Consumer medicine information

Gabitril Tablets

Tiagabine

BRAND INFORMATION

Brand name

Gabitril

Active ingredient

Tiagabine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about GABITRIL. It does not contain all the available information. It 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 you taking GABITRIL against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What GABITRIL is used for

This medicine is used with other medicines to control some types of seizures (fits) in people with epilepsy. Epilepsy is a condition where you have repeated seizures. There are many different types of seizures, ranging from mild to severe.

This medicine belongs to a group of medicines called antiepileptics or anticonvulsants.

It works by increasing the level of a chemical in the brain (gamma-aminobutyric acid, or GABA). This controls the signals in nerve cells so that seizures do not happen.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor’s prescription.

There is not enough information to recommend the use of this medicine for children under the age of 12 years.

Before you take it

When you must not take it

Do not take GABITRIL if you have an allergy to:

  • any medicine containing tiagabine
  • 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 this medicine:

  • if you have severe liver disease
  • in combination with St John Wort (hypericum perforatum).

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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 allergies to any other medicines, foods, preservatives or dyes.

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

  • anxiety disorders
  • depression

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking GABITRIL.

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 GABITRIL may interfere with each other. These include:

  • some other medicines used to treat epilepsy, such as phenytoin, carbamazepine, phenobarbitone and primidone
  • St John Wort (hypericum perforatum).

These medicines may be affected by GABITRIL or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take it

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

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

How much to take

Your doctor or pharmacist will tell you how many tablets you will need to take each day. This may depend on your condition and what other antiepileptic medicines you are taking.

Your doctor may recommend that you start with a low dose and slowly increase the dose to the lowest amount needed to control your epilepsy.

How to take it

Swallow the tablets with a full glass of water.

When to take it

Take your medicine at about the same times each day. Taking it at the same times each day will have the best effect. It will also help you remember when to take it.

Take your medicine during or immediately after a meal. If you take GABITRIL on an empty stomach, it may cause stomach upset.

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. Therefore you must take your medicine every day, even if you feel well.

Do not stop taking your medicine or lower the dosage without checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays. Stopping this medicine suddenly may make your condition worse. If you do need to stop taking it, your doctor may slowly reduce your dose before you stop taking it completely.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 131126) for advice or go to Accident and Emergency at the nearest hospital if you think that you or anyone else may have taken too much GABITRIL. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include sleepiness, dizziness, tremor, unsteadiness when walking, incoordination, impaired consciousness, agitation, hostility, aggression, confusion, disorientation, difficulty in speaking, vomiting, difficulty in breathing, headache, urinary incontinence, temporary paralysis, increased seizures and coma and non-convulsive status epilepticus (prolonged and repeated fits or seizures without any recovery between attacks).

While you are taking it

Things you must do

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

  • increasing signs of depression
  • unusual changes in mood or behaviour
  • suicidal thoughts
  • suicidal behaviour
  • thoughts about self-harm.

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

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking GABITRIL.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Tell your doctor if you feel this medicine is not helping your condition. Your doctor may need to change your medicine.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may change your treatment unnecessarily.

Keep all of your doctor’s appointments so that your progress can be checked.

Things you must not do

Do not take GABITRIL to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine, or lower the dosage, unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how GABITRIL affects you. This medicine may cause dizziness and tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness or tiredness may be worse.

Side effects

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

This medicine helps most people with epilepsy, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of 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 and they worry you:

  • dizziness
  • tiredness
  • nervousness (for no apparent reason)
  • tremor
  • difficulty in concentrating
  • diarrhoea
  • hostility
  • difficulty in speaking.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • skin rash
  • feeling depressed
  • problems with your vision
  • seeing, feeling or hearing things that are not there
  • unusual bleeding or bruising, for example bruises that appear for no apparent reason.

The above list includes serious side effects which may require medical attention. Serious side effects are uncommon.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • an increase in the number of seizures, or different types of seizures to those you have had before
  • if you have never had a seizure before but have since developed seizures while on this treatment.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Some of these side effects for example, changes in liver function, can only be found when your doctor does tests from time to time to check your progress.

After taking it

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25C. Do not refrigerate the tablets.

Do not store GABITRIL or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it 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 it looks like

GABITRIL 5 mg tablets are white, round, biconvex film-coated tablets (marked 251).

GABITRIL 10 mg tablets are white, oval, biconvex film-coated tablets (marked 252).

