Consumer medicine information

Tetrabenazine Tablets

Tetrabenazine

BRAND INFORMATION

Brand name

Tetrabenazine Tablets

Active ingredient

Tetrabenazine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tetrabenazine Tablets.

What is in this leaflet

This leaflet answers some common questions about Tetrabenazine Tablets. It does not contain all the available information. Reading this leaflet does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of your taking Tetrabenazine Tablets against the benefits they expect it will have for you.

If you have any concerns about taking Tetrabenazine Tablets, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Tetrabenazine Tablets are used for

Tetrabenazine is used for the treatment of diseases, which cause jerky, irregular, uncontrollable movements such as Huntington's chorea, senile chorea and hemiballismus.

Tetrabenazine affects some chemicals in the brain, and by doing so it helps to control jerky and irregular movements.

Ask your doctor if you have any questions about why Tetrabenazine Tablets have been prescribed for you.

Your doctor may have prescribed Tetrabenazine Tablets for another use.

Tetrabenazine Tablets are not addictive.

Tetrabenazine Tablets are only available on a doctor's prescription.

Before you take Tetrabenazine Tablets

When you must not take it

Do not take Tetrabenazine Tablets if you have an allergy to:

  • Any medicine containing tetrabenazine.
  • Any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • Shortness of breath
  • Wheezing or difficulty breathing
  • Swelling of the face, lips, tongue or other parts of the body
  • Rash, itching or hives on the skin.

Do not take Tetrabenazine Tablets if you are also taking:

  • Medicine containing reserpine.
  • Medicine containing levodopa
  • Medicine known as a monoamine oxidase inhibitor or have taken this medicine in the past 2 weeks.

Tetrabenazine can affect action of these medicines.

Do not take Tetrabenazine Tablets if you have:

  • Parkinson's disease.
  • Depression.
  • Galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Tetrabenazine Tablets contain lactose.

Do not take Tetrabenazine tablets if you are pregnant or breastfeeding.

Tetrabenazine may harm your unborn baby. Tetrabenazine has been found in breast milk.

Do not take Tetrabenazine Tablets after the expiry date printed on the bottle.

Do not take Tetrabenazine Tablets if the bottle seems to have been opened or the tablets do not look quite right.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have or have had any of the following medical conditions:

  • Allergy to any other medicines, foods, preservatives or dyes
  • Lactose intolerance.
    Tetrabenazine Tablets contain lactose.
  • Depression
  • Suicidal thoughts or behaviour
  • Parkinson's disease
  • Abnormal heart rate or rhythm
  • Kidney disease
  • Liver disease.

Tell your doctor your CYP2D6 metaboliser status, if known.

Your CYP2D6 metaboliser status may affect the dose of tetrabenazine you need and the dose of other medicines you may be taking.

Tell your doctor if you are pregnant or intend to become pregnant or to breastfeed.

If you have not told your doctor about any of the above, tell him/her before you start taking Tetrabenazine Tablets.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Tetrabenazine Tablets may interfere with each other. These include:

  • Reserpine and levodopa
  • Medicines used to treat depression, such as monoamine oxidase inhibitors (MAOIs) and CYP2D6 inhibitors, such as fluoxetine, paroxetine, quinidine, duloxetine, terbinafine, amiodarone, or sertraline
  • Medicines that affect the brain and nervous system including medication used to treat psychiatric conditions, strong painkillers and medication used to help sleep
  • Medicines used to treat psychosis, such as haloperidol, chlorpromazine and metoclopramide
  • Medicines, including beta-blockers used to treat high blood pressure.

Some medicines, when used in combination with Tetrabenazine, may interfere with the rate and rhythm of heart beats. These include medications used to treat psychiatric conditions, antibiotics and medications used to treat problems with heart rhythm conditions.

How to take Tetrabenazine Tablets

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Your doctor will decide the best dose for you.

The usual starting dose in adults is one tablet twice a day. This may increase to a total of 200 mg (8 tablets) a day.

The doctor will decide the best dose for children and elderly patients.

Do not take more than the dose your doctor has recommended.

If you feel unwell during your course of treatment, tell your doctor.

How to take it

Swallow the tablet or tablets with water.

When to take it

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take Tetrabenazine Tablets

If you forget to take a dose of Tetrabenazine Tablets, skip that dose completely. Take your next dose at the normal time it is due.

Do not take a double dose to make up for the dose that you missed.

This may increase your chance of getting an unwanted side effect.

If you have trouble remembering when to take Tetrabenazine Tablets, ask your pharmacist for some hints.

If you take too many Tetrabenazine Tablets

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too many Tetrabenazine Tablets. Do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose may include nausea, vomiting, diarrhoea, confusion, hallucinations, sedation, drowsiness, sweating, low blood pressure and abnormally low body temperature.

While you are taking Tetrabenazine Tablets

Things you must do

Make sure that all of your doctors and pharmacists know you are taking Tetrabenazine Tablets. Remind them if any new medicines are about to be started.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things you must not do

Do not use Tetrabenazine Tablets to treat any complaint other than that directed by your doctor.

It may not be safe to use Tetrabenazine Tablets for another complaint.

Tetrabenazine Tablets should only be used by the person for whom it was prescribed. Do not give Tetrabenazine Tablets to anyone else even if they have the same condition as you.

It may not be safe for another person to use Tetrabenazine Tablets.

Do not stop taking your medicine or change the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Tetrabenazine Tablets affects you.

This medicine may cause drowsiness in some people.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or get worse, talk to your doctor.

Avoid or limit the use of alcohol when taking tetrabenazine Tablets.

Alcohol can increase some side effects of tetrabenazine such as dizziness, drowsiness and difficulty in concentrating.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Tetrabenazine Tablets.

Like all medicines, Tetrabenazine Tablets may have some side effects. Sometimes they are serious, most of the time they are not.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following:

  • Sleepiness and drowsiness
  • Depression
  • Uncontrollable movements of the hands, arms, legs and head (similar to those in Parkinson's disease)
  • Digestive problems
  • Lowering of blood pressure
  • Feeling nervous or anxious
  • Worsening aggression
  • Trouble sleeping
  • Skin rash.

Tell your doctor immediately if you notice any of the following:

  • Difficulty in swallowing
  • Choking attacks
  • Stiffness or tightness in the arms or legs
  • Confusion or having thoughts of irrational ideas not shared by others
  • Suicidal thoughts or behaviour.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

After taking Tetrabenazine Tablets

Storage

Keep Tetrabenazine Tablets in their bottle until it is time to take your dose.

If you take them out of their container, they may not keep well.

Keep Tetrabenazine Tablets in a cool dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it on a window sill or in the car on hot or cold days.

Heat and dampness can destroy some medicines.

Keep Tetrabenazine Tablets where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What Tetrabenazine Tablets look like

Tetrabenazine Tablets 25 mg are buff coloured. They are scored and marked with "CL" over "25".

Ingredients

Each Tetrabenazine Tablet contains 25 mg of the active ingredient, tetrabenazine, and 64 mg lactose.

Tetrabenazine Tablets also contain the following inactive ingredients:

  • Starch
  • Talc
  • Magnesium stearate
  • Iron oxide yellow.

Tetrabenazine Tablets are available in plastic bottles containing 112 tablets.

Supplier

Tetrabenazine Tablets are distributed in Australia by:

iNova Pharmaceuticals (Australia) Pty Limited
ABN: 13 617 871 539
Level 10, 12 Help Street
Chatswood NSW 2067
Tel: 1800 630 056

AUST R 13695

This leaflet was prepared in November 2017.

BRAND INFORMATION

Brand name

Tetrabenazine Tablets

Active ingredient

Tetrabenazine

Schedule

S4

 

1 Name of Medicine

Tetrabenazine.

6.7 Physicochemical Properties

The chemical name of tetrabenazine is 1,3,4,6,7,11b-hexahydro- 9,10-dimethoxy-3- (2-methylpropyl)- 2H-benzo -[a]quinolizin-2-one. Tetrabenazine is white to slightly yellow crystalline powder. Tetrabenazine is soluble in hot water, but practically insoluble in acetone. UV max (alcohol): 230, 284 nanometer (E 7780, 3820).

Chemical structure.


CAS number.

58-46-8.

2 Qualitative and Quantitative Composition

Each tablet contains 25 mg tetrabenazine.
Contains lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet, uncoated.
A cylindrical, biplanar tablet with bevelled edges, yellowish colour. upper face marked CL25, lower face single break bar.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tetrabenazine is a synthetic derivative of benzylquinolizine 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 presynaptic 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.

5.2 Pharmacokinetic Properties

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 50 mg 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 gastrointestinal 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 as a result 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.

5.3 Preclinical Safety Data

Genotoxicity.

Tetrabenazine and its major metabolites, α-dihydrotetrabenazine 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-dihydrotetrabenazine 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 six 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) similar to the clinical exposure. As the effect of tetrabenazine on prolactin levels is not known, the relevance of this finding is uncertain.

4 Clinical Particulars

4.1 Therapeutic Indications

May be useful for the control of chorea, hemiballismus, tardive and buccolingual dyskinesias and certain dystonic syndromes.

4.3 Contraindications

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 persons 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.

4.4 Special Warnings and Precautions for Use

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 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 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 minimise 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 metabolisers this increase may be greater (30 msec). 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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dysphagia and choking.

Dysphagia and choking attacks with a 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 malsorption, 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.

Paediatric 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interaction may occur when the following medications are administered with tetrabenazine (see Section 4.3 and Section 4.4).

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 a MAOI and initiation of treatment with tetrabenazine.

Tricylic antidepressants.

Have been reported to antagonise 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 tetrabenzine and its metabolites α and β-dihydotetrabenazine 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 metaboliser status. A reduction in the dose of tetrabenazine should be considered.

Antipsychotics, antibiotics and class Ia and III antiarrythmic medications.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data available on the potential of tetrabenazine to affect fertility.
(Category B3)
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, tetrabenazine should not be used during pregnancy. In the developmental toxicity tests there was no evidence of in utero mortality, growth retardation or teratogenicity in 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 are unclear.
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.

4.8 Adverse Effects (Undesirable Effects)

Side effects include drowsiness, depression (which has on occasion been reported to be associated with suicidal ideation and behaviour) and parkinsonism.
The most commonly reported side effects are as follows (see Table 1).
Other adverse reactions which have been reported are as follows (see Table 2).
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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage given below is a guide only. For each patient, the dose of tetrabenazine should be titrated to determine the most appropriate dose. Treatment should be reassessed periodically in the context of the patient's underlying condition and concomitant medications.

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.

Note.

Only very limited information on use in children is available.
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.

4.7 Effects on Ability to Drive and Use Machines

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.

4.9 Overdose

Signs and symptoms of overdosage may include nausea, vomiting, diarrhoea, confusion, hallucinations, sedation, drowsiness, sweating, hypotension and hypothermia.
Management should be supportive. There is no information available on the effect of pharmacological antagonists or of dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose, monohydrate, maize starch, purified talc, magnesium stearate and iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

HDPE Bottle: 112 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes