4.1. Therapeutic indications

Gabitril is an anti-epileptic drug indicated as add-on therapy for partial seizures with or without secondary generalisation where control is not achieved by optimal doses of at least one other anti-epileptic drug.

4.2. Posology and method of administration

Gabitril should be taken orally with meals.

Dosing schemes may need to be individualised based upon a patient's particular characteristics such as age and concomitant medications.

Concomitant use with drugs involving CYP 3A4/5 metabolism: As CYP3A4/5 is involved in the metabolism of tiagabine, it is recommended that the dose of tiagabine is adjusted when it is taken in combination with CYP3A4/5 inducers (see section 4.5 Interactions with other medicinal products and other forms of interactions).

Following a given dose of tiagabine, the estimated plasma concentration in non-induced patients is more than twice that in patients receiving enzyme-inducing agents. To achieve similar systemic exposures of tiagabine, non-induced patients require lower and less frequent doses of tiagabine than induced patients. These patients may also require a slower titration of tiagabine compared to that of induced patients.

Adults and children over 12 years: The initial daily dose is 5-10 mg tiagabine, followed by weekly increments of 5-10 mg/day. The usual maintenance dose in patients taking enzyme-inducing drugs is 30-45 mg/day. In patients not taking enzyme-inducing drugs, the maintenance dose should initially be reduced to 15-30 mg/day. The initial daily dose should be taken as a single dose or divided into two doses. The daily maintenance dose should be divided into two or three single doses.

Children under 12 years: There is no experience with Gabitril in children under 12 years of age and as such Gabitril should not be used in this age group.

Elderly: There is limited information available on the use of Gabitril in elderly patients, but pharmacokinetics of tiagabine are unchanged, hence there should be no need for dose modification.

Patients with renal insufficiency: Renal insufficiency does not affect the pharmacokinetics of tiagabine, therefore the dosage does not need to be modified in these types of patients.

Patients with impaired liver function: Tiagabine is metabolised in the liver and since the pharmacokinetics of tiagabine in patients with mild to moderate impaired liver function is modified (see Section 5.2), the Gabitril dosage should be adjusted by reducing the individual doses and/or prolonging the dose intervals.

Gabitril should not be used in patients with severely impaired hepatic function (see Section 4.3).

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Severely impaired liver function.

Gabitril in combination with St John's Wort (Hypericum perforatum) (see section 4.5).

4.4. Special warnings and precautions for use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Gabitril.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Post-marketing reports have shown that Gabitril use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Confounding factors that may have contributed to development of seizures include underlying medical conditions or concomitant medications that can reduce seizure threshold, reported overdose and manner of dose administration (e.g. high dosage, fast titration rate).

Safety and effectiveness of Gabitril have not been established for any indication other than as adjunctive therapy for partial seizures in adults and adolescents over 12 years.

Gabitril is eliminated by hepatic metabolism and therefore caution should be exercised when administering the product to patients with impaired hepatic function. Reduced doses and/or dose intervals should be used and patients should be monitored closely for adverse events such as dizziness and tiredness.

Although Gabitril may slightly prolong the CNS depressant effect of triazolam, this interaction is unlikely to be relevant to clinical practice.

Anti-epileptic agents that induce hepatic enzymes (such as phenytoin, carbamazepine, phenobarbital and primidone) enhance the metabolism of tiagabine. Consequently, patients taking enzyme-inducing drugs may require doses of tiagabine above the usual dose range.

Although there is no evidence of withdrawal seizures following Gabitril, it is recommended to taper off treatment over a period of 2-3 weeks.

Serious rash, including vesiculobullous rash, has occured in patients receiving Gabitril (see section 4.8 Undesirable effects).

Spontaneous bruising has been reported. Therefore, if bruising is observed full blood count, including platelet count is to be performed.

Rare cases of visual field defects have been reported with tiagabine. If visual symptoms develop, the patient should be referred to an ophthalmologist for further evaluation including perimetry.

Gabitril tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

Rapid titration and/or large dose increments of tiagabine may not be well-tolerated and should be avoided (see section 4.2).

4.5. Interaction with other medicinal products and other forms of interaction

Anti-epileptic agents that induce hepatic enzymes (such as phenytoin, carbamazepine, phenobarbital and primidone) enhance the metabolism of tiagabine. The plasma concentration of tiagabine may be reduced by a factor 1.5-3 by concomitant use of these drugs.

