Pharmacy & Therapeutics - December 2008 - (Page 692)

DRUG FORECAST pairment (Child–Pugh scores of 5 to 9) and 12 patients with normal hepatic function were given a single 25-mg dose of tetrabenazine.6 Plasma concentrations of tetrabenazine in patients with hepatic impairment were similar to or higher than the concentrations of alpha-HTBZ, indicating a decreased metabolism of the parent compound into the active metabolite. The mean tetrabenazine Cmax was approximately seven-fold to 190-fold higher in hepatically impaired patients than in healthy patients.6 The elimination halflife of tetrabenazine was increased to 17.5 hours in this group, as were the half-lives of alpha-HTBZ (10 hours) and beta-HTBZ (eight hours). Exposure to alpha-HTBZ and beta-HTBZ was approximately 30% to 39% greater in patients with hepatic impairment, compared with the healthy group.6 Because the safety and efficacy of this increase in exposure is unknown, it is not possible to adjust the dosage to ensure safe use of the drug. Therefore, tetrabenazine is contraindicated in hepatically impaired patients.6 Renally impaired patients. The effects of renal impairment on the elimination of tetrabenazine have not been evaluated in controlled studies. Pregnant and lactating women. Tetrabenazine does cross the placenta, even though teratogenicity has not been reported.13 No adequate, well-controlled studies have been performed in pregnant women, and tetrabenazine is therefore currently classified as a Pregnancy Category C drug. The medication is also excreted in breast milk; therefore, women taking tetrabenazine should avoid breastfeeding.13 Pediatric populations. No controlled studies with tetrabenazine for HD have been performed in these patients. pine to tetrabenazine, at least 20 days should lapse between the discontinuation of reserpine and the start of tetrabenazine.6 Proper dosing involves careful titration of therapy to determine the optimal dose for each patient. Before patients are given a daily dose exceeding 50 mg, they should be tested for CYP 2D6 gene polymorphisms to determine their type of metab olism so that the dose can be adjusted accordingly.6 Because tetrabenazine reduces dopamine transmission, there is a potential for the development of neuroleptic malignant syndrome (NMS). Clinicians should be alert to any possible symptoms related to this syndrome. Tetrabenazine should not be taken with alcohol, because the drug increases sedation and affects liver function.6 Tetrabenazine causes a small increase of approximately 8 milliseconds in the corrected QT (QTc) interval. Caution should therefore be used when this agent is combined with others that also increase the QTc interval.6 DRUG INTERACTIONS The CYP 2D6 isoenzyme is the major enzyme involved in the metabolism of tetrabenazine. Prescribers must use caution when giving any strong CYP 2D6 inhibitor, such as fluoxetine (Prozac, Eli Lilly), paroxetine (Paxil, GlaxoSmithKline), or quinidine, to patients receiving a stable dose of tetrabenazine. If this is the case, the dosage of tetrabenazine should be decreased by half. The effect of moderate or weak CYP 2D6 inhibitors has not been evaluated.6 Reserpine is an irreversible inhibitor of VMAT-2 and has a long duration of action. When switching a patient from reserpine to tetrabenazine, the physician should wait until chorea re-emerges before commencing treatment with tetrabenazine to avoid overdosage or major depletion of serotonin and norepinephrine. There should be an interval of at least 20 days between stopping reserpine and initiating tetrabenazine.6 CLINICAL EFFICACY Kenney et al.17 Kenney and colleagues observed the short-term effects of tetrabenazine on chorea in patients with HD. Ten patients, with ages ranging from 35 to 71, were included in the study. They met clinical criteria for HD and were disabled enough by chorea to justify an intervention with medication. Patients also displayed 40 or more CAG repeats in the huntingtin gene. Stable tetrabenazine dosing was also a requirement for inclusion in the study. Patients took their last dose of tetrabenazine the evening before participating in the study. At least 12 hours had to elapse between the last dose and the baseline assessment. One rater completed all evaluations, which consisted of the motor portion of the Unified Huntington’s Disease Rating Scale (UHDRS) and the Beck Depression Inventor y (BDI). All patients then took their regularly scheduled morning dose and underwent an assessment of UHDRS motor scores every 90 to 150 minutes. At least four assessments were completed before re-emergence of the baseline chorea indicated that the benefit of tetrabenazine was wearing off. This duration of effect was established as being the time needed for the chorea score on the UHDRS to reach the baseline value. ADVERSE DRUG EFFECTS Known risks with tetrabenazine include suicidality, depression, and NMS. Tetrabenazine carries a black-box warning because of an increase in depression and suicidality, and clinicians must carefully weigh the risks along with the need for choreiform movement control.6 In a controlled trial in HD, 19% of 54 patients receiving tetrabenazine experienced depression compared with none of the patients in the placebo group. In addition, one patient committed suicide and one patient had suicidal ideation, with no incidence of these effects in the placebo group.6,16 Other risks include akathisia and parkinsonism. Tardive dyskinesia is also a theoretical risk because of the presynaptic depletion of dopamine, although no cases have been reported with tetrabenazine or reserpine.6 Adverse events leading to discontinuation of titration or reduction in the dose of study dr ug consisted of sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%).6 The most commonly repor ted adverse ef fects include sedation and somnolence, insomnia, depression, anxiety, akathisia, nausea, and fatigue.6,16 INDICATION Tetrabenazine is indicated for the treatment of chorea associated with HD. CONTRAINDICATIONS AND PRECAUTIONS Tetrabenazine should not be prescribed for patients who are actively suicidal, for patients with untreated or inadequately treated depression, or for patients with hepatic impairment. It should not be used in conjunction with monoamine oxidase inhibitors or reserpine. If a patient is switching from reser- 692 P&T® • December 2008 • Vol. 33 No. 12

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Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

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