Tetrabenazine

Sparingly soluble

Sparingly soluble in water

Soluble in ethanol

3.61e-01 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

126-129 °C

Crystals. MP: 208-210 °C. Soluble in hot water; practically insoluble in acetone. UV max (alcohol): 230, 284 nm (epsilon 7780, 3820) /Tetrabenazine hydrochloride/

Bitter crystals. Sensitive to light. MP: 126-130 °C. Sparingly soluble in water, soluble in alcohol, practically insoluble in ether /Tetrabenazine methanesulfonate/

128 °C

6.51

pKa = 6.51

Mixture of (R,R)- and (S,S)- isomers

Colorless crystals from DME-hexanes. MP: 126 °C. Specific optical rotation: +37.2 deg at 26 °C/D (c = 0.41 in CH2Cl2) /R,R-Tetrabenazine/

Warning

H302 (97.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 44 reports by companies from 3 notifications to the ECHA C&L Inventory.

This chemical does not meet GHS hazard criteria for 100% (2 of 2) of all reports.

Not Classified

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tetrabenazine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Acute Tox. 4 (97.7%)

Not Classified

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Store at 25 °C (77 °F); excursions permitted to 15 deg to 30 °C (59 deg to 86 °F).

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2 - 8 °C.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Avoid breathing dust. Environmental precautions: Do not let product enter drains.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition.

The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission. /The objective of the study was/ to investigate pharmacological interactions between pridopidine and tetrabenazine. Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison. Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine. Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine-induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy.

The risk for Parkinsonism, neuroleptic malignant syndrome (NMS), and akathisia may be increased by concomitant use of Xenazine and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone)

Potential pharmacologic interaction (serotonin and norepinephrine depletion in the CNS). Concomitant therapy is contraindicated. Clinicians should wait for signs of chorea to re-emerge after discontinuing reserpine before initiating tetrabenazine therapy. At least 20 days should elapse after reserpine discontinuance prior to initiating tetrabenazine therapy.

For more Interactions (Complete) data for Tetrabenazine (12 total), please visit the HSDB record page.

Tetrabenazine has not been associated with rates of serum enzyme elevations greater than occur with placebo therapy, but information on liver test results during therapy is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation or dose modification have been reported by the sponsor. In prelicensure pivotal registration trials in several hundred patients, tetrabenazine was not associated with cases of jaundice or hepatitis. Since licensure, there have been no published reports of clinically apparent liver injury, jaundice or hepatitis attributed to tetrabenazine. Thus, clinically apparent liver injury with jaundice due to tetrabenazine must be rare, if it occurs at all.

IDENTIFICATION AND USE: Tetrabenazine is a solid. It is used as adrenergic uptake inhibitor for the treatment of chorea associated with Huntington's disease. Pharmacology studies demonstrate that betrabenzaine reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. HUMAN STUDIES: Adverse effects are dose and age related and include depression, fatigue, parkinsonism, and somnolence. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving tetrabenazine and other drugs that reduce dopaminergic transmission. Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose have been reported in the literature. The dose of the drug in these patients ranged from 100 mg to 1 g. Adverse reactions associated with overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Completed suicide, attempted suicide, and 6 cases of suicidal ideation were reported in 187 tetrabenazine recipients. Major human metabolite 9-Desmethyl-beta-dihydrotetrabenazine was not clastogenic in an in vitro chromosomal aberration assay in human peripheral blood mononuclear cells in the presence or absence of metabolic activation. ANIMAL STUDIES: No increase in tumors was observed in transgenic mice treated orally with a major human metabolite, 9-desmethyl-beta-dihydrotetrabenazine (20, 100, and 200 mg/kg/day), for 26 weeks. Oral administration of tetrabenazine (5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when male rats were treated orally with tetrabenazine (5, 15, or 30 mg/kg/day. However, because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-dihydrotetrabenazine, a major human metabolite, this study may not have adequately assessed the potential of the drug to impair fertility in humans. Oral administration of 9-desmethyl-beta-dihydrotetrabenazine (8, 15, and 40 mg/kg/day) to pregnant and lactating rats throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. When 9-desmethyl-beta-dihydrotetrabenazine (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (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. Maternal toxicity was seen at the highest dose. Tetrabenazine and metabolites alpha-dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ), and 9-desmethyl-beta-dihydrotetrabenazine were negative in an in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. a-HTBZ and b-HTBZ were clastogenic in an in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus assays 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.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of March 27, 2018: http://actor.epa.gov/dashboard/]

/HUMAN EXPOSURE STUDIES/ Vesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deutetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deutetrabenazine and tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods. Data from the Phase III, 12-week, parallel-group, clinical trials First-HD (N=90) and TETRA-HD (N=84) were used to conduct an ITC of the tolerability of deutetrabenazine versus tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in >/= 10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deutetrabenazine and tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and p-values were obtained from z-tests. Compared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p<0.05 for each). Deutetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses (p<0.001 for each). Deutetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant. This indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine.

/SIGNS AND SYMPTOMS/ Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving tetrabenazine and other drugs that reduce dopaminergic transmission.

/SIGNS AND SYMPTOMS/ Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with Xenazine have been reported in the literature. The dose of Xenazine in these patients ranged from 100 mg to 1 g. Adverse reactions associated with Xenazine overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.

/CASE REPORTS/ Although tetrabenazine is widely used as an effective treatment for chorea and other hyperkinetic movement disorders, it has been associated with rare instances of parkinsonism and acute dystonic reactions. There have been no prior reports of tardive dyskinesia with this drug. Generalized choreiform dyskinesia developed after 10 months of conventional-dosage tetrabenazine treatment, persisting for several weeks after the drug was discontinued. As might be anticipated from its pharmacological profile, tetrabenazine has the potential to cause tardive dyskinesia. Such an occurrence may be difficult to detect in a clinical population already affected with involuntary movements.

