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Mechanism of Action
US Drug Names
NOTE: The FDA has designated tetrabenazine an orphan drug for this indication.
Initially, 12.5 mg PO each morning. After one week, increase to 12.5 mg PO twice daily. The dose may be increased by 12.5 mg each week. Dosage must be individualized. Patients who require doses more than 50 mg per day should be genotyped for CYP2D6 expression. In patients who do not express CYP2D6 (i.e., poor metabolizers of CYP2D6) and require a daily dose of 37.5 mg to 50 mg, administer in 3 divided doses. The maximum recommended single dose is 25 mg with a maximum daily dose of 50 mg. In patients who do express CYP2D6 (i.e., intermediate or extensive metabolizers of CYP2D6) and require a daily dose of at least 50 mg, administer in 3 divided doses. The maximum recommended single dose is 37.5 mg with a maximum daily dose of 100 mg. For patients receiving concomitant strong CYP2D6 inhibitors, the maximum single dose should not exceed 25 mg and the daily dose should not exceed 50 mg. If adverse events such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety, or intolerable sedation occur, reduce the dose. If the adverse event does not resolve, consider discontinuing tetrabenazine or initiating treatment for the adverse effect (e.g., antidepressant). Tetrabenazine may be abruptly discontinued, but chorea may occur 12 to 18 hours after the last dose. If tetrabenazine therapy is interrupted for 5 or more days, retitration of the dose is advised.
100 mg/day PO in patients who express CYP2D6; 50 mg/day PO in patients who do not express CYP2D6.
Safety and efficacy have not been established.
Tetrabenazine is contraindicated in patients with hepatic impairment.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Tetrabenazine, a synthetic benzoquinolizine derivative, is a monoamine depleter and dopamine receptor blocker that improves the symptoms associated with Huntington's disease (HD), and is considered a first line treatment for HD associated chorea by the American Academy of Neurology. Tetrabenazine appears to have the best effect in HD but has shown improvement in other hyperkinetic movements disorders, such as tardive dyskinesia (TD), dystonia, Tourette's syndrome, and myoclonus. Tetrabenazine may also have synergistic effects when used in combination with the dopamine antagonist pimozide. One case report describes the successful use of tetrabenazine as part of combination therapy to treat refractory orofacial tardive dyskinesia. A randomized, double-blind, placebo-controlled study in patients with HD examined the efficacy of tetrabenazine in treating chorea. Patients were randomized to receive tetrabenazine (n = 54) or placebo (n = 30) for 12 weeks. The primary outcome was the change from baseline in the chorea score as measured by the Unified Huntington's Disease Rating Scale (UHDRS). After 12 weeks, the mean chorea score in the tetrabenazine group declined significantly compared to the placebo group (a reduction of 5 vs. 1.5 points, respectively). Tetrabenazine was superior to placebo as assessed by the clinical global improvement scale. However, more patients in the active treatment group (89%) experienced at least one adverse effect compared to the placebo group (70%). Tetrabenazine decreased the chorea of HD, but it also caused slight worsening in mood, cognition, rigidity, and functional capacity. Because tetrabenazine can increase the risk of depression and suicidal thoughts and behavior, the benefit of tetrabenazine should be weighed against the risks of treatment, particularly in those with a history of depression or suicidal attempts or ideation. In addition, HD patients may be predisposed to develop tardive dyskinesia with typical dopamine antagonists; however, tetrabenazine has never been reported to cause TD. Pseudoparkinsonism has been documented with tetrabenazine. Tetrabenazine is available in Europe and Australia as Xenazine and in Canada as Nitoman for the treatment of hyperkinetic movement disorders. Tetrabenazine has been granted orphan drug status by the FDA for chorea in people with Huntington's disease. A Specialty Pharmacy Network will send all Xenazine prescriptions directly to the physician office or patient. Tetrabenazine was approved for the treatment of chorea in people with Huntington's disease in August 2008.
For storage information, see the specific product information within the How Supplied section.
