Drug Description
Each film-coated tablet contains 50 mg of retigabine.Each film-coated tablet contains 100 mg of retigabine.Each film-coated tablet contains 200 mg of retigabine.Each film-coated tablet contains 300 mg of retigabine.Each film-coated tablet contains 400 mg of retigabine.

Presentation
Film-coated tablet (tablet).50 mg tablets:Purple, round, film-coated tablets, marked with “RTG 50” on one side.100 mg tablets:Green, round, film-coated tablets, marked with “RTG 100” on one side.200 mg tablets:Yellow, oblong, film-coated tablets, marked with “RTG-200” on one side.300 mg tablets:Green, oblong, film-coated tablets, marked with “RTG-300” on one side.400 mg tablets:Purple, oblong, film-coated tablets, marked with “RTG-400” on one side

Indications
Trobalt is indicated as adjunctive treatment of partial onset seizures with or without secondary generalisation in adults aged 18 years and above with epilepsy.

Adult Dosage
PosologyTrobalt must be titrated, according to individual patient response, in order to optimise the balance between efficacy and tolerability.The maximum total daily starting dose is 300 mg (100 mg three times daily). Thereafter, the total daily dose is increased by a maximum of 150 mg every week, according to the individual patient response and tolerability. An effective maintenance dose is expected to be between 600 mg/day and 1,200 mg/day.The maximum total maintenance dose is 1,200 mg/day. The safety and efficacy of doses higher than 1,200 mg/day have not been established.If patients miss one dose or more, it is recommended that they take a single dose as soon as they remember.After taking a missed dose, at least 3 hours should be allowed before the next dose and then the normal dosing schedule should be resumed.When withdrawing Trobalt, the dose must be gradually reduced (see section 4.4).Renal impairmentRetigabine and its metabolites are eliminated principally by renal excretion.No dose adjustment is required in patients with mild renal impairment (creatinine clearance 50 to 80 ml/min; see section 5.2).A 50% reduction in the initial and maintenance dose of Trobalt is recommended in patients with moderate or severe renal impairment (creatinine clearance <50 ml/min; see section 5.2). The total daily starting dose is 150 mg, and it is recommended that during the titration period, the total daily dose is increased by 50 mg every week, to a maximum total dose of 600 mg/day.The effect of haemodialysis on retigabine clearance has not been adequately eva luated.Hepatic impairmentNo dose reduction is required in patients with mild hepatic impairment (Child-Pugh score 5 to 6; see section 5.2).A 50% reduction in the initial and maintenance dose of Trobalt is recommended in patients with moderate or severe hepatic impairment (Child-Pugh score 7; see section 5.2). The total daily starting dose is 150 mg, and it is recommended that during the titration period, the total daily dose is increased by 50 mg every week, to a maximum total dose of 600 mg/day.Paediatric populationThe safety and efficacy of retigabine in children below 18 years of age have not been established yet. No data are available.Elderly (65 years of age and above)There are only limited data on the safety and efficacy of retigabine in patients aged 65 years and above. A reduction in the initial and maintenance dose of Trobalt is recommended in elderly patients. The total daily starting dose is 150 mg/day and during the titration period the total daily dose should be increased by a maximum of 150 mg every week, according to the individual patient response and tolerability. Doses greater than 900 mg/day are not recommended (see sections 4.4 and 5.2).Method of administrationTrobalt must be taken orally in three divided doses each day. It may be taken with or without food (see section 5.2). The tablets should be swallowed whole, and not chewed, crushed or divided.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.

Special Precautions
Urinary retentionUrinary retention, dysuria and urinary hesitation were reported in controlled clinical studies with retigabine, generally within the first 8 weeks of treatment (see section 4.8). Trobalt must be used with caution in patients at risk of urinary retention, and it is recommended that patients are advised about the risk of these possible effects.QT intervalA study of cardiac conduction in healthy subjects has demonstrated that retigabine titrated to 1,200 mg/day produced a QT-prolonging effect. A mean increase in Individual Corrected QT Interval (QTcI) of up to 6.7 ms (upper bound of 95% one-sided CI 12.6 ms) was observed within 3 hours of dosing. Caution should be taken when Trobalt is prescribed with medicinal products known to increase QT interval and in patients with known prolonged QT interval, congestive cardiac failure, ventricular hypertrophy, hypokalaemia or hypomagnesaemia and in patients initiating treatment who are 65 years of age and above.In these patients it is recommended that an electrocardiogram (ECG) is recorded before initiation of treatment with Trobalt and in those with a corrected QT interval>440ms at baseline, an ECG should be recorded on reaching the maintenance dose.Psychiatric disordersConfusional state, psychotic disorders and hallucinations were reported in controlled clinical studies with retigabine (see section 4.8). These effects generally occurred within the first 8 weeks of treatment, and frequently led to treatment withdrawal in affected patients. It is recommended that patients are advised about the risk of these possible effects.Suicide riskSuicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of antiepileptic 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 Trobalt.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 if signs of suicidal ideation or behaviour emerge.Elderly (65 years of age and above)Elderly patients may be at increased risk of central nervous system events, urinary retention and atrial fibrillation. Trobalt must be used with caution in this population and a reduced initial and maintenance dose is recommended (see sections 4.2 and 5.2).Withdrawal seizuresAs with other antiepileptic drugs, Trobalt must be withdrawn gradually to minimise the potential for rebound seizures. It is recommended that the Trobalt dose is reduced over a period of at least 3 weeks, unless safety concerns require an abrupt withdrawal.

