TARDIBEN Tablet Ref.[8565] Active ingredients:

The dose of tetrabenazine should be titrated to determine the most appropriate dose for each patient.

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).

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.

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).

Tetrabenazine is a central monoamine depleting agent which can cause extrapyramidal symptoms and theoretically cause tardive dyskinesia in humans.

Parkinsonism

Tetrabenazine can induce parkinsonism and exacerbate pre-existing symptoms of Parkinson’s disease. In such a case, the dose should be reduced and discontinuation of tetrabenazine be considered if the event does not resolve.

Sedation and Somnolence

Sedation is the most common dose-limiting adverse effect of tetrabenazine. Patients should be cautioned about performing activity requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine and know how the drug affects them.

Neuroleptic Malignant Syndrome

A Neuroleptic Malignant Syndrome has been described under the use of tetrabenazine and after abrupt withdrawal.

Neuroleptic Malignant Syndrome is a rare complication of tetrabenazine therapy. Neuroleptic Malignant Syndrome most often occurs early in treatment, in response to changes in dose or after prolonged treatment. The main symptoms of this condition are mental changes, rigidity, hyperthermia, autonomic dysfunction (sweating and fluctuations in blood pressure) and elevated creatinine phosphokinase levels. If Neuroleptic Malignant Syndrome is suspected tetrabenazine should be withdrawn immediately and appropriate treatment initiated.

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 arrhythmias (see section 4.5).

Depression/Suicidality

Tetrabenazine may cause depression or worsen pre-existing depression. Cases of suicidal ideation and behaviour have been reported in patients taking this product. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation (see also section 4.3). 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.

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

MAO-inhibitors are contraindicated (see section 4.3) and should be stopped 14 days before the treatment with tetrabenazine starts.

Akathisia, Restlessness, and Agitation

Patients taking tetrabenazine should be monitored for the presence of extrapyramidal symptoms and akathisia and also 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. Some patients may require discontinuation of therapy.

Orthostatic Hypotension

Tetrabenazine may induce postural hypotension at therapeutic doses. This should be considered in patients who may be vulnerable to hypotension or its effects. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.

Hyperprolactinemia

Tetrabenazine elevates serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, maximum 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 hyperprolactinaemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of tetrabenazine.

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.

Hepatic Insufficiency

Tardiben should be used with caution in patients with hepatic impairment (see section 4.2).

Drug-Disease Interactions, Lactose intolerance

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

Paediatric Population

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

Tetrabenazine should not be used concomitantly with reserpine, MAO inhibitors.

Levodopa should be administered with caution in the presence of Tardiben.

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

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. Neuroleptic malignant syndrome has been observed in isolated cases.

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

No interaction studies with tetrabenazine have been performed in vivo, and metabolising enzymes are partly unknown. In vitro studies indicate that tetrabenazine may be a CYP2D6 inhibitor and therefore cause increased plasma concentrations of medicinal products metabolised by CYP2D6.

In vitro and in vivo studies indicate that the tetrabenazine metabolites α-HTBZ and β-HTBZ are substrates for CYP2D6. Inhibitors of CYP2D6 (e.g. fluoxetine, paroxetine, terbinafine, moclobemide and quinidine) may result in increased plasma concentrations of the active metabolites α-HTBZ and β-HTBZ, why they should only be combined with caution. A reduction of the tetrabenazine dose may be necessary.

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 antiarrhythmic medications (e.g. quinidine, procainamide, amiodarone, sotalol).

Pregnancy

Animal studies are insufficient with respect to effects on pregnancy, embryofetal development, birth, or development postpartum (see section 5.3). There are no adequate data from the use of tetrabenazine in pregnant women and the potential risk for humans is unknown. Tetrabenazine should not be used during pregnancy unless no other treatment is available.

Lactation

Tetrabenazine is contraindicated during lactation (see section 4.3). Breast-feeding must be stopped, if treatment with tetrabenazine is necessary.

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 tetrabenazine may cause somnolence 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.

The following undesirable effects are ranked according to system organ class and to their frequency:

Very common (≥ 1/10)
Common (≥1/100 to < 1/10)
Uncommon (≥1/1,000 to < 1/100)
Rare (≥ 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)

Psychiatric disorders

Very common: depression

Common: anxiety, insomnia, confusion

Nervous system disorders

Very common: somnolence (with higher dosages), Parkinson-like syndrome (with higher dosages)

Uncommon: altered levels of consciousness

Rare: Neuroleptic Malignant Syndrome (NMS) (see section 4.4)

Vascular disorders

Common: hypotension

Gastrointestinal disorders

Common: dysphagia, nausea, vomiting, diarrhoea, obstipation

Musculoskeletal and connective tissue disorders

Uncommon: severe extrapyramidal symptoms including muscular rigidity, autonomic dysfunction

Very rare: skeletal muscle damage

General disorders and administration site conditions

Uncommon: hypothermia

For the following side-effects, it is not possible to estimate the incidence from available data:

Psychiatric disorders: disorientation, nervousness

Nervous system disorders: ataxia, akathisia, dystonia, dizziness, amnesia

Vascular disorders: bradycardia, epigastric pain, dry mouth, orthostatic hypotension

Reproductive system and breast disorders: irregular menstrual cycle

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.

Not applicable.