Tetrabenazine 25 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tetrabenazine 25 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25 mg Tetrabenazine.
Each tablet contains 60.8 mg lactose.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Yellow, round, with a break line on one-side and 'TE25' engraved on the reverse side.
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
The tablets are for oral use. The therapy should be supervised by a doctor experienced in treating hyperkinetic disorders.
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 occurence 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.
Children
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
- 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)
- Depression
- Breast feeding
- Pheochromocytoma
- Pro-lactin-dependent 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 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.
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 fluctuations 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 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 (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.
Lactation
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 Uncommon: 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
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: 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.
6.1 List of excipients
Pregelatinised maize starch Lactose monohydrate Talc
Iron oxide yellow E172 Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
This medicinal product does not require any special temperature storage conditions.
6.5 Nature and contents of container
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
No special requirements
7 MARKETING AUTHORISATION HOLDER
AOP Orphan Pharmaceuticals AG Wilhelminenstrasse 91/II f 1160 Wien Austria
8 MARKETING AUTHORISATION NUMBER(S)
PL 21344/0015
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/07/2010
10 DATE OF REVISION OF THE TEXT
17/03/2016