This information is intended for use by health professionals

1. Name of the medicinal product

Tardiben 25 mg tablets

2. Qualitative and quantitative composition

Each tablet contains 25 mg Tetrabenazine.

Excipient with known effect

Each tablet contains 64.05 mg lactose monohydrate corresponding to 60.8 mg lactose (see section 4.4).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet.

Yellow, 7.0 x 2.8 mm round, with one-side break notch.

The tablet can be divided into equal halves.

4. Clinical particulars
4.1 Therapeutic indications

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

Tardiben is also indicated for the treatment of moderate to severe tardive dyskinesia, which is disabling and/or socially embarrassing, if

- the condition persists despite withdrawal of antipsychotic therapy

- withdrawal of antipsychotic medication is not a realistic option

- the condition persists despite a reduction in dosage of antipsychotic medication or

- the condition persists despite switching to atypical antipsychotic medication

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 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.

Tardive Dyskinesia

Recommended starting dose of 12.5 mg a day, subsequently titrated according to response. Medication should be discontinued if there is no clear benefit or if the side-effects cannot be tolerated.

Elderly population

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

The safety and efficacy in children have not yet been established. No data are available.

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-syndrome (Parkinsonism).

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

- Breast feeding.

- Pheochromocytoma.

- Prolactin-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).

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.

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 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).

4.6 Fertility, pregnancy and lactation

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).

4.7 Effects on ability to drive and use machines

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.

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:

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.

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other nervous system drugs, ATC code: N07XX06

Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system.

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

Absorption/Distribution

Tetrabenazine is quickly and completely absorbed after oral administration. Its absorption is not affected by the intake of food.

Clinical testing has shown that a single dose of tetrabenazine undergoes extensive absorption (≥75%) from the gastro-intestinal tract.

Plasma levels of tetrabenazine decline rapidly, with a half-life of 1.9 hours.

Biotransformation

Tetrabenazine has a low and erratic bioavailability (4.9% to 6%). It appears to be extensively metabolised by first-pass metabolism. Major metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (ß-HTBZ) are formed by reduction.

Primary metabolites α-HTBZ and ß-HTBZ are mainly metabolised by cytochrome P450 2D6 liver enzyme. CYP2D6 inhibitors may increase the plasma concentration of these metabolites.

Elimination

Tetrabenazine is mostly eliminated in metabolised form in urine (only 2.1% of tetrabenazine is excreted unchanged in the urine).

Linearity

After administration of single doses from 12.5 to 50 mg mg of tetrabenazine, the maximum plasma concentration and the area under the curve increased in proportion to the dose, indicating a linear kinetic.

Special populations

Hepatic impairment

Mild and moderate hepatic impairment increases the exposure and prolongs the half-lives of tetrabenazine and hydroxytetrabenazine (data in 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.

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.

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 (Cornstarch) pre-gelatinised

Lactose monohydrate

Talc

Ferric oxide yellow E172

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 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.

Tardiben is available in pack sizes of 42 and112 tablets.

Not all pack-sizes may be marketed.

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 Vienna

Austria

8. Marketing authorisation number(s)

PL 21344/0016

9. Date of first authorisation/renewal of the authorisation

07/07/2016

10. Date of revision of the text

14/04/2017