Serotonin and noradrenaline depletion are likely mechanisms of tetrabenazine-induced depression, which has been reported to occur in roughly 19% to 35% of patients treated with the drug. In a 12 week randomized, placebo-controlled trial, 19% of patients with Huntington's disease associated chorea who received tetrabenazine 100 mg daily (n = 54) experienced depression or worsening depression, compared to 0% of placebo recipients (n = 30). During 2 open-label studies, depression occurred in 35% of tetrabenazine recipients. In a retrospective chart review involving the use of tetrabenazine in movement disorders, 272 patients (52.5 %) had a documented history of depression and/or prior treatment with antidepressant therapy. During tetrabenazine treatment, 50 patients (18.4%) had an exacerbation of their depression or required a change in antidepressant (15.4%) and 28 patients (11.4%) experienced depression for the first time. A total of 16 patients (3.1%) discontinued treatment due to an adverse event of depression. The percentage of patients who discontinued treatment was not statistically different in patients with a prior history of depression (3.3%) and those with no prior history of depression (2.8%). Tetrabenazine increases the risk of suicidal ideation and behavior. Across all clinical studies of Huntington's disease chorea (n = 187), 1 patient committed suicide, 1 attempted suicide, and 6 had suicidal ideation. Because tetrabenazine can increase the risk of depression and suicidal ideation or behavior, and patients with Huntington's disease are at increased risk for depression or suicidal ideation/behaviors due to their natural disease, extreme caution is necessary when administering the drug. Instruct patients, as well as their caregivers and families, to promptly report the occurrence of depression, worsening depression, or suicidal intentions to their healthcare providers.
Sedation and somnolence (or drowsiness) as well as insomnia are 2 frequently reported adverse reactions to tetrabenazine. Drowsiness was observed with tetrabenazine in 31% of Huntington's disease patients with chorea (n = 54) during a randomized, placebo-controlled trial, compared to 3% in the placebo group (n = 30); incidence rates up to 57% were observed during open-label experience. Drowsiness appears to be dose related, as decreases in doses yielded less drowsiness. Insomnia was noted in 22% of patients. Tetrabenazine may cause pseudoparkinsonism; symptoms suggestive of pseudoparkinsonism (e.g., hypertonia, rigidity, or bradykinesia) were noted in up to 15% of patients during clinical trials. As rigidity may develop as part of the natural disease process in Huntington's disease, tetrabenazine-induced pseudoparkinsonism may be difficult to diagnose; consider dose reduction or discontinuation in patients who develop symptoms of parkinsonism. Akathisia was observed in 19% to 20% of tetrabenazine recipients during randomized, placebo-controlled and open-label trials for chorea; restlessness and agitation may be indicators of akathisia development. Overall, 33% of patients experienced some type of extrapyramidal event during a placebo-controlled trial, defined as akathisia, hyperkinesis, restlessness, bradykinesia, pseudoparkinsonism, hypertonia, or other extrapyramidal disorders. Other CNS effects include anxiety (15%), irritability (9%), anorexia (4%), obsessive reactions (4%), balance difficulty (9%), drooling, and subjective weakness.  Dizziness, dysarthria, gait unsteadiness, and headache occurred in 4% of tetrabenazine recipients. Postural dizziness was observed in healthy volunteers who received single doses of tetrabenazine 25 or 50 mg; syncope and orthostatic hypotension occurred. Tremor, confusion, and worsening aggression have been reported during post-marketing experience. Neuroleptic malignant syndrome (NMS) and acute dystonic reaction have also been observed. Symptoms of NMS may include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac arrhythmias). Myoglobinuria, rhabdomyolysis, and acute renal failure may also occur. If NMS is diagnosed, tetrabenazine should be discontinued immediately, and appropriate supportive treatment given. NMS recurrence among tetrabenazine recipients has been observed. If treatment is needed following NMS recovery, monitor for signs of recurrence. Many adverse events with tetrabenazine appear to be dose-related and may improve following a reduction in dosage. Long-term studies have not shown the development of tolerance to the beneficial effects of the drug.
