binding affinity for dopamine type 2 (D2) receptors.1 13 21 23 Does not possess binding affinity for GABA, glutamate, glycine, histamine, or norepinephrine receptors or ion channels.7

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

• Take with or without food.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• 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 more than 5 days of taking this medicine. Talk with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• A fast heartbeat.
• A heartbeat that does not feel normal.
• Very bad dizziness or passing out.
• Trouble swallowing.
• A very bad and sometimes deadly health problem called neuroleptic malignant syndrome (NMS) may happen. Call your doctor right away if you have any fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, heartbeat that does not feel normal, or are sweating a lot.
• Some people who take tetrabenazine may get a very bad muscle problem called tardive dyskinesia. This muscle problem may not go away even if this medicine is stopped. Sometimes, signs may lessen or go away over time after tetrabenazine is stopped. The risk of tardive dyskinesia may be greater in people with diabetes and in older adults, especially older women. The risk is also greater the longer you take this medicine or with higher doses. Muscle problems may also occur after short-term use with low doses. Call your doctor right away if you have trouble controlling body movements or if you have muscle problems with your tongue, face, mouth, or jaw like tongue sticking out, puffing cheeks, mouth puckering, or chewing.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Hepatic impairment; patients who are actively suicidal or who have untreated or inadequately treated depression; coadministration of monoamine oxidase inhibitors (MAOIs) or use of tetrabenazine within 2 weeks of discontinuation of MAOI therapy; coadministration with reserpine, ≥20 days should pass after discontinuing reserpine before initiating tetrabenazine therapy

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to tetrabenazine or any component of the formulation; history or current episode of clinical depression unless under the care of a psychiatrist who is familiar with the patient's disorder and tetrabenazine’s pharmacology

-Initial Dose: 12.5 mg orally per day once in the morning; increase to 12.5 mg orally twice a day after one week.
-Maintenance Dose: Titrate up slowly at weekly intervals by 12.5 mg daily.
-Maximum Single Dose: 25 mg

Comments:
-Administer doses 37.5 mg/day or greater in a 3 times a day regimen.
-Determine CYP450 2D6 metabolizer status in patients who require doses of greater than 50 mg per day.

Use: Chorea associated with Huntington's disease.

AU and UK: Use is contraindicated. US: A decision should be made to discontinue the drug or to discontinue breastfeeding, taking into account the importance of the drug to the mother. Excreted into human milk: Yes Comments: The effects in the nursing infant are unknown.

Tetrabenazine is used to treat chorea (sudden movements that you cannot control) caused by Huntington's disease (an inherited disease that causes the progressive breakdown of nerve cells in the brain). Tetrabenazine is in a class of medications called vesicular monoamine transporter 2 (VMAT2) inhibitors. It works by changing the activity of certain natural substances in the brain that affect nerves and muscles.

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 excess heat and moisture (not in the bathroom).

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

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.

Keep all appointments with the laboratory. Your doctor may order certain lab tests to check your body's response to tetrabenazine.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.