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Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. Although XENAZINE has been shown to decrease the chorea of HD in a 12-week controlled trial, it was also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown. Therefore, proper use of the drug requires attention to all facets of the underlying disease process over time. Prescribers should periodically re-evaluate the need for XENAZINE in their patients by assessing the beneficial effect on choreiform movements and possible adverse effects, including depression, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness and disability. It may be difficult to distinguish between drug-induced side-effects and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician distinguish between the two possibilities. In some patients, underlying chorea itself may improve over time, decreasing the need for XENAZINE.

Need for Careful Dosing of Xenazine

Proper dosing of XENAZINE involves careful titration of therapy to determine an individualized dose for each patient. When first prescribed, XENAZINE therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is well tolerated (see DOSAGE AND ADMINISTRATION). Some adverse effects such as depression, fatigue, insomnia, sedation/somnolence, parkinsonism and akathisia may be dose-dependent and may resolve or lessen with dosage adjustment or specific treatment. If the adverse effect does not resolve or decrease, consideration should be given to discontinuing tetrabenazine.

Doses above 50 mg should not be given without CYP2D6 genotyping (see WARNINGS: Laboratory Tests and PRECAUTIONS – DRUG INTERACTIONS).

Risk of Depression and Suicidality

Patients with Huntington's disease are at increased risk for depression and suicidal ideation and behavior (suicidality). Tetrabenazine increases these risks. All patients treated with tetrabenazine should be observed closely for new or worsening depression or suicidality.

In a 12-week, double-blind placebo-controlled study in patients with chorea associated with Huntington's disease, 10 of 54 patients (19%) treated with tetrabenazine were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received XENAZINE for up to 48 weeks; in the second study, 75 patients received XENAZINE for up to 80 weeks), the rate of depression/worsening depression was 35%.

In all of the HD chorea studies of tetrabenazine (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation.

Clinicians should be alert to the heightened risk of suicide in patients with Huntington's disease regardless of depression indices. Reported rates of completed suicide among individuals with Huntington's disease range from 3-13%; over 25% of patients attempt suicide at some point in the illness.

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with XENAZINE and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately. (See PATIENT INFORMATION).

If depression or suicidality occurs, the dose of XENAZINE should be reduced. Initiating treatment with, or increasing the dose of, a concomitant antidepressant may also be useful. In patients with new onset depression who require antidepressants that are strong CYP2D6 inhibitors (such as paroxetine and fluoxetine), the total dose of XENAZINE should be halved (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). If depression or suicidality does not resolve, consideration should be given to discontinuing treatment with tetrabenazine.

Caution should be exercised in treating patients with XENAZINE who have a history of depression or prior suicide attempts or ideation, as these patients may be at increased risk for suicidal behavior (See PATIENT INFORMATION). Patients who are actively suicidal or with untreated or inadequately treated depression should not be treated with tetrabenazine (see CONTRAINDICATIONS)

Antidepressants that are strong CYP2D6 inhibitors significantly increase exposure to α- and βHTBZ. (See PRECAUTIONS: DRUG INTERACTIONS)

Laboratory Tests

Before patients are given a daily dose of greater than 50 mg, they should be tested for the CYP2D6 gene to determine whether they are poor metabolizers (PMs) or extensive or intermediate metabolizers (EMs or IMs). When a dose of tetrabenazine is given to PMs, exposure will be substantially higher (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than it would be in EMs. The dosage should therefore be adjusted according to a patient's CYP2D6 metabolizer status by limiting the dose to 50 mg in patients who are CYP2D6 poor metabolizers. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine and other drugs that reduce dopaminergic transmission. 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 diagnostic evaluation of patients with this syndrome is complicated. In arriving at the diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). 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 tetrabenazine and other drugs not essential to concurrent therapy; (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.

If the patient requires treatment with tetrabenazine after recovery from NMS, the potential reintroduction of therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Akathisia, Restlessness, and Agitation

In a 12-week, double blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of XENAZINE-treated patients and 0% of placebo-treated patients. In an 80-week open label study, akathisia was observed in 20% of XENAZINE-treated patients. Akathisia was not observed in a 48-week open-label study. Patients receiving XENAZINE should be monitored for the presence of akathisia. Patients receiving XENAZINE should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the XENAZINE dose should be reduced; however, some patients may require discontinuation of therapy.

Parkinsonism

XENAZINE can cause parkinsonism. In a 12-week double-blind, placebo-controlled study in patients with chorea associated with HD, symptoms suggestive of parkinsonism (i.e., bradykinesia, hypertonia and rigidity) were observed in 15 % of XENAZINE-treated patients compared to 0% of placebo-treated patients. In 48-week and 80-week open-label studies, symptoms suggestive of parkinsonism were observed in 10% and 3% of XENAZINE-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntington's disease, it may be difficult to distinguish between this drug-induced side-effect 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 tetrabenazine, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.

Dysphagia

Dysphagia is a component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. The latter symptom may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of XENAZINE-treated patients and 3% of placebo-treated patients. In 48-week and 80-week open label studies, dysphagia was observed in 10% and 8% of XENAZINE-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown. XENAZINE and other drugs that reduce dopaminergic transmission should be used with caution in patients with Huntington's disease at risk for aspiration pneumonia.

Sedation and Somnolence

Sedation is the most common dose-limiting adverse effect of tetrabenazine. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence was observed in 17/54 (31%) tetrabenazine-treated patients and in 1 (3%) placebo-treated patient. Sedation was the reason upward titration of tetrabenazine was stopped and/or the dose of tetrabenazine was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of tetrabenazine resulted in decreased sedation. In 48-week and 80-week open-label studies, sedation/somnolence was observed in 17% and 57% of XENAZINE treated patients, respectively. In some patients, intolerable sedation occurred at doses that were lower than the efficacious doses.

Patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine and know how the drug affects them (see PATIENT INFORMATION).

QTc Prolongation

XENAZINE causes a small increase (about 8 msec) in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases (see CLINICAL PHARMACOLOGY- Pharmacodynamics). The use of XENAZINE should be avoided in combination with other drugs that are known to prolong QTc, including antipsychotic medications (e.g., chlorpromazine, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, or any other medications known to prolong the QTc interval. XENAZINE 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.

Concomitant Use of Neuroleptic Drugs

Patients taking neuroleptic drugs (e.g., haloperidol, chlorpromazine, risperidone, olanzapine) were excluded from clinical studies during the tetrabenazine development program. Adverse reactions associated with tetrabenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists.

Interaction with Alcohol

Patients should be advised that the concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence (see PATIENT INFORMATION).

Hypotension and Orthostatic Hypotension

XENAZINE induced postural dizziness in healthy volunteers receiving single doses of 25 or 50 mg. One subject had syncope and one subject with postural dizziness had documented orthostasis. Dizziness occurred in 4% of tetrabenazine-treated patients (vs. none on placebo) in the 12-week controlled trial; blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.

Hyperprolactinemia

Tetrabenazine elevates serum prolactin concentrations in humans. Following administration of 25 mg 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 tetrabenazine 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 tetrabenazine development program) 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 tetrabenazine.

Tardive Dyskinesia (TD)

A potentially irreversible syndrome of involuntary, dyskinetic movements may develop in patients treated with neuroleptic drugs. In an animal model of orofacial dyskinesias, acute administration of reserpine, a monoamine depletor, has been shown to produce vacuous chewing in rats. Although the pathophysiology of tardive dyskinesia remains incompletely understood, the most commonly accepted hypothesis of the mechanism is that prolonged post-synaptic dopamine receptor blockade leads to supersensitivity to dopamine. Neither reserpine nor tetrabenazine, which are dopamine depletors, have been reported to cause clear tardive dyskinesia in humans, but as pre-synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine, and tetrabenazine can cause the extrapyramidal symptoms also known to be associated with neuroleptics (e.g., parkinsonism and akathisia) physicians should be aware of the possible risk of tardive dyskinesia. If signs and symptoms of TD appear in a patient treated with XENAZINE, drug discontinuation should be considered.

Use in Patients with Concomitant Illness Clinical experience with tetrabenazine in patients with systemic illnesses is limited. Caution is advised in using tetrabenazine in patients with a history of depression or suicidality (see WARNINGS - Risk of Depression and Suicide). Caution is also advised in using tetrabenazine in patients with diseases, conditions, or treatments that could cause depression or increased suicidality. Tetrabenazine is contraindicated in patients with hepatic impairment (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY - Special Populations) and in patients with untreated or inadequately treated depression or who are actively suicidal.

XENAZINE has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials.

Binding to Melanin-Containing Tissues

Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of eye was conducted in the chronic toxicity study in dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.

The clinical relevance of tetrabenazine'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.

Information for Patients

Physicians are advised to discuss the following issues with patients and their families:

Patients and their families should be told that XENAZINE may increase the risk of patients considering or attempting suicide. Patients and their families should be encouraged to be alert to the emergence of suicidal ideation and should report it immediately to the patient's physician.

Patients and their families should be told that XENAZINE may cause depression or may worsen pre-existing depression. They should be encouraged to be alert to the emergence of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks and should report such symptoms promptly to the patient's physician.

Patients and their families should be told that the dose of XENAZINE will be titrated up slowly to the dose that is best for each patient. Sedation, akathisia, parkinsonism, depression, and difficulty swallowing may occur. Such symptoms should be promptly reported to the physician and may require dose reduction or tetrabenazine discontinuation.

Patients should be told that XENAZINE may induce sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Patients should be advised that until they learn how they respond to XENAZINE they should be careful doing activities that require them to be alert, such as driving a car or operating machinery.

Patients and their families should be advised that alcohol may potentiate the sedation induced by XENAZINE.

Patients and their families should be advised to notify the physician if the patient becomes pregnant or intends to become pregnant during XENAZINE therapy, or is breast-feeding or intending to breast-feed an infant during therapy.

Patients and their families should be advised to notify the physician of all medications the patient is taking and to consult with the physician before starting any new medications.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies have not been conducted with tetrabenazine.

Mutagenesis

Tetrabenazine and metabolites α-HTBZ and β-HTBZ were negative in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. α-HTBZ and β-HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus tests were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats, but produced an equivocal response in female rats.

Impairment of Fertility

Fertility and early embryonic development studies have not been conducted with tetrabenazine.

Pregnancy

Pregnancy Category C

Tetrabenazine had no clear effects on embryo-fetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m² basis). Tetrabenazine had no effects on embryo-fetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m² basis).

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. The no-effect dose for stillbirths and postnatal mortality was 0.5 times the MRHD on a mg/m² basis.

There are no adequate and well-controlled studies in pregnant women. XENAZINE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See PATIENT INFORMATION)

Labor and Delivery

The effect of tetrabenazine on labor and delivery in humans is unknown.

Nursing Mothers

It is not known whether tetrabenazine or its metabolites are excreted in human milk.

Since many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from tetrabenazine, a decision should be made whether to discontinue nursing or to discontinue tetrabenazine, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of tetrabenazine in children have not been established.

Last reviewed on RxList: 6/13/2011
This monograph has been modified to include the generic and brand name in many instances.