TETREN

Dosage Form: Tablet

Strength: 25 mg

Generic Name: Tetrabenazine

Pack Size: 3*10

Packing: Blister

Therapeutic Indications

Indicated for the treatment of chorea associated with Huntington’s disease.

To control of chorea, hemiballismus, tardive and buccolingual dyskinesias and certain dystonic syndromes.

Dosage

Adults

An initial dosage in adults of 25 mg twice a day is recommended. This can be increased by 25 mg a day every 3 or 4 days until the desired therapeutic effect is achieved, or until 200 mg/day is given, or unwanted side effects intervene.

Children

In children, 12.5 mg twice a day has been used as an initial dose with increments of

12.5 mg every 3 to 4 days until the desired therapeutic effect is obtained, or an upper limit

of 3 mg/kg/day is reached, or unwanted side effects intervene.

Dosage Adjustment

Dosage may need to be reduced in patients with impaired renal or hepatic function or in

elderly patients. It is reported that if no improvement is found after 7 to 10 days at the

maximum dose then it is unlikely that a higher dose or a longer duration of therapy will

benefit the patient.

• Tetrabenazine should not be given closer than one day before or in combination with levodopa or reserpine as it blocks the action of these drugs, particularly the central action.
• Tetrabenazine should not be administered to people with a known sensitivity to tetrabenazine or to any of the excipients.
• Tetrabenazine should not be given to patients with Parkinsonism or depression, as it may worsen these conditions. It should not be administered within two weeks of treatment with a monoamine oxidase inhibitor (MAOI).
• Tetrabenazine is contraindicated during breast-feeding.

Identified Precautions

As for other CNS active drugs, the effect of combination of tetrabenazine and other central

depressants including alcohol should be considered. Tetrabenazine may potentiate the action

of antihypertensive drugs.

Depression

Tetrabenazine may cause depression or worsen pre-existing depression. Cases of suicide ideation and behavior have been reported in patients taking the product. 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 should be controlled by reducing the dose 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 should not be used until at least two weeks have elapsed since the

last tetrabenazine dose, to avoid restlessness, disorientation and confusion, as well as a

potentially serious drug interaction resulting in hypertensive crisis.

Parkinsonism

Tetrabenazine can induce Parkinsonism and exacerbate pre-existing symptoms of

Parkinson’s disease. The tetrabenazine dose should be adjusted as clinically indicated to

minimize this side effect.

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome is a rare complication of tetrabenazine therapy. Neuroleptic Malignant Syndrome most often occurs early in treatment or in response to changes in dose. 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 (about 8 msec) in the corrected QT interval. In slow

metabolizers this increase may be greater (30msec). Tetrabenazine should be used with

caution with other drugs known to prolong QTc and in patients with congenital long QT

syndromes and a history of cardiac arrhythmias.

Dysphagia and Choking

Dysphagia and choking attacks with possibly consequent bronchopneumonia appear to be

the only acutely dangerous adverse effects of tetrabenazine reported so far. If these occur,

therapy should be discontinued.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency

or glucose-galactose malabsorption, should not take tetrabenazine tablets as they contain

lactose.

Orthostatic Hypotension

Tetrabenazine may induce postural hypotension at therapeutic doses and symptoms may

include postural dizziness and fainting. These 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.

Use in Renal Impairment

The use of tetrabenazine in patients with renal insufficiency has not been studied.

Use in the Elderly

No specific studies have been performed in the elderly.

Pediatric Use

No adequately controlled clinical studies have been performed in children.

Effects on Laboratory Tests

There are no special requirements to monitor effects on laboratory tests.

INTERACTION

Interaction may occur when the following medications are administered with tetrabenazine

Reserpine and Levodopa:

Inhibit the action of these drugs and thereby attenuate their effects.

MAOIs:

Possible serious interactions resulting in hypertensive crisis. At least 14 days should

elapse between the discontinuation of MAOI and initiation of treatment with Tetrabenazine.

Tricyclic Antidepressants:

It has been reported to antagonize the locomotor activity induced by Tetrabenazine in

animals.

CNS Stimulants and Depressants:

Possible additive sedative effects should be considered when used in conjunction with

CNS depressants (including alcohol, neuroleptics, hypnotics and opioids).

