4.1. Therapeutic indications

Tetrabenazine is indicated for hyperkinetic motor disorders with Huntington's chorea.

4.2. Posology and method of administration

Posology

Adults

Huntington's chorea

Dosage and administration are individual in each patient and therefore only a guide is given.

An initial starting dose of 12.5 mg/day one to three times a day is recommended. This can be increased every three or four days by 12.5 mg until the optimal effect is observed or up to the occurrence of intolerance effects (sedation, Parkinsonism, depression).

The maximum daily dose is 200 mg a day.

If there is no improvement at the maximum dose in seven days, it is unlikely that the compound will be of benefit to the patient, either by increasing the dose or by extending the duration of treatment.

Elderly

No specific studies have been performed in the elderly, but tetrabenazine has been administered to elderly patients in standard dosage without apparent ill effect. Parkinson-like adverse reactions are quite common in these patients and could be dose-limiting.

Paediatric population

No adequate controlled studies have been performed in children. The treatment is not recommended in children.

Hepatic impairment

Tetrabenazine is contraindicated in patients with hepatic impairment, Child Pugh 5 to 9 (see also sections 4.3 and 5.2).

Renal impairment

No studies have been performed in patients with renal impairment. Caution is advised in the treatment of these patients.

Method of administration

The tablets are for oral administration. The therapy should be supervised by a doctor experienced in treating hyperkinetic disorders.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Tetrabenazine can block the action of reserpine. Thus these substances should not be taken concomitantly.

Use of monoamine oxidase inhibitors- tetrabenazine should not be administered within two weeks after treatment with MAOIs

Presence of a hypokinetic-rigid-syndrome (Parkinsonism)

Untreated or inadequately treated depression. Patients who are actively suicidal.

Breast feeding

Pheochromocytoma

Pro-lactin-dependent tumours, e.g. pituitary or breast cancer

Patients with liver failure, with a Child-Pugh scale of 5 to 9

Concomitant use with reserpine (see section 4.5)

4.4. Special warnings and precautions for use

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).

It is known that dose dependent adverse events such as sedation, depression and the occurrence of a hypokinetic-rigid-syndrome (Parkinsonism) are possible. In such a case, the dose should be reduced and discontinuation of tetrabenazine be considered if events do not resolve.

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 (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 suicidal ideation is profound, or persists, discontinuation of tetrabenazine and initiation of antidepressant therapy should be considered.

MAOI antidepressants are contraindicated and should be stopped 14 days before the treatment with tetrabenazine starts, and should not be used until at least 14 days have elapsed after the treatment with tetrabenazine has ended, to avoid a potentially serious drug interaction (see 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.

Tardive dyskinesia

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

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a rare complication of tetrabenazine therapy.

Neuroleptic malignant syndrome most often occurs early in treatment or in response to changes in dose or after prolonged treatment, and has also been described after abrupt withdrawal.

The main symptoms of this condition are mental changes, rigidity, hyperthermia, autonomic dysfunction (sweating and irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure.

If NMS is suspected tetrabenazine should be withdrawn immediately and appropriate treatment initiated.

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

Tetrabenazine causes a small increase (up to 8msec) 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).

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 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; however, some patients may require discontinuation of therapy.

Sedation and somnolence

Sedation is the most common dose-limiting adverse effect of tetrabenazine. Patients should be cautioned about performing activities 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.

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, 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.

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 have been reported in trials with tetrabenazine. In controlled trials, tetrabenazine caused a small mean increase in ALT and AST laboratory values as compared to placebo.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Tetrabenazine should not be used concomitantly with MAO inhibitors. At least 14 days should elapse between the discontinuation of a MAOI and initiation of treatment with tetrabenazine.

Reserpine

Concomitant use of tetrabenazine and reserpine is contraindicated (see section 4.3). 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 tetrabenazine. The physician should wait for chorea to re-emerge before administering tetrabenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. Since the effects of reserpine can be prolonged, clinical judgment and caution should be used regarding time to discontinuation before starting tetrabenazine.

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

Concomitant use with tricyclic antidepressants, alcohol, opioids, beta blocking agents, antihypertensive drugs, hypnotics and neuroleptics is not recommended.

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.

