SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Revocon™ 25mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25 mg tetrabenazine.

Each tablet contains 55.50 mg lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Light yellow coloured un-coated, circular, flat bevel edged tablets with break line on one side and SUN debossing on the other side. The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

The tablets are for oral use.

The therapy should be supervised by a doctor experienced in treating hyperkinetic disorders.

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 tetrabenezine 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.

Patients with 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).

Patients with renal impairment

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

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-syndorme    (Parkinsonism)

-    Depression

-    Breast feeding

-    Pheochromocytoma

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

4.4 Special warnings and precautions for use

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

It is known that dose dependant adverse events such as sedation, depression and the occurrence of a hypotkinetic-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.

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

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

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 fluctuantions in blood pressure) and elevated creatinine phosphokinase levels. If Neuroleptic Malignant syndrome is suspected tetrabenazine should be withdrawn immediately and appropriate treatment initiated.

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 arrythmias (see section 4.5).

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 tetrabanazine.

Concomitant use with tricyclic antidepressants, alcohol, CYP2D6 inhibitors, 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 (e.g. gatifloxacin, moxifloxacin) and Class IA and III antiarrythmic medications (e.g. quinidine, procainamide, amiodarone, sotalol).

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies are insufficient with respect to effects on pregnancy, embryofetal development, birth, or development post partum (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.

Breastfeeding

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

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 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: drowsiness (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, constipation

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 hyperthermia

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

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.

4.9    Overdose

Signs and symptoms produced by 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:N07XX06

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.

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 first-pass 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 repeat-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; however, carcinogenicity studies have not been performed.

Studies to investigate the effects on fertility have not been conducted. Tetrabenazine was not embryotoxic or teratogenic in the rabbit; however the observed systemic exposure was lower than that observed clinically. The potential embryotoxic and teratogenic effects were also insufficiently studied in the rat. In a peri/postnatal study in the rat, increased neonatal mortality was observed, the cause of which is unknown.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize Starch Lactose monohydrate Microcrystalline cellulose Purified Talc Magnesium Stearate Colloidal Anhydrous Silica Sodium Starch Glycolate (Type A) Iron oxide yellow E172

6.2 Incompatibilities

Not applicable.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 04/03/2010 Date of latest renewal: 17/04/2013

10 DATE OF REVISION OF THE TEXT

23/01/2014