XENAZINE Tablet Ref.[51041] Active ingredients: Tetrabenazine

In the treatment of chorea, the dose of tetrabenazine should be titrated to determine the most appropriate dose for each patient. When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is well tolerated. If the adverse effect does not resolve or decrease, consideration should be given to discontinuing tetrabenazine.

In vitro and in vivo studies indicate that the tetrabenazine metabolites α-HTBZ and β-HTBZ are substrates for CYP2D6 (see section 5.2). Therefore dosing requirements may be influenced by a patient’s CYP2D6 metaboliser status and concomitant medications which are strong CYP2D6 inhibitors (see section 4.5).

Once a stable dose has been achieved, treatment should be reassessed periodically in the context of the patient’s underlying condition and their concomitant medications (see section 4.5).

Tardive Dyskinesia

Pre-synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine. Tetrabenazine is a central monoamine depleting agent which can cause extrapyramidal symptoms and theoretically cause tardive dyskinesia in humans.

There have been cases of tardive dyskinesia with tetrabenzine reported in the literature and in post-marketing; therefore, physicians should be aware of the possible risk. If signs and symptoms of tardive dyskinesia appear in a patient treated with tetrabenazine, drug discontinuation should be considered.

Depression/Suicidality

Tetrabenazine may cause depression or worsen pre-existing depression. Cases of suicidal ideation and behaviour have been reported in patients taking the product. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation.

Patients should be closely monitored for the emergence of such adverse events, and patients and their caregivers should be informed of the risks and instructed to report any concerns to their doctor immediately.

If depression or suicidal ideation occurs, it may be controlled by reducing the dose of tetrabenazine and/or initiating antidepressant therapy. If depression or suicidal ideation is profound, or persists, discontinuation of tetrabenazine and initiation of antidepressant therapy should be considered.

MAOI antidepressants should not be used until at least two weeks have elapsed since the last tetrabenazine dose to avoid a potentially serious drug interaction (see section 4.3, 4.5 and 4.8).

Anger and Aggression

There is a potential risk of anger and aggressive behavior occurring or worsening in patients taking tetrabenazine with a history of depression or other psychiatric illnesses.

Parkinsonism

Tetrabenazine can induce parkinsonism and exacerbate pre-existing symptoms of Parkinson’s disease. The tetrabenazine dose should be adjusted as clinically indicated to minimise this side effect.

Dysphagia

Dysphagia is a component of Huntington’s disease. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pheumonia. In clinical trials, some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine and other drugs that reduce dopaminergic transmission. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure.

The management of NMS should include (1) immediate discontinuation of tetrabenazine and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for NMS.

If the patient requires treatment with tetrabenazine after recovery from NMS, the potential reintroduction of therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

QTc Prolongation

Tetrabenazine causes a small increase (up to 8 msec) in the corrected QT interval.

Tetrabenazine should be used with caution in combination with other drugs known to prolong QTc and in patients with congenital long QT syndromes and a history of cardiac arrythmias (see section 4.5).

Cardiac Disease

Tetrabenazine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

Akathisia, Restlessness, and Agitation

Patients taking tetrabenazine should be monitored for the presence of akathisia. Patients taking tetrabenazine should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine dose should be reduced; however, some patients may require discontinuation of therapy.

Orthostatic Hypotension

Tetrabenazine can induce postural dizziness. Patients who are vulnerable to hypotension should be closely monitored in the initial stages of therapy.

Hyperprolactinemia

Tetrabenazine elevates serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if tetrabenazine is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia and impotence can be caused by elevated serum concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown.

Chronic increase in serum prolactin levels (although not evaluated in the tetrabenazine development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of tetrabenazine.

Drug-Disease Interactions

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malsorption should not take this medicine.

Binding to Melanin-Containing Tissues

Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. The clinical relevance of tetrabenazine’s binding to melanin-containing tissues is unknown.

Although there are no specific recommendations for periodic ophthalmic monitoring, prescribers should be aware of the possibility of ophthalmologic effects after long term exposure.

Laboratory Tests

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

Paediatric Population

The safety and efficacy of tetrabenazine in children have not been established.

Use in the Elderly

The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.

Levodopa

Tetrabenazine inhibits the action of levodopa and thereby attenuates its effect.

Monoamine Oxidase Inhibitors

Tetrabenazine should not be administered in the presence of MAOIs because of the risk of possible serious interactions resulting in hypertensive crisis (see sections 4.3 Contraindications and 4.8 Undesirable Effects). At least 14 days should elapse between the discontinuation of a MAOI and initiation of treatment with tetrabenazine.

Concomitant Use of Neuroleptic Drugs

Adverse reactions associated with tetrabenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists. There is a potential for significant dopamine depletion when administering tetrabenazine concomitantly with neuroleptic agents (e.g., haloperidol, chlorpromazine, metoclopramide, etc.) and patients should be monitored clinically for the development of parkinsonism.

Antihypertensive Drugs and Beta-Blockers

The concurrent use of tetrabenazine with anti-hypertensive drugs and beta-blockers may increase the risk of orthostatic hypotension.

Interaction with CNS Depressants

The possibility of additive sedative effects should be considered when tetrabenazine is used in conjunction with CNS depressants (including alcohol, neuroleptics, hypnotics, and opioids).

Patients Taking CYP2D6 Inhibitors

In vitro and in vivo studies indicate that the tetrabenazine metabolites 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 approximately 30% increase in C_max 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, C_max 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 β-HTBZ was approximately 14 hours when tetrabenazine was given with paroxetine. Caution should be used when adding a strong CYP2D6 inhibitor (such as fluoxetine, paroxetine or quinidine) to a patient already receiving a stable dose of tetrabenazine and a reduction in the dose of tetrabenazine should be considered. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline has not been evaluated.

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.

Medicines known to Prolong QTc

Tetrabenazine should be used with caution with drugs known to prolong QTc including antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin) and Class IA and III antiarrythmic medications (e.g., quinidine, procainamide, amiodarone, sotalol).

Digoxin

Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that tetrabenazine (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors.

Paediatric Population

Interaction studies have only been performed in adults.

Pregnancy

There are no adequate and well controlled studies for the use of tetrabenazine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tetrabenazine is not recommended during pregnancy and in women of childbearing potential not using contraception. The effect of tetrabenazine on labour and delivery in humans is unknown.

Lactation

It is unknown whether tetrabenazine or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Tetrabenazine is contraindicated during breast-feeding (see section 4.3).

Fertility

In animal studies with tetrabenazine there was no evidence of effect on pregnancy or in utero survival. Female cycle lengths were increased and a delay in fertility was seen (see section 5.3).

Patients should be advised that Xenazine 25 may cause drowsiness and therefore may modify their performance at skilled tasks (driving ability, operation of machinery, etc.) to a varying degree, depending on dose and individual susceptibility.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Not applicable.