Concomitant use of tetrabenazine with antihypertensive drugs and beta-blockers may increase the risk of orthostatic hypotension.

Digoxin

Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that tetrabenazine (25 mg twice daily for 3days) 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.

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.

Inhibitors of CYP2D6 (e.g. fluoxetine, paroxetine, duloxetine, terbinafine, moclobemide, quinidine, amiodarone, or sertraline) may result in increased plasma concentrations of the active metabolite dihydrotetrabenazine, hence they should only be combined with caution. A reduction of the tetrabenazine dose may be necessary.

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.

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).

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).

4.6. Fertility, pregnancy and lactation

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 should not be used during pregnancy unless no other treatment is available. The effect of tetrabenazine on labour and delivery in humans is unknown.

Breastfeeding

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). 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).

4.7. Effects on ability to drive and use machines

Patients should be advised that tetrabenazine 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.

4.8. Undesirable effects

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

Very common (≥1/10)

Common (≥1/100 and <1/10)

Uncommon (≥1/1000 and <1/100)

Rare (≥1/10,000 and <1/1000)

Very rare (<1/10,000)

Not known (it is not possible to estimate the incidence from available data).

System/Organ categories

Frequency

Event

Infections and infestations

Very rare

Pneumonia

Blood & lymphatic system disorders

Very rare

Leukopaenia

Psychiatric disorders

Very common

Depression

Common

Anxiety, insomnia, confusion, agitation

Very rare

Anger, aggression, suicidal ideation, suicide attempt

Not known

Disorientation, nervousness, restlessness, sleep disorders

Metabolism and nutrition disorders

Common

Decreased appetite

Very rare

Dehydration

Not known

Increased appetite

Nervous system disorders

Very common

Drowsiness (with higher dosages), Parkinson-like syndrome (with higher dosages), tremor, excessive salivation

Uncommon

Altered levels of consciousness

Rare

Neuroleptic malignant syndrome (see section 4.4)

Not known

Ataxia, akathisia, dystonia, dizziness, amnesia

Eye disorders

Very rare

Oculogyric crisis, photophobia

Cardiac disorders

Not known

Bradycardia

Vascular disorders

Common

Postural hypotension

Not known

Hypertensive crisis

Gastro-intestinal disorders

Common

Dysphagia, nausea, vomiting, diarrhoea, constipation, epigastric pain, dry mouth

Skin and subcutaneous tissue disorders

Very rare

Rash, pruritus, urticaria

Not Known

Hyperhidrosis

Musculoskeletal and connective tissue disorders

Uncommon

Severe extrapyramidal symptoms including muscular rigidity, autonomic dysfunction

Very rare

Skeletal muscle damage

Reproductive system and breast disorders

Not known

Irregular menstrual cycle

General disorders and administration site conditions

Uncommon

Hyperthermia

Not known

Fatigue, weakness, hypothermia

Investigations

Very rare

Weight loss

Not known

Weight increase

Injury, poisoning and procedural complications

Very rare

Falls

Rarely, a neuroleptic malignant syndrome (NMS) has been described in association with tetrabenazine treatment (see section 4.4). This may occur soon after initiation of therapy, following changes in dosage or after prolonged treatment. The main symptoms are altered mental status, muscle rigidity, hyperthermia, autonomic dysfunction, elevated levels of creatinine phosphokinase. If NMS is suspected, treatment with tetrabenazine should be discontinued immediately and appropriate supportive treatment instituted (see section 4.4).

To avoid the risk of potentially serious interactions that may occur in the form of hypertensive crisis, at least 14 days should elapse between discontinuation of treatment with an MAOI and initiation of treatment with tetrabenazine, as well as between discontinuation of treatment with tetrabenazine and initiation of treatment with the MAOI.

Cardiac abnormalities including QT prolongation and ventricular arrhythmias (including ventricular tachycardia and ventricular fibrillation) leading to cardiac arrest or sudden unexplained death have been reported during treatment with neuroleptics.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms of overdosage may include acute dystonia, oculogyric crisis, nausea, vomiting, diarrhoea, sweating, hypotension, confusion, hallucinations, hypothermia, sedation, rubor and tremor.

Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control centre on the treatment of any overdose.