GABITRIL 15 mg tablets are white, oval, biconvex film-coated tablets (marked 253).

Available in bottles of 50 tablets.

Ingredients

GABITRIL tablets contain 5 mg, 10 mg or 15 mg of tiagabine (as tiagabine hydrochloride monohydrate) as the active ingredient.

They also contain:

  • colloidal anhydrous silica
  • microcrystalline cellulose
  • ascorbic acid
  • pregelatinised maize starch
  • crospovidone
  • vegetable oil (hydrogenated)
  • stearic acid
  • lactose
  • hypromellose
  • magnesium stearate
  • hyprolose
  • titanium dioxide.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Teva Pharma Australia Pty Ltd
37 Epping Rd
Macquarie Park, NSW, 2113
Australia

GABITRIL is a registered trade mark of Novo Nordisk A/S used under licence by Teva Pharma Australia Pty Ltd

Australian Registration Numbers:

GABITRIL 5 mg, AUST R 120271

GABITRIL 10 mg, AUST R 120272

GABITRIL 15 mg, AUST R 120273.

This leaflet was revised in February 2018.

Published by MIMS August 2018

BRAND INFORMATION

Brand name

Gabitril

Active ingredient

Tiagabine

Schedule

S4

 

1 Name of Medicine

Tiagabine hydrochloride monohydrate.

2 Qualitative and Quantitative Composition

Tiagabine hydrochloride monohydrate has an asymmetric centre. Gabitril contains only the R(-)-enantiomer named (R)-N-(4,4)-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid, hydrochloride monohydrate. It is a white to off-white crystalline powder and is sparingly soluble in water (22 mg/mL), soluble in ethanol and practically insoluble in non-polar solvents such as diethyl ether. For the carboxylic acid moiety pKa = 3.3; for the amine pKa = 9.4.
Gabitril is an antiepileptic drug. The active ingredient is tiagabine, present as tiagabine hydrochloride monohydrate. Contains lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Gabitril 5 mg tablets are white, round, biconvex film-coated tablets (marked 251). Each 5 mg tablet contains tiagabine 5 mg in the form of tiagabine hydrochloride monohydrate.
Gabitril 10 mg tablets are white, oval, biconvex film-coated tablets (marked 252). Each 10 mg tablet contains tiagabine 10 mg in the form of tiagabine hydrochloride monohydrate.
Gabitril 15 mg tablets are white, oval, biconvex film-coated tablets (marked 253). Each 15 mg tablet contains tiagabine 15 mg in the form of tiagabine hydrochloride monohydrate.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of partial seizures, as add-on therapy in patients who are not controlled satisfactorily with other antiepileptic drug(s).

4.2 Dose and Method of Administration

Adults and children over 12 years.

Gabitril should be taken with meals in three daily doses. For optimal results the dose of Gabitril should be titrated for each patient as follows. The initial dosage is 7.5-15 mg daily, followed by weekly increments of 5-15 mg daily. The usual maintenance dose is in the range of 30-50 mg daily within which a clear dose-response is seen. Doses up to 70 mg daily have been well tolerated. In patients who are not taking enzyme-inducing drugs, the maintenance dose should initially be 15-30 mg/day. Adjustment of the maintenance tiagabine dosage should be considered when adding or stopping other anti-epileptic drugs. Although there is no evidence of withdrawal seizures with Gabitril, it is recommended to taper off treatment over a period of 2-3 weeks (see Section 4.4 Special Warnings and Precautions for Use).

Children under 12 years.

Safety and effectiveness in children below the age of 12 years have not been established. Therefore, the drug should not be used in children under 12 years.

Use in elderly.

Tiagabine should be used with caution in this age group (see Section 4.4 Special Warnings and Precautions for Use).

Use in patients with mild to moderate hepatic impairment.

Tiagabine is metabolised in the liver and since the pharmacokinetics of tiagabine with mild to moderate impaired liver function is modified, the Gabitril dosage should be adjusted by reducing the individual doses and/or prolonging the dose interval.

4.3 Contraindications

Gabitril should not be used in the case of the following.
Known hypersensitivity to tiagabine or any of the tablet components.
Severely impaired liver function.
Combination with St. John’s wort (Hypericum perforatum).

