Retigabine Other names: Ezogabine

Caution should be taken when retigabine 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 retigabine and in those with a corrected QT interval >440ms at baseline, an ECG should be recorded on reaching the maintenance dose.

Co-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 retigabine with alcohol.

A 50% reduction in the initial and maintenance dose of retigabine is recommended in patients with moderate or severe renal impairment (creatinine clearance <50 ml/min). 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.

For patients with end-stage renal disease receiving haemodialysis, the three daily doses should be taken as usual on the dialysis day. In addition, a single supplemental dose is recommended immediately after haemodialysis. If breakthrough seizures occur towards the end of dialysis then an additional supplemental dose may be considered at the start of subsequent dialysis sessions.

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). 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.

Retigabine may increase the duration of anaesthesia induced by some anaesthetics (for example thiopental sodium).

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%

Risk related to antiepileptic medicinal products in general

Specialist advice should be given to women who are of childbearing potential. The need for treatment with antiepileptic medicinal products should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of antiepileptic medicine therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child.

The risk of congenital malformations is increased by a factor of 2 to 3 in the offspring of mothers treated with antiepileptic medicinal products compared with the expected incidence in the general population of approximately 3%. The most frequently reported defects are cleft lip, cardiovascular malformations and neural tube defects. Therapy with multiple antiepileptic medicinal products is associated with a higher risk of congenital malformations than monotherapy and therefore monotherapy should be used whenever possible.

Risk related to retigabine

There are no adequate data from the use of retigabine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity because the plasma levels achieved in these studies were less than those reached in humans at recommended doses. In a developmental study in rats whose mothers were treated with retigabine during pregnancy, there was a delay in auditory startle response development of the offspring. The clinical significance of this finding is not known.

Retigabine is not recommended during pregnancy and in women of childbearing age, not using contraception.

It is unknown whether retigabine is excreted in human breast milk. Animal studies have shown excretion of retagabine and/or its metabolites in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with retigabine should be made taking into account the benefit of breast-feeding to the child and the benefit of retigabine therapy to the woman.

Fertility

There were no treatment-related effects of retigabine on fertility in animal studies. However, the plasma levels achieved in these studies were less than those reached in humans at recommended doses.

The effect of retigabine on human fertility has not been established.

Adverse reactions such as dizziness, somnolence, diplopia and blurred vision were reported in controlled clinical studies, particularly during titration. It is recommended that patients are advised about the risk of such adverse reactions at treatment initiation and following each titration step, and that they are advised not to drive or operate machinery until they have established how retigabine affects them.

Summary of the safety profile

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.

Tabulated list of adverse reactions

The following convention has been used for the classification of adverse reactions:

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

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Adverse reactions related to voiding dysfunction, including urinary retention, were reported in 5% of retigabine-treated patients in the pooled safety dataset. 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. The majority of adverse reactions occurred in the first 8 weeks of treatment, and there was an apparent dose-relationship for confusional state only. Adverse event data from clinical trial subjects showed a rate of event of discolouration of the nails, lips, skin and/or mucosa per patient year of exposure of 3.6%. The cumulative incidences of an event at 1 year, 2 years, 3 years, 4 years and 5 years of exposure are approximately 1%, 1.8%, 4.4%, 10.2% and 16.7% respectively.

Approximately 30-40% of clinical trial subjects who were being treated with retigabine and underwent a skin and/or ophthalmological examination had findings of discolouration of nails, lips, skin and/or mucosa or non-retinal ocular pigmentation, and approximately 15-30% of clinical trial subjects who were being treated with retigabine and underwent an ophthalmological examination had retinal pigmentation findings. In addition, cases of acquired vitelliform-type maculopathy have been identified, both in clinical studies and as spontaneous reports.

Data from elderly patients indicates that they may be more likely to experience certain central nervous system events, including somnolence, amnesia, coordination abnormal, vertigo, tremor, balance disorder, memory impairment and gait disturbance.