During a 12-week placebo-controlled clinical trial of Huntington's disease associated chorea, dysphagia occurred in 4% of tetrabenazine recipients compared to 3% of those who received placebo. In 48-week and 80-week open-label studies, dysphagia occurred in 10% and 8% of treated patients, respectively. Dysphagia may occur as part of the underlying disease process of Huntington's disease; however, dysphagia has been observed with the use of drugs that reduce dopaminergic transmission such as tetrabenazine. Aspiration pneumonia did occur with dysphagia in some cases. Other gastrointestinal side effects of tetrabenazine reported by patients in clinical trials include nausea (13%), vomiting (6%), and diarrhea (1.9%). During an open-label trial, diarrhea began during tetrabenazine titration and normalized during maintenance dosing. 
Tetrabenazine may cause prolongation of the QT interval; a small increase of approximately 8 msec has been observed. As QT prolongation may lead to serious cardiac effects such as torsade de pointes, avoid the use of tetrabenazine in patients whose cardiac condition or history may predispose them to the development of dangerous arrhythmias. Tetrabenazine should also not be used in combination with other drugs known to prolong the QT interval.
Elevated prolactin concentrations may occur with tetrabenazine treatment, leading to potential symptoms associated with hyperprolactinemia. In healthy volunteers, administration of tetrabenazine 25 mg increased peak plasma prolactin concentrations 4- to 5-fold. It is unknown if chronic elevations of prolactin occur with treatment. Patient conditions that may be prolactin-dependent (e.g., breast cancer, amenorrhea, galactorrhea, gynecomastia, and impotence) may develop or worsen; use caution and weigh the risk and benefits of tetrabenazine treatment. If hyperprolactinemia is suspected, laboratory assessments should occur and discontinuation of tetrabenazine should be considered.
For the body as a whole, fatigue was commonly reported, occurring in 22% of tetrabenazine recipients (n = 54) compared to 13% of those who took placebo (n = 30) during a randomized trial. Ecchymosis occurred in 6% of patients given tetrabenazine. Falls and head lacerations were reported in 15% and 6% of patients, respectively. Hyperhidrosis and rash (unspecified) have been reported during post-marketing experience.
Dysuria was observed in 4% of patients with Huntington's disease associated chorea given tetrabenazine during a randomized, controlled trial.
Respiratory adverse reactions reported during tetrabenazine treatment in a randomized, placebo-controlled trial include upper respiratory tract infection (11%), dyspnea (4%), and bronchitis (4%). Pneumonia has been observed during post-marketing surveillance.
Tetrabenazine should be avoided in patients with a previous hypersensitivity to tetrabenazine or any other component of the commercial product.
Tetrabenazine is contraindicated in those with active suicidal ideation or who have untreated or inadequately treated depression. The drug should be used with caution in patients with a history of depression or suicidal thoughts or behavior. Patients with Huntington's disease (HD) are at increased risk for depression and suicidal ideation or behaviors (suicidality). Tetrabenazine use increases the risk for suicidality in patients with HD. Unusual changes in mood, behaviors, or actions should be reported promptly to the treating physician. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine. Tetrabenazine should be prescribed in the smallest quantity consistent with good management in order to reduce the risk of overdose.
Tetrabenazine may induce a variety of CNS effects and should be used cautiously in those with preexisting forms of neurological disease. Because tetrabenazine may cause CNS depression, it is not recommended for use in coma or other forms of severe CNS depression.
Tetrabenazine has the potential to impair cognitive and motor skills. Sedation is the most common dose-limiting side effect of tetrabenazine. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness, until they know how tetrabenazine affects them. Alcohol consumption may exacerbate sedation associated with the drug. Extreme caution is advisable in patients with alcoholism.