Neuroleptic Agents:

Potential for significant dopamine depletion when administering with neuroleptic agents

e.g. haloperidol, chlorpromazine and metoclopramide. Patients should be monitored

clinically for the development of Parkinsonism. Neuroleptic malignant syndrome has

been observed in isolated cases.

Antihypertensives:

May increase risk of orthostatic hypotension.

Beta-blockers:

May increase risk of orthostatic hypotension.

CYP2D6 inhibitors:

In vitro and in vivo studies indicate that tetrabenazine and its metabolites, α- and βdihydotetrabenazine and are substrates for CYP2D6. β-HTBZ was also an inhibitor of

CYP2D6 at clinically relevant concentrations. Caution should be used when adding a

CYP2D6 inhibitor (such as fluoxetine, paroxetine, quinidine, duloxetine, terbinafine,

amiodarone, or sertraline) to a patient already receiving a stable dose of tetrabenazine,

or if the dose is influenced by the patient’s CYP2D6 metabolizer status. A reduction in

the dose of tetrabenazine should be considered.

Antipsychotics, antibiotics and Class IA and III antiarrhythmic medications:

Tetrabenazine causes a small increase (about 8 msec) in the corrected QT interval.

Effects on Fertility

There is no data available on the potential of tetrabenazine to affect fertility.

Use in Pregnancy - Category B3 (TGA)

• Category C (FDA)

There is inadequate evidence of safety of the drug in human pregnancy, and the potential

risk to humans is unknown. Tetrabenazine crosses the placenta and, because of the lack of

data and tetrabenazine should not be used during pregnancy. In the developmental toxicity tests, there was no evidence of utero mortality, growth retardation or teratogenicity either

rats or rabbits at oral doses up to 5 and 27 times the clinical dose based on body surface

area. When tetrabenazine was administered orally to female rats from the beginning of

organogenesis to weaning, an increase in stillbirths and postnatal mortality was observed

from 15 mg/kg/day, while delayed development was seen at 30 mg/kg/day. The no-effect

dose for neonatal effects (5 mg/kg/day) was approximately equivalent to the clinical dose

based on body surface area. The relative contributions of in utero and neonatal exposure and

Postnatal maternal neglect to these effects is unclear.

Use in Lactation

Tetrabenazine is excreted in milk. Oral administration to rats from early gestation to

weaning was associated with increased stillbirths, hypothermia and neonatal mortality in

pups (15 mg/kg/day, twice the clinical dose based on body surface area), and delayed pup

development (30 mg/kg/day, 5-fold the clinical dose). The relative contributions of in utero

and neonatal exposure and postnatal maternal neglect to these effects are unclear.

Tetrabenazine is contraindicated during breast-feeding.

As drowsiness may occur in up to 20% of patients, caution should be used when driving or

operating machines until competence to do so under treatment has been established. It might

be possible to reduce the drowsiness by careful dosage adjustment, especially initially.

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

Side effects include drowsiness, depression (which has on occasion been reported to be

associated with suicidal ideation and behavior) and Parkinsonism. The most commonly

reported side effects are as follows:

Central And Peripheral Nervous System Disorders:

Drowsiness (20%)

Parkinsonism (2 to 12%) at higher doses (may

include balancing problems, tremors or excess salivation)

Psychiatric Disorders:

Depression (6 to 10%)

Agitation (2.7%)

Anxiety (2 to 9%)

Insomnia (2 to 9%)

Confusion (1%)

Gastrointestinal System Disorders:

Dysphagia and choking attacks (4%) with

possibly consequent bronchopneumonia.

Respiratory Disorders:

Bronchopneumonia

Central And Peripheral Nervous System Disorders:

Ataxia

Akathisia

Dizziness

Dyskinetic seizures

Dystonia

Memory impairment

Neuroleptic malignant syndrome (<0.01%)

Gastrointestinal System Disorders:

Nausea

Anorexia

Dryness of the mouth

Sialorrhea

Constipation

Diarrhea

Vomiting

Epigastric pain

Dysphagia

Psychiatric Disorders:

Disorientation

Feelings of unreality

Restlessness

Nervousness

Sleep disorders

Worsening aggression

General Disorders:

Lassitude

Hypothermia

Weight gain

Weaknesses

Fatigue

Cardiovascular Disorders:

Postural hypotension (1%)

