This information is intended for use by health professionals

1. Name of the medicinal product

Tetrabenazine 12.5 mg tablets

Tetrabenazine 25 mg tablets

2. Qualitative and quantitative composition

Each tablet contains 12.5 mg tetrabenazine.

Each tablet contains 25 mg tetrabenazine.

Excipient with known effect:

12.5 mg: Each tablet contains 42.750 mg lactose.

25 mg: Each tablet contains 85.300 mg of lactose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

12.5 mg tablet: White to off-white, circular, flat faced bevelled edge uncoated tablet with “1” on one side and plain on the other site. The tablet has a diameter of 5 mm and a thickness of 2.3 mm to 2.7 mm.

25 mg tablets: Yellow, circular, flat faced bevelled edge uncoated tablet debossed with “179” on one side and scored on the other side. The tablet has a diameter of 7 mm and a thickness of 2.3 mm to 2.7 mm).

The tablet can be divided into equal halves.

4. Clinical particulars
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

In patients with mild and moderate hepatic impairment half the initial dose and a slower up-titration of the dose is recommended. Patients with severe hepatic impairment have not been studied, therefore additional caution is advised in these patients (see also section 4.4 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

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

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.

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

Depression

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.

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 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).

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 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

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).

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

4.5 Interaction with other medicinal products and other forms of interaction

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

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.

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, terbinafine, moclobemide and quinidine) may result in increased plasma concentrations of the active metabolite dihydrotetrabenazine, 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 (eg gatifloxacin, moxifloxacin) and Class IA and III antiarrythmic medications (eg quinidine, procainamide, amiodarone, sotalol).

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

Psychiatric disorders

Very common

Depression

Common

Anxiety, insomnia, confusion

Not known

Disorientation, nervousness

Metabolism and nutrition disorders

Not known

Increased appetite

Nervous system disorders

Very common

Drowsiness (with higher dosages), Parkinson-like syndrome (with higher dosages)

Uncommon

Altered levels of consciousness

Rare

Neuroleptic malignant syndrome (NMS) (see section 4.4)

Not known

Ataxia, akathisia, dystonia, dizziness, amnesia

Vascular disorders

Common

Hypotension

Not known

Bradycardia, epigastric pain, dry mouth

Gastro-intestinal disorders

Common

Dysphagia, nausea, vomiting, diarrhoea, constipation

Musculoskeletal and connective tissue disorders

Uncommon

Severe extrapyramidal symptoms including muscular rigidity, autonomic dysfuntion

Very rare

Skeletal muscle damage

General disorders and administration site conditions

Uncommon

Hyperhermia

Investigations

Not known

Weight increase

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 drowsiness, sweating, hypotension and hypothermia.

Treatment is symptomatic.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC Code: NO7XX06

The central effects of tetrabenazine closely resemble those of reserpine, but it differs from the latter in having less peripheral activity and being much shorter acting.

Mechanism of action

Animal studies have shown that tetrabenazine disturbs the metabolism of biogenic amines, for instance that of serotonin and noradrenaline, and that this activity is limited to the brain. The supposition is that this effect of tetrabenazine on amines in the brain explains the clinical effects in the brain.

Tetrabenazine inhibits the re-uptake of monoamines in the neuroterminal of the presynaptic neurons of the central nervous system. This results in a depletion of monoamines, including dopamine. Dopamine depletion results in hypokinesis leading to a reduction in chorea severity.

Tetrabenazine inhibits the re-uptake of monoamines in synaptic nerve terminals by a reversible and short-term binding to the vesicular monoamine transporter (VMAT). VMAT2 transports monoamines especially in peripheral and central neurons, while VMAT1 regulates the transport in peripheral chromaffine tissues. Tetrabenazine has a higher affinity for VMAT2 than for VMAT1. Thus, tetrabenazine has a short, hardly peripheral effect.

5.2 Pharmacokinetic properties

Tetrabenazine has a low and erratic bioavailability. It appears to be extensively metabolised by firstpass metabolism. The major metabolite, hydroxytetrabenazine, is formed by reduction. Little unchanged tetrabenazine can be detected in the urine. Since hydroxytetrabenazine is reported to be as active as tetrabenazine in depleting brain amines, it is likely that this is the major therapeutic agent.

Special populations

Hepatic impairment

Mild and moderate hepatic impairment increases the exposure and prolongs the half-lives of tetrabenazine and hydroxytetrabenazine (4 patients with Child Pugh score 5-6 and 1 patient with Child Pugh score 9.) Severe hepatic impairment has not been studied.

5.3 Preclinical safety data

In repeated dose toxicity studies, the effects observed with orally administered tetrabenazine were related to depletion of central stores of monoamines. Common symptoms were hypoactivity, lethargy, strabismus, or closed eyes. Primarily pharmacological effects such as sedation were observed and considered dose limiting.

The genotoxic potential of tetrabenazine has been studied using a series of conventional tests. In vitro, tetrabenazine was negative for point mutations and positive for chromosomal aberrations in Chinese hamster ovary cells, at cytotoxic concentrations only. Tetrabenazine was not genotoxic in an in vivo chromosomal aberration test.

Tetrabenazine did not reveal any carcinogenic potential when administered for 26 weeks in the transgenic p53 heterozygous mouse model at doses up to 30 mg/kg/day and in a limited study in male rats tetrabenazine was noncarcinogenic when administered for 94 weeks at doses up to 12 mg/kg/day.

In a fertility and early embryonic development study at systemic exposures below those observed clinically there was no evidence of effect on pregnancy or in utero survival in rats. Length of the estrous cycle was increased and a delay in fertility was seen in female rats. Reproduction was unaffected in male rats.

In embryo-fetal developmental toxicity studies there was no evidence of embryotoxicity or teratogenicity in either rats or rabbits. In a perinatal and postnatal study in rats, neonatal deaths and delayed pup maturation were observed at systemic exposures below those observed clinically. These effects could either be indirect effects due to inadequate maternal care or a direct effect of tetrabenazine on the pups.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose, anhydrous

Maize starch

Sodium starch glycolate

Talc

Silica, colloidal anhydrous

Magnesium stearate

25 mg tablets: Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Tetrabenazine is packed in a white round high-density polyethylene (HDPE) tablet container with a child resistant, tamper-evident polypropylene (PP) screw cap with mounted desiccant, containing 112 tablets.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing authorisation number(s)

PL 31750/0063 (12.5 mg)

PL 31750/0064 (25 mg)

9. Date of first authorisation/renewal of the authorisation

25/08/2016

10. Date of revision of the text

05/06/2018