There are no adequate data on the developmental risk associated with tetrabenazine use during pregnancy. In rat studies, administration of tetrabenazine from the beginning of organogenesis through the lactation period was associated with an increase in stillbirths and offspring postnatal mortality at doses of 15 and 30 mg/kg/day (3 times the maximum recommended human dose of 100 mg/day on a mg/m2 basis); delayed pup maturation was observed at doses of 5 to 30 mg/kg/day. However, no clear effects of tetrabenazine on embryofetal development have been observed during animal studies. When 9-desmethyl-beta-DHTBZ, a major metabolite of tetrabenazine, was administered to pregnant rats during organogenesis, increases in embryofetal mortality were observed at doses of 15 and 40 mg/kg/day, and decreased fetal body weights were observed at a dose of 40 mg/kg/day. Increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weight (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed with 9-desmethyl-beta-DHTBZ administration to pregnant rats throughout organogenesis and lactation. The 9-desmethyl-beta-DHTBZ no-effect dose for developmental toxicity of 8 mg/kg/day in rats was associated with an AUC lower than that in humans at the maximum recommended human dose. In a case report, tetrabenazine treatment (75 mg/day) was initiated late in the second trimester in a woman with chorea gravidarum. Although the infant was born with a small ventricular septal defect, an association to the tetrabenazine therapy was thought to be unlikely since fusion of the intraventricular septum is normally complete by 8 weeks gestation. Extrapyramidal and withdrawal symptoms including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported after delivery in neonates exposed to dopamine antagonists (e.g., antipsychotics) during the third trimester. These effects have varied in severity ranging from self-limited to requiring intensive care unit stays and prolonged hospitalization.   As a central dopamine depletor, tetrabenazine has the potential to cause similar effects. It is not clear if tetrabenazine, through its effect on prolactin, would affect labor or delivery.
There are no data on the presence of tetrabenazine or its metabolites in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tetrabenazine and any potential adverse effects on the breast-fed infant from the drug or the mother's underlying condition. Tetrabenazine elevates serum prolactin concentrations in humans, and thus, interference with proper lactation is possible. Previous American Academy of Pediatrics (AAP) did not make specific recommendations regarding tetrabenazine use during breast-feeding, but the AAP cautioned that psychotropic medications affect neurotransmitter function in the developing central nervous system, and therefore, the accurate prediction of long-term adverse effects may not be possible.
Tetrabenazine may cause an increase in the corrected QTc interval in some patients. Other drugs that prolong the QT interval have been associated with torsade de pointes (TdP), a life-threatening arrhythmia; existent QT prolongation increases the risk of TdP. Tetrabenazine should be avoided in those with QT prolongation associated with congenital long QT syndrome or those with a history of cardiac arrhythmias. Tetrabenazine should not be used in combination with medications known to prolong the QT interval, because the risk for TdP may be increased. Use tetrabenazine with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, pyrexia or elevated body temperature, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. It should be noted that patients with recent myocardial infarction or unstable heart disease were excluded from clinical trials; therefore, the effects of the drug in patients with these conditions are generally unknown. Postural dizziness, syncope, and orthostatic hypotension have been reported. Hypotension caused by hypovolemia, antihypertensive drugs, or dehydration may be potentiated. The pharmacokinetics of tetrabenazine have not been formally studied in geriatric patients. Caution is advisable in the elderly since this patient population may be more susceptible to the cardiac effects of the drug.    
Tetrabenazine should be used with caution in those patients with Parkinson's disease because of possible aggravation of EPS due to dopamine-receptor blockade.
Safety and efficacy of tetrabenazine use in children has not been established. Routine cardiovascular monitoring has been suggested for children receiving psychotropic medications due to the potential of these agents to produce adverse cardiac effects.
The safe use of tetrabenazine in renal disease has not been fully evaluated. Caution is recommended when tetrabenazine is prescribed to patients with renal failure or any degree of renal impairment.
Tetrabenazine is contraindicated in patients with any degree of hepatic impairment or hepatic disease. Pharmacokinetic evaluations indicate that patients with hepatic impairment experience a 7- to 190-fold higher maximum blood concentration of tetrabenazine than healthy subjects. In addition, the half-lives of tetrabenazine and its metabolites are prolonged. The safety and efficacy of increased exposure to tetrabenazine and its metabolites in those with hepatic impairment is unknown.
Caution is advised for patients on tetrabenazine who will receive general anesthesia, due to the potential for CNS effects. Check with the anesthesiologist regarding the continuation of tetrabenazine in a patient who is scheduled for surgery.
Neuroleptic malignant syndrome has been reported in association with the use of tetrabenazine. In the presence of high fever, the possibility of this complication should be considered. Additionally, fever may increase the risk of prolonging the QT interval when using tetrabenazine.    