Interactions
Interaction studies have only been performed in adults.Other antiepileptic drugsIn vitro data indicated a low potential for interaction with other antiepileptic drugs (see section 5.2). The drug interaction potential was therefore eva luated based on a pooled analysis across clinical studies and whilst not considered as robust as stand-alone clinical interaction studies, the results support the in vitro data.Based on these pooled data, retigabine did not cause clinically significant effects on the plasma trough concentrations of the following antiepileptic drugs:- carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, valproate, zonisamide.Further, based on pooled data, there were no clinically significant effects of the following antiepileptic drugs on retigabine pharmacokinetics:- lamotrigine, levetiracetam, oxcarbazepine, topiramate, valproate.This analysis also showed no clinically significant effect of the inducers (phenytoin, carbamazepine and phenobarbital) on retigabine clearance.However, steady-state data from a limited number of patients in smaller phase II studies indicated that:- phenytoin can reduce retigabine systemic exposure by 35%- carbamazepine can reduce retigabine systemic exposure by 33%Interaction with digoxinData from an in vitro study showed that the N-acetyl metabolite of retigabine (NAMR) inhibited P-glycoprotein-mediated transport of digoxin in a concentration-dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of Trobalt at therapeutic doses may increase digoxin serum concentrations.Interaction with anaestheticsTrobalt may increase the duration of anesthesia induced by some anaesthetics (for example thiopental sodium; see section 5.1).Interaction with alcoholCo-administration of ethanol (1.0 g/kg) with retigabine (200 mg) resulted in an increase in visual blurring in healthy volunteers. It is recommended that patients are advised about the possible effects on vision if they take Trobalt with alcohol.Laboratory testsRetigabine has been shown to interfere with clinical laboratory assays of both serum and urine bilirubin, which can result in falsely elevated readings.

Adverse Reactions
In pooled safety data from three multicentre, randomised, double-blind, placebo-controlled studies, adverse reactions were generally mild to moderate in intensity, and were most commonly reported in the first 8 weeks of treatment. There was an apparent dose-relationship for dizziness, somnolence, confusional state, aphasia, coordination abnormal, tremor, balance disorder, memory impairment, gait disturbance, blurred vision and constipation.Adverse reactions that were most frequently reported to lead to discontinuation were dizziness, somnolence, fatigue and confusional state.The following convention has been used for the classification of adverse reactions:Very common:1/10Common:1/100 to <1/10Uncommon:1/1,000 to <1/100Rare:1/10,000 to <1/1,000Very rare:<1/10,000.Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.System Organ ClassVery commonCommonUncommonMetabolism and nutrition disordersWeight increasedIncreased appetitePsychiatric disordersConfusional statePsychotic disordersHallucinationsDisorientationAnxietyNervous system disordersDizzinessSomnolence1Amnesia1AphasiaCoordination abnormal1Vertigo1ParaesthesiaTremor1Balance disorder1Memory impairment1DysphasiaDysarthriaDisturbance in attentionGait disturbance1MyoclonusHypokinesiaEye disordersDiplopiaBlurred visionGastrointestinal disordersNauseaConstipationDyspepsiaDry mouthDysphagiaHepatobiliary disordersIncreased liver function testsSkin and subcutaneous disordersSkin rashHyperhidrosisRenal and urinary disordersDysuriaUrinary hesitationHaematuriaChromaturiaUrinary retentionNephrolithiasisGeneral disorders and administrative site conditionsFatigueAstheniaMalaisePeripheral oedema1Data from elderly patients indicates that they may be more likely to experience certain central nervous system events.Description of selected adverse reactionsAdverse reactions related to voiding dysfunction, including urinary retention, were reported in 5% of retigabine-treated patients in the pooled safety dataset (see section 4.4). The majority of events occurred in the first 8 weeks of treatment, and there was no apparent dose-relationship.In retigabine-treated patients in the pooled dataset, confusional state was reported in 9% of patients, hallucinations in 2% of patients and psychotic disorders in 1% of patients (see section 4.4). The majority of adverse reactions occurred in the first 8 weeks of treatment, and there was an apparent dose-relationship for confusional state only.

Owner
GlaxoSmithKline UK

Drug Availability
POM – Prescription only medicine

Updated
18 May 2011