For more Human Toxicity Excerpts (Complete) data for Tetrabenazine (12 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Tetrabenazine

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No increase in tumors was observed in Tg.rasH2 transgenic mice treated orally with a major human metabolite, 9-desmethyl-beta-dihydrotetrabenazine (20, 100, and 200 mg/kg/day), for 26 weeks. /9-Desmethyl-beta-dihydrotetrabenazine/

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine (5, 15, and 30 mg/kg/day) for 26 weeks.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Oral administration of tetrabenazine (5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day (less than the maximum recommended human dose (MRHD) on a mg/sq m basis). ... Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-dihydrotetrabenazine, a major human metabolite, /this study/ may not have adequately assessed the potential of Xenazine to impair fertility in humans.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (5, 15, or 30 mg/kg/day; up to 3 times the maximum recommended human dose (MRHD) on a mg/sq m basis) prior to and throughout mating with untreated females. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-dihydrotetrabenazine, a major human metabolite, /this study/ may not have adequately assessed the potential of Xenazine to impair fertility in humans.

For more Non-Human Toxicity Excerpts (Complete) data for Tetrabenazine (10 total), please visit the HSDB record page.

Because the safety and efficacy of the increased exposure to Xenazine and other circulating metabolites are unknown, it is not possible to adjust the dosage of Xenazine in hepatic impairment to ensure safe use. The use of Xenazine in patients with hepatic impairment is contraindicated.

Prior to administering tetrabenazine dosages exceeding 50 mg daily, the manufacturer recommends patients be tested to determine their cytochrome P-450 (CYP) isoenzyme 2D6 status (i.e., poor metabolizers, extensive metabolizers, intermediate metabolizers). Drug exposure will be substantially higher (about threefold for alpha-dihydrotetrabenazine (a-HTBZ) and ninefold for beta-dihydrotetrabenazine (beta-HTBZ), both active metabolites) when a dose is given to a poor metabolizer than when given to an extensive metabolizer. The manufacturer recommends limiting the dosage of tetrabenazine to 50 mg daily and single doses of the drug to 25 mg in patients who are poor CYP2D6 metabolizers.

Caution should be exercised in treating patients with tetrabenazine who have a history of depression or prior suicide attempts or ideation since these patients may be at an increased risk for suicidal behavior. Patients who are actively suicidal or those with untreated or inadequately treated depression should not be treated with the drug.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Treatment should consist of those general measures employed in the management of overdosage with any CNS-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.

LD50 Mouse iv 150 mg/kg

LD50 Mouse sc 400 mg/kg

LD50 Mosue ip 250 mg/kg

LD50 Mouse oral 550 mg/kg

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tetrabenazine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N - Nervous system

QN - Nervous system

Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).

... Pharmacology studies demonstrate that betrabenzaine reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. ...

There is interindividual variability in elimination half-life. The elimination half-life of tetrabenazine was 10 hours following intravenous bolus administration. The oral half-lives of its metabolites, α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are seven hours, five hours and 12 hours, respectively. Following a single oral dose of 25 mg tetrabenazine, the elimination half-life was approximately 17.5 hours in subjects with hepatic impairment.

alpha-Dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) and 9-desmethyl-beta-dihydrotetrabenazine have half-lives of 7 hours, 5 hours and 12 hours respectively. /Tetrabenazine metabolites/

Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine.

In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine, and fecal recovery accounted for approximately 7 to 16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of alpha-dihydrotetrabenazine (a-HTBZ) or beta-dihydrotetrabenazine (b-HTBZ) accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated.

The results of in vitro studies do not suggest that tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) or 9-desmethyl-beta-dihydrotetrabenazine are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its a- or b-HTBZ or 9-desmethyl-beta-dihydrotetrabenazine metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.

After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. alpha-Dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) and 9-desmethyl-beta-dihydrotetrabenazine are the major circulating metabolites and are subsequently metabolized to sulfate or glucuronide conjugates. a-HTBZ and b-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. a-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-alpha-dihydrotetrabenazine, a minor metabolite. b-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-beta-dihydrotetrabenazine.

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites alpha-dihydrotetrabenazine (a-HTBZ) and beta-dihydrotetrabenazine (b-HTBZ). a-HTBZ and b-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of a-HTBZ and b-HTBZ are reached within 1 to 1 1/2 hours post-dosing. a-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-a-DHTBZ. b-HTBZ is subsequently metabolized to another major circulating metabolite, 9-desmethyl-b-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.

Z9O08YRN8O

TETRABENAZINE

Established Pharmacologic Class [EPC] - Vesicular Monoamine Transporter 2 Inhibitor

Mechanisms of Action [MoA] - Vesicular Monoamine Transporter 2 Inhibitors

Tetrabenazine is a Vesicular Monoamine Transporter 2 Inhibitor. The mechanism of action of tetrabenazine is as a Vesicular Monoamine Transporter 2 Inhibitor.

TETRABENAZINE

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin.

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose.

Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex.

IV, 1.67 L/min in HD or tardive dyskinesia patients

The in vitro protein binding of tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), and beta-dihydrotetrabenazine (b-HTBZ) was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, a-HTBZ binding ranged from 60% to 68%, and b-HTBZ binding ranged from 59% to 63%.

Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of (11)C-labeled tetrabenazine or alpha-dihydrotetrabenazine (a-HTBZ), with the highest binding in the striatum and lowest binding in the cortex.

Adrenergic Uptake Inhibitors

MEDICATION

Use (kg; approx.) in Germany (2009): >50