4.4 Special Warnings and Precautions for Use

It is important to follow the recommended rate of dosage titration with Gabitril (see Section 4.2 Dose and Method of Administration) in order to minimise the potential for adverse events to tiagabine which may result from a too rapid increment in dosage during the titration period. The dose of Gabitril which has been tailored to the patient's needs will be better tolerated.
In view of the GABAergic mode of action of tiagabine and the data from animal studies, a risk of aggravation of absences in patients with generalized epilepsy treated with tiagabine cannot be excluded.
As with other antiepileptic drugs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with tiagabine. These phenomena may be the consequence of an overdosage, a decrease in plasma concentrations of concomitant antiepileptic treatment, a progress of the disease, or a paradoxical effect.
Non-convulsive status epilepticus (paradoxical) has been reported with tiagabine in a relatively-resistant population requiring add-on therapy, particularly during dose titration. The dose should be carefully titrated to reduce the risk of paradoxical seizure-like activity. Should non-convulsive status epilepticus occur, reduction or cessation of the dose of tiagabine should be considered.
Although there is no evidence of withdrawal seizures with Gabitril it is recommended to taper off treatment over 2-3 weeks (see Section 4.2 Dose and Method of Administration).
In patients with a history of serious behavioural problems including generalised anxiety and depression, there is a risk of recurrence of these symptoms during Gabitril treatment. Treatment with Gabitril should therefore be initiated with low doses and patients observed carefully.
Rare cases of visual field defects have been reported with tiagabine. Some patients were asymptomatic. If visual symptoms develop, or if a field defect is suspected, the patient should be referred to an ophthalmologist for further evaluation including perimetry.
Spontaneous bruising has been reported. If such bruising is observed, full blood count, including platelets, should be performed.
Serious rash, including vesiculobullous rash has occurred in patients receiving Gabitril.

Seizures in patients without epilepsy.

Post marketing reports have shown that Gabitril has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking doses of Gabitril as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, opioids) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing. The safety and efficacy of Gabitril have not been established for any indication other than the treatment of partial seizures, as add on therapy in patients who are not controlled satisfactorily with other antiepileptic drugs. In non-epileptic patients who develop seizures while taking Gabitril, treatment should be discontinued and patients should be evaluated for an underlying seizure disorder. Seizures and status epilepticus are known to occur with Gabitril overdosage (see Section 4.9 Overdose).

Suicidal behaviour and ideation.

Antiepileptic drugs, including tiagabine hydrochloride monohydrate, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in the placebo-treated patients, but the number is too small to allow any conclusions about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with the AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing tiagabine hydrochloride monohydrate or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour or thoughts about self-harm. Behaviours of concern should be reported immediately to the treating doctor.

Use in hepatic impairment.

Tiagabine is metabolised in the liver. The pharmacokinetics of tiagabine in patients with mild to moderate impaired liver function is modified (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

The pharmacokinetic properties of tiagabine do not seem to be significantly modified in the elderly. However, only limited information is available on the use of Gabitril in elderly patients. It is therefore recommended to use tiagabine with caution in this age group.

Paediatric use.

Safety and effectiveness in children below the age of 12 years have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Findings from a series of pharmacokinetic interaction studies support the conclusion that tiagabine does not have any clinically significant effect on the plasma concentrations of phenytoin, carbamazepine, phenobarbitone, valproate, warfarin, digoxin, theophylline and hormones used in oral contraceptives.
However, anti-epileptic drugs which induce hepatic enzymes (e.g. phenytoin, carbamazepine, phenobarbitone and primidone) enhance the metabolism of tiagabine. The plasma concentration of tiagabine may be reduced by a factor of 1.5-3 by concomitant use of these drugs.
The combination of tiagabine with St. John’s wort (Hypericum perforatum) may lead to lower exposure and loss of efficacy of tiagabine, due to the potent induction of CYP3A4 by St. John’s wort (increasing tiagabine metabolism). Therefore, the combination of tiagabine with St. John’s wort is contraindicated (see Section 4.3 Contraindications).
Cimetidine does not have a clinically significant effect on tiagabine plasma levels. Although tiagabine may slightly prolong the CNS depressant effect of triazolam, the interaction is unlikely to be relevant to clinical practice. Formal interaction studies with other benzodiazepines have not been conducted, however, clinically relevant interactions were not noted in the clinical trials.
In-vitro data showed that tiagabine is 96% bound to human plasma protein and, therefore, has the potential to interact with other highly protein bound compounds. Such an interaction can potentially lead to higher free fractions of either tiagabine or the competing drug.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In rats where both sexes were treated with tiagabine, post-implantation loss was increased. Following maternal treatment at 100 mg/kg/day, male pups had reduced body weight up to 21 weeks of age. After 12 months treatment of beagle dogs with tiagabine, ovarian and uterine weights were significantly reduced.
(Category B3)

Risk associated with epilepsy and antiepileptics.