Gabitril does not have any clinically significant effect on the plasma concentrations of phenytoin, carbamazepine, phenobarbital, warfarin, digoxin, theophylline and hormones from oral contraceptive pills. Gabitril reduces the plasma concentration of valproate by about 10%, and cimetidine increases the bioavailability of tiagabine by about 5%. Neither of these findings are considered clinically important and do not warrant a dose modification.

The combination of tiagabine with St John Wort (Hypericum perforatum) may lead to lower exposure and loss of efficacy of tiagabine, due to the potent induction of CYP3A4 by St John Wort (increasing tiagabine metabolism). Therefore, the combination of tiagabine with St John's Wort is contra-indicated (see also section 4.3).

4.6. Fertility, pregnancy and lactation

Pregnancy

Animal experiments have not shown a teratogenic effect of tiagabine. Studies in animals have however, revealed peri- and post-natal toxicity of tiagabine at very high doses.

Clinical experience of the use of Gabitril in pregnant women is limited.

Breast-feeding

No information on Gabitril during breast-feeding is available.

Consequently, as a precautionary measure, it is preferable not to use Gabitril during pregnancy or breast-feeding unless in the opinion of the physician, the potential benefits of treatment outweigh the potential risks.

4.7. Effects on ability to drive and use machines

Gabitril may cause dizziness or other CNS related symptoms, especially during initial treatment. Therefore caution should be shown by patients driving vehicles or operating machinery.

4.8. Undesirable effects

Adverse events are mainly CNS related.

A full list of adverse reactions reported with Gabitril during clinical studies and post marketing experience is shown in the table below. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: 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), not known (cannot be estimated from the available data):

The following undesirable effects have been reported with Gabitril:

System Organ Class

Frequency

Undesirable effects

Psychiatric disorders

Very common

Nervousness (non-specific)

Common

Concentration difficulties, depressed mood, emotional lability, confusion, insomnia, hostility/aggression

Uncommon

Depression, psychosis

Rare

Hallucinations, delusion

Nervous system disorders

Very common

Dizziness, tremor

Common

Ataxia, abnormal gait, speech disorder

Uncommon

Somnolence

Rare

Non-convulsive status epilepticus

Not known

Encephalopathy, amnesia

Eye disorders

Common

Vision blurred

Rare

Visual field defects

Gastrointestinal disorders

Very common

Nausea

Common

Diarrhoea, vomiting, abdominal pain

Skin and subcutaneous tissue disorders

Uncommon

Dermatitis bullous, bruising

Not known

Vesiculobullous rash, exfoliative dermatitis

Musculoskeletal and connective tissue disorders

Common

Muscle twitching

General disorders and administration site conditions

Very common

Tiredness

Injury, poisoning and procedural complications

Common

Accidental injury

In patients with a history of serious behavioural problems there is a risk of recurrence of these symptoms during treatment with Gabitril, as occurs with certain other anti-epileptic drugs.

Although not statistically significant, routine laboratory screening during placebo controlled studies showed a low white blood cell count (<2.5 x 109 per litre) more frequently during Gabitril treatment (4.1%) than placebo (1.5%).

Postmarketing reports have shown that Gabitril use has been associated with new onset seizures and status epilepticus in patients without epilepsy treated by tiagabine for unapproved indication (see section 4.4 Special warnings and special precautions for use).

During post-marketing experience, there have been reports of vision blurred, vomiting, ataxia, abnormal gait, speech disorder, hostility, insomnia, dermatitis bullous, vesiculobullous rash, muscle twitching and amnesia. In case reports, amnesia occurred within days after initiation or dose increase of tiagabine and was reversible upon discontinuation of tiagabine or dose decrease.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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, respiratory depression, respiratory arrest, coma, loss of consciousness, spike wave stupor, encephalopathy, amnesia, confusion, disorientation, somnolence, dyskinesia, myoclonus, tremors, ataxia or incoordination, dizziness, nystagmus, impaired speech, headache, psychotic disorder, hallucinations, hostility, aggression, agitation, vomiting, hypersalivation, bradycardia, tachycardia, ST wave changes, hypertension, hypotension and urinary incontinence. In more severe instances, mute and withdrawn appearance of the patient and risk of convulsion have been reported.

From post-marketing experience, there have been no reports of fatal overdoses 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.

In case of overdose, standard symptomatic treatment and medical observation with supportive care is recommended. Hospitalisation can be recommended in cases of severe overdoses. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of more than 2 mg/kg.