Monoamine Depleting Agent
Action And Clinical Pharmacology: The central effects of tetrabenazine closely resemble those of reserpine, but it differs from the latter in having less peripheral activity and in being much shorter acting. In laboratory animals, tetrabenazine interferes with vesicular storage of biogenic amines, including dopamine as well as serotonin and norepinephrine; this effect is mainly limited to the brain.
Hydroxytetrabenazine is believed to be the principle active moiety, and it is thought that its clinical activity in movement disorders results from its action on monoamine storage in the brain. The duration of action of tetrabenazine ranges from 16 to 24 hours.
Tetrabenazine also has dopamine antagonistic effects, such as displacing -spiperone from striatal binding sites in vitro, and blocking dopaminergic inhibition of prolactin release in vitro and in vivo.
Pharmacokinetics: Tetrabenazine has a low and erratic bioavailability. It is extensively metabolised by first-pass metabolism. Little to no unchanged tetrabenazine can be detected in the urine. The major metabolite, hydroxytetrabenazine, is formed by reduction. Following i.v. administration of radiolabelled tetrabenazine to humans, the radioactivity decreased to minimal levels within 10 hours and could not be detected 3 days later. Forty percent of total activity was found in the urine within 24 hours and 2.5% in the feces. Fifty four percent of the total activity was excreted after 48 hours.
Indications And Clinical Uses: In the treatment of hyperkinetic movement disorders such as Huntington’s chorea, Hemiballismus, Senile Chorea, Tic and Gille’s de la Tourette Syndrome and Tardive Dyskinesia.
Tetrabenazine is not indicated for the treatment of levodopa-induced dyskinetic/choreiform movements (see Warnings).
Tetrabenazine should only be used by (or in consultation with) physicians who are experienced in the treatment of hyperkinetic movement disorders.
Contra-Indications: Patients with a known hypersensitivity to the drug or to any of the components of the formulation.
Tetrabenazine is contraindicated in patients with a current episode or a history of clinical depression (see Warnings).
Tetrabenazine should not be administered together with a MAO inhibitor. At least 14 days should elapse between the discontinuation of an MAO inhibitor and initiation of treatment with tetrabenazine, as well as between the discontinuation of tetrabenazine and the initiation of treatment with an MAO inhibitor (see Precautions, Drug Interactions).
Manufacturers’ Warnings In Clinical States: Depression: Tetrabenazine may cause depression. Recognition of depression may be difficult because this condition may often be disguised by somatic complaints. The drug should be stopped immediately at the first signs or symptoms of depression. The depression can be profound, and the possibility of suicide should be kept in mind until the depression clears. There is no information on the safety or efficacy of antidepressant drug treatment in tetrabenazine-induced depression.
Parkinsonism: Tetrabenazine can induce symptoms of parkinsonism, which are seen more frequently in the elderly and at relatively low doses. Tetrabenazine dosage should be adjusted as tolerated and needed. Levodopa-induced dyskinetic/choreiform movements should be treated by reducing the dose of levodopa, and not by giving tetrabenazine, since the latter exacerbates parkinsonian symptoms.
Precautions: General: Occupational Hazards: Tetrabenazine may cause drowsiness and orthostatic hypotension. Therefore caution is recommended when driving, operating machinery, or performing other skilled tasks until the effect of tetrabenazine is known.
Pregnancy: Animal reproductive studies have not been performed with tetrabenazine. There is no information on the safety of the drug in human pregnancy. However, tetrabenazine has been used for many years and no cases of malformation have been reported.
Lactation: Limited information indicates that tetrabenazine is excreted in milk, therefore it should be avoided in breast-feeding mothers.
Drug Interactions: Levodopa: Tetrabenazine exacerbates Parkinsonian symptoms, and thereby attenuates the effect of levodopa (see Warnings).
Antidepressants and MAO Inhibitors: Central excitation and possibly hypertension have occurred when tetrabenazine was added to existing therapy with desipramine or MAO inhibitors.
There is no information on the safety and efficacy of antidepressant drugs, including MAO inhibitors, in the treatment of tetrabenazine-induced depression (see Contraindications).
Neuroleptic Agents: There is a potential for severe manifestations of dopamine deficiency, when administering tetrabenazine concomitantly with neuroleptic agents (e.g., haloperidol, chlorpromazine, metoclopramide, etc.).
Adverse Reactions: The most commonly observed adverse reactions with tetrabenazine include, in decreasing order of frequency and observed during clinical use of the drug: signs and symptoms of Parkinsonism; drowsiness, fatigue, weakness; depression; anxiety, nervousness; insomnia; restlessness, akathisia; drooling; irritability, agitation; nausea, vomiting, epigastric pain; confusion, disorientation; hypotension; dizziness.
Although tetrabenazine has been in clinical use for a number of years, controlled clinical trials with the drug are limited.
Symptoms And Treatment Of Overdose: Symptoms Signs and symptoms of overdosage may include drowsiness, sweating, hypotension and hypothermia.
Treatment: Treatment is symptomatic.
Dosage And Administration: General: The initial dose should be low, and dosage should be titrated slowly according to the tolerance and responsiveness of the individual patient.
Adults: An initial starting dose of 12.5 mg 2 to 3 times a day is recommended. This can be increased by 12.5 mg a day every 3 to 5 days until the maximal tolerated and effective dose is reached for the individual, and may have to be up/down titrated depending on individual tolerance. In most cases the maximal tolerated dose will be 25 mg t.i.d. In very rare cases, a 200 mg dose has been reached (the maximum recommended dose in some publications).
If there is no improvement at the maximal tolerated dose in 7 days, it is unlikely that tetrabenazine will be of benefit to the patient, either by increasing the dose or by extending the duration of treatment.
Geriatrics and Debilitated Patients: No adequately controlled clinical studies have been performed in the elderly and/or debilitated patients. Clinical experience suggests that a reduced initial and maintenance dose should be used. Parkinsonian-like adverse reactions are relatively common in these patients and may be dose-limiting.
Children: No adequately controlled clinical studies have been performed in children. Limited clinical experience suggests that treatment should be started at approximately half the adult dose, and titrated slowly and carefully according to tolerance and individual response.
Availability And Storage: Each round, yellowish-buff tablet, with ROCHE imprinted across one face and a single break bar on the other, contains: tetrabenazine 25 mg. Nonmedicinal ingredients: iron oxide, lactose, magnesium stearate, starch maize white and talc. Bottles of 120. Store in well-closed containers. Store at 15 to 30°C.
NITOMAN® Roche Tetrabenazine Monoamine Depleting Agent