Tetrabenazine can cause hyperprolactinemia, likely due to central D2 antagonism. Elevations in prolactin may induce infertility in either men or women, or may induce other endocrine abnormalities. Some human breast cancers may be prolactin-dependent and therefore tetrabenazine should be used cautiously in those who have a history of breast cancer.
Tetrabenazine should be used cautiously in patients with dysphagia or other conditions causing difficulty swallowing. Esophageal dysmotility and aspiration have been associated with the use of other anti-dopaminergic drugs.
Tetrabenazine is contraindicated in patients who are receiving MAOI therapy or reserpine.
Mechanism of Action: Tetrabenazine is a selective, reversible, centrally-acting dopamine depleting drug that works by inhibiting vesicular monoamine transporter 2 (VMAT2). Tetrabenazine depletes presynaptic dopamine, norepinephrine, and serotonin storage and antagonizes postsynaptic dopamine receptors. In vitro data indicate that tetrabenazine exhibits a weak binding affinity at the dopamine-2 receptor. Clinically, tetrabenazine improves the symptoms associated with hyperkinetic movement disorders such as Huntington's disease.
Tetrabenazine is administered orally. The protein binding of tetrabenazine and its metabolites is less than 90%. Although 19 metabolites have been identified, the major metabolites are alpha-HTBZ, beta-HTBZ, and 9-desmethyl-beta-DHTBZ. The activity of 9-desmethyl-beta-DHTBZ relative to tetrabenazine is unknown. The alpha-HTBZ and beta-HTBZ metabolites are formed primarily by carbonyl reductase in the liver. Subsequently, alpha-HTBZ is O-dealkylated to 9-desmethyl-alpha-DHTBZ principally by CYP2D6, and CYP1A2 to a lesser extent while beta-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-beta-DHTBZ. The half-lives of alpha-HTBZ, beta-HTBZ, and 9-desmethyl-beta-DHTBZ are 7 hours, 5 hours, and 12 hours, respectively. Approximately 75% and 7—16% of a dose is eliminated in the urine and feces, respectively. Sulfate and glucuronide conjugates of HTBZ metabolites account for the majority of renally eliminated metabolites, with less than 10% of a dose found in the urine as alpha-HTBZ and beta-HTBZ.
Affected cytochrome P450 isoenzymes and drug transporters: none
In vitro data suggest that tetrabenazine, alpha-HTBZ, and beta-HTBZ are not likely to be clinically significant inhibitors of CYP2D6, CYP1A2, CYP2C8, CYP2C9, CYPC19, CYP2E1, CYP3A, or P-glycoprotein (P-gp). In vitro data also suggest that tetrabenazine, alpha-HTBZ, and beta-HTBZ are not likely to be clinically significant inducers of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. According to the manufacturer, in vitro data indicate that clinically significant interactions with CYP inhibitors other than 2D6 are unlikely. It should be noted that the potential of the 9-desmethyl-beta-DHTBZ metabolite to interact with other drugs, including any possible involvement of the CYP450 system, has not been studied.
Absorption following oral administration is at least 75% of the dose. Plasma concentrations of tetrabenazine will likely be below detectable levels after single doses up to 50 mg due to extensive and rapid hepatic metabolism. Peak plasma concentrations of the active metabolites alpha-dihydrotetrabenzaine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ) are reached within 1—1.5 hours following a dose. The major metabolite 9-desmethyl-beta-DHTBZ, which is formed from beta-HTBZ, reaches peak plasma concentrations approximately 2 hours post-dose. Food has no effect on the pharmacokinetics of the drug; therefore, it may be given without regard to meals.
Pharmacokinetic evaluations in a limited number of subjects indicated that those with mild to moderate hepatic impairment experienced a 7—190-fold higher maximum blood concentration of tetrabenazine than healthy subjects. The elimination half-life of tetrabenazine was approximately 17.5 hours, and the elimination half-lives of alpha-HTBZ and beta-HTBZ were 10 and 8 hours, respectively. The safety and efficacy of increased exposure to tetrabenazine and its metabolites in those with hepatic impairment is unknown; therefore, the drug is contraindicated in patients with any degree of hepatic dysfunction.
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