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During its development, tetrabenazine was administered to 773 unique subjects and patients. The conditions and duration of exposure to tetrabenazine varied greatly, and included single and multiple dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n= 84) in patients.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of adverse effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

In a randomized, 12-week, placebo-controlled clinical trial of HD subjects, adverse events (AEs) were more common in the tetrabenazine group than in the placebo group. Forty-nine of 54 (91%) patients who received XENAZINE experienced one or more AEs at any time during the study. The AEs most commonly reported (over 10%, and at least 5% greater than placebo) were sedation/somnolence (31% vs. 3% on placebo), fatigue (22% vs. 13% on placebo), insomnia (22% vs. 0% on placebo), depression (19% vs. 0% on placebo), akathisia (19% vs. 0% on placebo), and nausea (13% vs. 7% on placebo). The number and percentage of the most commonly reported AEs that occurred at any time during the study in ≥ 4% of tetrabenazine-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1 in decreasing order of frequency within body systems for the tetrabenazine group.

Table 1: Treatment Emergent Adverse Events in Patients Treated with Tetrabenazine and with a Greater Frequency than Placebo in the 12-Week, Double-Blind, Placebo-Controlled Trial of XENAZINE

Dose titration was discontinued or dosage of study drug was reduced because of one or more AEs in 28 of 54 (52%) patients randomized to tetrabenazine. These AEs consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one AE and are therefore counted more than once.

The following table describes the incidence of events considered to be extrapyramidal adverse reactions.

Table 2: Treatment Emergent Extrapyramidal Symptoms in Patients Treated with Tetrabenazine and with a Greater Frequency than Placebo in the 12-Week, Double-Blind, Placebo-Controlled Trial of XENAZINE

Laboratory Tests

No clinically significant changes in laboratory parameters were reported in clinical trials with XENAZINE. In controlled clinical trials, XENAZINE caused a small mean increase in ALT and AST laboratory values as compared to placebo.

Vital Signs

In controlled clinical trials, tetrabenazine did not affect blood pressure, pulse, and body weight. Orthostatic blood pressure was not consistently measured in the XENAZINE clinical trials.

Drug Abuse And Dependence

Controlled Substance Class

Tetrabenazine is not a controlled substance.

Physical and Psychological Dependence

Clinical trials did not reveal any tendency for drug seeking behavior, though these observations were not systematic. Abuse has not been reported from the postmarketing experience in countries where tetrabenazine has been marketed. 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. As with any CNS-active drug, physicians 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, incrementation of dose, drug-seeking behavior).

CYP2D6 inhibitors: In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of tetrabenazine and its metabolites was studied in 25 healthy subjects following a single 50 mg dose of tetrabenazine given after 10 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. There was an approximately 30% increase in Cmax and an approximately 3-fold increase in AUC for α-HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine given alone. For β-HTBZ, the Cmax and AUC were increased 2.4- and 9-fold, respectively, in subjects given paroxetine prior to tetrabenazine given alone. The elimination half-life of α-HTBZ and βHTBZ was approximately 14 hours when tetrabenazine was given with paroxetine. Caution should be used when giving any strong CYP2D6 inhibitor (such as fluoxetine, paroxetine, quinidine) to a patient already receiving a stable dose of tetrabenazine and the daily dose of tetrabenazine should be halved (see DOSAGE AND ADMINISTRATION). The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline has not been evaluated. (See DOSAGE AND ADMINISTRATION)

Other Cytochrome P450 inhibitors: Based on in vitro studies, a clinically significant interaction between tetrabenazine and other P450 inhibitors (other than CYP2D6 inhibitors) is not likely. (See CLINICAL PHARMACOLOGY)

Reserpine: Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Caution should therefore be used when switching a patient from reserpine to XENAZINE. The physician should wait for chorea to re-emerge before administering XENAZINE to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting XENAZINE. XENAZINE and reserpine should not be used concomitantly (see CONTRAINDICATIONS).

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