Patients who require doses of tetrabenazine greater than 50 mg per day, should be first tested and genotyped to determine if they are poor (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of tetrabenazine should then be individualized accordingly to their status as either poor (PMs) or extensive metabolizers (EMs) [see DOSAGE AND ADMINISTRATION (2.2), WARNINGS AND PRECAUTIONS (5.3), CLINICAL PHARMACOLOGY (12.3)].
Poor CYP2D6 metabolizers (PMs) will have substantially higher levels of exposure to the primary metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) compared to EMs. The dosage should, therefore, be adjusted according to a patient’s CYP2D6 metabolizer status by limiting a single dose to a maximum of 25 mg and the recommended daily dose to not exceed a maximum of 50 mg/day in patients who are CYP2D6 PMs [see DOSAGE AND ADMINISTRATION (2.2), WARNINGS AND PRECAUTIONS (5.3), CLINICAL PHARMACOLOGY (12.3)].
Extensive / Intermediate Metabolizers
In extensive (EMs) or intermediate metabolizers (IMs), the dosage of tetrabenazine can be titrated to a maximum single dose of 37.5 mg and a recommended maximum daily dose of 100 mg [see DOSAGE AND ADMINISTRATION (2.2), DRUG INTERACTIONS (7.1), CLINICAL PHARMACOLOGY (12.3)].
Clinical trials did not reveal patients developed drug seeking behaviors, though these observations were not systematic. Abuse has not been reported from the postmarketing experience in countries where tetrabenazine has been marketed.
As with any CNS-active drug, prescribers should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of tetrabenazine misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior).
Abrupt discontinuation of tetrabenazine from patients did not produce symptoms of withdrawal or a discontinuation syndrome; only symptoms of the original disease were observed to re-emerge [see DOSAGE AND ADMINISTRATIONS (2.4)].
Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with tetrabenazine have been reported in the literature. The dose of tetrabenazine in these patients ranged from 100 mg to 1g. Adverse reactions associated with tetrabenazine overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.
Treatment should consist of those general measures employed in the management of overdosage with any 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.
Tetrabenazine is a monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.43; the pKa is 6.51. Tetrabenazine is a hexahydro-dimethoxy-benzoquinolizine derivative and has the following chemical name: cis rac –1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)2H-benzo[a]quinolizin-2-one.
The empirical formula C19 H27 NO3 is represented by the following structural formula:
Each tetrabenazine tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient.
Tetrabenazine tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, corn starch, magnesium stearate, sodium starch glycolate and talc. The 25 mg strength tablet also contains yellow iron oxide as an inactive ingredient.
Tetrabenazine Tablets are supplied as
12.5 mg: White to off-white, round shaped, flat faced tablets with bevelled edges, non-scored, debossed with ‘LU’ one side and ‘L71’ on the other side.
25 mg: Light yellow colored, round shaped, flat faced tablets with bevelled edges, debossed with ‘L’ and ‘U’ separated by scoreline on one side and ‘L72’ on other side.
The precise mechanism by which tetrabenazine exerts its anti-chorea effects is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 (VMAT2) (Ki ≈ 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), a mixture of α-HTBZ and β-HTBZ. α-and β-HTBZ, major circulating metabolites in humans, exhibit high in vitro binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).
The effect of a single 25 or 50 mg dose of tetrabenazine on the QT interval was studied in a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg, tetrabenazine caused an approximately 8 msec mean increase in QTc (90% CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given a single 50 mg dose of tetrabenazine does not further increase the effect on the QTc interval. Effects at higher exposures to either tetrabenazine or its metabolites have not been evaluated [see WARNINGS AND PRECAUTIONS (5.8), DRUG INTERACTIONS (7.5)].
Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing [see WARNINGS AND PRECAUTIONS (5.11)].
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 α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax ) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
The effects of food on the bioavailability of tetrabenazine were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax , or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ [see DOSAGE AND ADMINISTRATION (2.1)].
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