Hypertensive crisis

Heart Rate and Rhythm Disorders: Bradycardia

Reproduction Disorders:

Irregular menstrual cycle

Skin And Subcutaneous Tissue Disorders

Sweating

Skin rash

Blood and lymphatic systems disorders

Leucopenia

Eye disorders

Oculogyric crisis

Photophobia

Metabolism and Nutrition Disorders Increased Appetite

Neuroleptic malignant syndrome (NMS) associated with the use of tetrabenazine has been

reported rarely. This may occur soon after initiation of therapy, following an increase in

dosage or after prolonged treatment. The main symptoms are mental changes, rigidity,

hyperthermia, autonomic dysfunction and elevated creatinine phosphokinase levels. If NMS

is suspected tetrabenazine should be withdrawn and appropriate supportive therapy instituted; treatment with dantrolene and bromocriptine may be effective.

Signs and symptoms of overdosage may include nausea, vomiting, diarrhea, confusion,

hallucinations, sedation, drowsiness, sweating, hypotension and hypothermia.

Management should be supportive. There is no information available on the effect of

pharmacological antagonists or dialysis.

Pharmacodynamic Properties

Mechanism of Action

Tetrabenazine is a synthetic derivative of benzyl quinolizine that causes depletion of

dopamine and other monoamines in the central nervous system.

Studies conducted in vitro have shown that tetrabenazine is an inhibitor of monoamine

transportation into pre-synaptic neuronal vesicles, by inhibition of VMAT2 (vesicular

monamine transporter 2), which is principally located in the central nervous system.

Dihydrotetrabenazine, the principal metabolite of tetrabenazine, has a similar affinity and

more significant selectivity for VMAT2, and both compounds are believed to contribute to

the pharmacological effect.

At a synaptic level tetrabenazine creates a reversible depletion of monamines in the

presynaptic vesicles. Animal studies have shown that tetrabenazine causes preferential

depletion of dopamine from nerve terminals in the CNS but neurotransmitter depletion by

a single dose of tetrabenazine is reversible and lasts only a few hours. This pharmacological

effect explains the therapeutic benefit of tetrabenazine in patients’ suffering from

hyperkinetic movement disorders.

Absorption

Based on metabolite levels, tetrabenazine is quickly and mostly absorbed after oral

administration. Its absorption is not affected by the taking of food. After administration of

single doses from 12.5 to 50mg of tetrabenazine, for the metabolites alpha and beta

dihydrotetrabenazine, the maximum plasma concentration and the area under the curve

increased approximately in proportion to the dose, indicating a linear kinetic. Clinical

testing has shown that a single oral dose of tetrabenazine undergoes extensive (>75%)

absorption from the gastro-intestinal tract.

Metabolism

The metabolism of tetrabenazine is complex, initially proceeding via the formation of alpha

and beta dihydrotetrabenazine. The majority of the observed metabolites appear to be

formed from these dihydrotetrabenazines because of O-dealkylation, hydroxylation and

conjugation. No significant build-up has been observed after daily administration. The

elimination half-life of dihydrotetrabenazine is approximately 5 to 6 hours.

Excretion

Tetrabenazine is mostly eliminated in metabolised form in urine.

Genotoxicity

Tetrabenazine and its major metabolites, α- and β-dihydrotetrabenazine, were negative in

the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro

chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic

activation, while α- and β-dihydrotetrabenazine were clastogenic in Chinese hamster lung

cells in the presence and absence of metabolic activation. In vivo micronucleus tests in rats

and mice with tetrabenazine were negative. The genotoxic potential of tetrabenazine is

considered to be low.

Carcinogenicity

A 6-month study in transgenic p53(+/-) heterozygous mice and a long-term study in male

rats at oral doses up to 30 mg/kg/day and 6 mg/kg twice daily, respectively, did not

provide any evidence of carcinogenic potential. These doses correspond to exposures

approximately 3 to 4 times the clinical exposure, based on plasma AUC or dose based on

body surface area. Mammary gland hyperplasia was observed in female rats that received

twice daily oral doses of 7.5 mg/kg or greater for 6 months associated with exposures

(plasma AUC) like clinical exposure. As the effect of tetrabenazine on prolactin

levels are not known, the relevance of this finding is uncertain.

Store below 30°C. Store in original container. Keep out of reach of children.