The risk of having an abnormal child as a result of antiepileptic medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy.
It is recommended that:
women on antiepileptic drugs (AEDs) receive pre-pregnancy counselling with regard to the risk of foetal abnormalities;
AEDs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as the risk of abnormality is greater in women taking combined medication;
folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception;
specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.

Risk associated with tiagabine.

Clinical experience of the use of Gabitril in pregnant women is limited. Studies in rats revealed that tiagabine and/or its metabolites crossed the placenta and were distributed in foetal tissue. Foetotoxicity and foetal abnormalities occurred at the maternotoxic dose. Pup birth weight and early postnatal survival was reduced in offspring of rats dosed with tiagabine 100 mg/kg/day from late gestation to weaning. In rabbits, post-implantation loss, foetal abnormalities, delayed ossification, reduced foetal viability and body weight occurred.
 As there is no information on the use of tiagabine during lactation, Gabitril should only be used during breast-feeding if the potential benefit outweighs the possible risks. Studies with C14-tiagabine indicated that tiagabine and/or its metabolites were found in the breast milk of rats after a single oral dose.

4.7 Effects on Ability to Drive and Use Machines

As with other antiepileptic drugs, caution should be shown when driving or operating machinery whilst on treatment with tiagabine.

4.8 Adverse Effects (Undesirable Effects)

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 https://www.tga.gov.au/reporting-problems.
The table below (Table 2) presents the adverse events experienced by at least 5% of the tiagabine treated patients in the 3 double blind, parallel, placebo-controlled studies (TIA 106, TIA 107 and TIA 109). The treatment duration in these studies was 16-22 weeks. The parallel, placebo-controlled studies allow a direct comparison of frequencies of adverse events between tiagabine and placebo.
Adverse events are generally mild to moderate. Most events occur during the titration phase and are often transient. The most commonly observed adverse events associated with the use of tiagabine in all placebo controlled clinical trials and which occur less frequently in patients treated with placebo are: dizziness, tiredness, somnolence, unspecific nervousness, tremor, difficulty in concentrating, diarrhoea, depressed mood (less than 5%) and emotional lability (less than 5%).

Post marketing experience.

Rare cases of seizures, non-convulsive status epilepticus (see Section 4.4 Special Warnings and Precautions for Use), slow-down EEG, encephalopathy, confusion, agitation, psychotic reactions (hallucination and delusion), and bruising have been reported in association with tiagabine therapy. The occurrence of seizures was confounded by other antiepileptic drugs and the underlying condition.
Rare cases of visual field defects have been reported including quadrantanopia, hemianopia and concentric field defects. Relationship to tiagabine was uncertain and, in some cases, confounded by other neurological conditions and the use of other antiepileptic drugs (see Section 4.4 Special Warnings and Precautions for Use).
Additional adverse events that have been reported with the use of Gabitril include: blurred vision, vomiting, ataxia, muscle twitching, abnormal gait, speech disorder, hostility, insomnia, bullous dermatitis, exfoliative dermatitis, vesiculobullous rash.
Isolated cases of thrombocytopenia have been reported in the context of associated viral infections and other antiepileptics.
Very rare cases of abnormal hepatic function (elevated SGPT, GGT) have been reported. Causation to tiagabine has not been definitely established. Seizures including status epilepticus in patients without epilepsy.

4.9 Overdose

Human experiences of acute overdose with Gabitril is limited. Eleven patients in clinical trials took single doses of Gabitril up to 800 mg. All patients fully recovered, usually within one day. The most common symptoms reported after overdose included somnolence, impaired consciousness, agitation, confusion, speech difficulty, hostility, depression, weakness and myoclonus. One patient who ingested a single dose of 400 mg experienced tonic-clonic status epilepticus, which responded to intravenous phenobarbital.
From post-marketing experience, there have been no reports of fatal overdose involving Gabitril alone (doses up to 720 mg), although a number of patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including Gabitril, have resulted in fatal outcomes.

Symptoms.

Symptoms most often accompanying Gabitril overdose, alone or in combination with other drugs, have included: seizures, including status epilepticus in patients with and without underlying seizure disorders, mute and withdrawn appearance of the patient, respiratory arrest, nonconvulsive status epilepticus, coma, loss of consciousness, ataxia, dizziness, encephalopathy, amnesia, confusional state, somnolence, dyskinesia, drowsiness, impaired speech, headache, psychotic disorder, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, aggression, temporary paralysis and urinary incontinence. Respiratory depression was seen in a number of patients, including children, in the context of seizures.

Treatment.

There is no specific antidote for overdose with Gabitril. If indicated, elimination of unabsorbed drug should be achieved by activated charcoal. General supportive care of the patient is indicated including monitoring of vital signs and observation of clinical status of the patient. Since tiagabine is mostly metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tiagabine is a potent and selective inhibitor of both neuronal and glial GABA (γ-amino-butyric acid) uptake, resulting in an increase in GABAergic mediated inhibition in the brain. Tiagabine lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites.

Clinical trials.

The efficacy of tiagabine as add-on therapy has been evaluated in 2 cross-over (non-pivotal) and 3 parallel (pivotal) trials in a total of 1032 patients, of whom 675 received Gabitril.
Doses in clinical trials are expressed as tiagabine hydrochloride anhydrous. Doses recommended are expressed as tiagabine (which is equivalent to 0.91 times the amount that of tiagabine hydrochloride anhydrous) (see Section 4.2 Dose and Method of Administration).

Cross-over trials.

The trials consisted of an initial screening period in which the dose was raised until a response or adverse events developed. Thereafter a 4-week fixed dose period followed. The patients who responded during the fixed dose period were randomised to the double-blind, cross-over period of 23 weeks duration.
A total of 182 patients entered these trials and 78 entered the cross-over phase. These two trials gave supportive evidence for the efficacy of Gabitril in the treatment of partial and secondary generalised seizures.

Parallel trials.

The parallel trials each included a placebo arm and investigated differing doses (TIA-106) or regimens (TIA-107, TIA-109). The parallel trials had an 8 or 12 week baseline period, then a double-blind period with a titration period of 4-6 weeks, followed by an 8-12 week fixed dose assessment period and a 4 week termination period.
A total of 850 patients were enrolled, 769 randomised, 493 of whom received tiagabine. Ages ranged from 12-77 years. Tiagabine treatment was added to existing antiepileptic medication including 1-3 anti-epileptic drugs.

TIA 106-dose finding trial.

Patients were randomised to treatment with placebo (n = 91), 16 mg tiagabine HCl daily (4 mg qid, n = 61), 32 mg tiagabine HCl daily (8 mg qid, n = 88) or 56 mg tiagabine HCl daily (14 mg qid, n = 57). 295 patients were assessable for efficacy.
The primary efficacy outcome measure was the change from baseline in 4-week complex partial seizure rates for the combined (32 mg + 56 mg) group. A significant decrease in the primary endpoint, complex partial seizure rate, was seen in this tiagabine treatment group compared with placebo. A significant decrease in 4-week seizure rate was also seen for combined partial and simple partial and secondary generalised tonic clonic seizures. In addition, the other secondary outcome measure of percentage of patients achieving ≥ 50% seizure reduction for the (32 mg + 56 mg) tiagabine treatment group was in the range of 24 - 44% for the different seizure types and was statistically significant over placebo for complex partial, simple partial and all partial seizure types.
Tiagabine HCl as add-on therapy was shown to be effective in the treatment of partial seizures at doses of 32 mg and 56 mg/day, with some efficacy at 16 mg/day in some patients.

TIA 107-dose frequency study (tid).

This trial examined three times daily dosing with 30 mg tiagabine HCl given as three 10 mg doses. 77 patients were randomised to tiagabine and 77 to placebo and all were included in the intent-to-treat analysis.
The primary endpoint of the study was the proportion of responders, that is the percentage of patients achieving a reduction of 50% or more in 4-weekly seizure rate for partial seizures compared to baseline. There was no significant difference from placebo in the proportion of responders for partial seizures overall, although the secondary endpoint of median reduction in 4-weekly seizure rates, was significantly better than placebo. However, for simple partial seizures there was a significant improvement in the proportion of responders and the median reduction in 4-weekly seizure rate in the tiagabine treatment group compared with placebo.

TIA 109-dose frequency study (bid vs. qid).

This trial compared a dose of 32 mg daily given as 16 mg bid or as 8 mg qid with placebo as add-on therapy for complex partial seizures. 108 patients received placebo, 106 received tiagabine HCl 16 mg bid, and 104 patients received tiagabine HCl 8 mg qid.
The primary efficacy measure was the change from baseline in 4 week complex partial seizure rates compared with placebo. Patients treated with tiagabine HCl 16 mg bid and 8 mg qid experienced fewer complex partial seizures per 4 weeks compared to placebo. The frequency of patients with ≥ 50% reduction in 4-week complex partial seizure rates were significantly higher in each of the 2 tiagabine groups compared to placebo. Approximately 20 - 30% of patients treated with tiagabine had at least a 50% reduction in complex partial and combined partial seizures.
The results of the pivotal parallel trials are shown in Table 3.

Summary.

The trials showed that tiagabine is efficacious in doses above 30 mg/day (with some efficacy at 16 mg/day) in the treatment of partial (simple and complex) and showed a tendency to efficacy for secondary generalised seizures. There was a trend towards better tolerance with a tid or qid dose regimen.

Monotherapy.

The experience with tiagabine monotherapy is still limited.

5.2 Pharmacokinetic Properties

Absorption.

Tiagabine is rapidly and virtually completely absorbed from Gabitril tablets with an absolute bioavailability of 80 to 90%. Administration of Gabitril with food results in a decreased rate, but not extent, of absorption. Within the therapeutic range, there is a linear relationship between the dose and extent of absorption and elimination of tiagabine.

Distribution.

The volume of distribution of tiagabine is approximately 1 L/kg and plasma protein binding is about 96%.

Metabolism.

Tiagabine is metabolised in the liver mainly by the cytochrome P450 isoenzyme CYP3A, with renal clearance being negligible. Less than 2% is excreted unchanged in the urine and faeces. No active metabolites have been identified. In epilepsy clinical trials, most patients were receiving hepatic enzyme-inducing agents (e.g. carbamezapine, phenytoin, primidone and phenobarbital). The pharmacokinetic profile in induced patients is significantly different from the non-induced population. The systemic clearance of tiagabine in induced patients is approximately 60% greater resulting in considerably lower plasma concentrations and an elimination half-life (t½) of 2 to 5 hours. Given this difference in clearance, the systemic exposure after a dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a non-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a non-induced population.
There is no evidence that tiagabine causes induction or inhibition of hepatic drug metabolising enzymes. In patients with mild to moderate hepatic impairment, the elimination half-life of tiagabine is increased to 12-16 hours. Therefore, these patients may require a reduction in dose.
There seems to be no difference in the pharmacokinetic profile of tiagabine in the elderly (> 65 years) and young adults.

Excretion.

The elimination half-life (t½) of tiagabine is 7 to 9 hours in normal volunteers.

5.3 Preclinical Safety Data

Genotoxicity.

The results of a wide range of mutagenicity tests showed that tiagabine is unlikely to be genotoxic to humans.

Carcinogenicity.

In long-term (2-year) carcinogenicity studies conducted in the rat and mouse, only the rat study revealed increased incidences of hepatocellular adenomas in females at 200 mg/kg/day (72 times the maximum anticipated clinical exposure based on plasma AUC) and benign Leydig cell tumours in males at 200 mg/kg/day (39 times the maximum anticipated clinical exposure).

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients are colloidal anhydrous silica, microcrystalline cellulose, ascorbic acid, lactose, pregelatinised maize starch, crospovidone, hydrogenated vegetable oil, stearic acid, magnesium stearate, hypromellose, hyprolose and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for further information.

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 25°C. Do not refrigerate.

6.5 Nature and Contents of Container

Gabitril 5 mg tablets are supplied in white HDPE bottles with a tamper proof cap of 50 tablets.
Gabitril 10 mg tablets are supplied in white HDPE bottles with a tamper proof cap of 50 tablets.
Gabitril 15 mg tablets are supplied in white HDPE bottles with a tamper proof cap of 50 tablets.
(Note: Not all strengths or pack sizes may be available in Australia.)

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


CAS number.

145821-57-4.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes