TROBALT Film-coated tablet Ref.[27968] Active ingredients: Retigabine

Eye disorders

Pigment changes (discolouration) of ocular tissues, including the retina have been reported in longterm clinical studies with retigabine, sometimes but not always in conjunction with pigment changes of the skin, lips or nails (see below paragraph and section 4.8). Reversibility of retinal pigmentation after retigabine discontinuation has been reported in some subjects. The long-term prognosis of these findings is currently unknown, but some of the reports have been associated with visual impairment.

In addition a distinct form of macular abnormality with features of vitelliform maculopathy (see section 4.8) has also been identified, in most cases diagnosed with optical coherence tomography (OCT) imaging. The rate of progression of vitelliform maculopathy and its impact on retinal and macular function and vision is unclear. Vision abnormalities (field constriction, loss of central sensitivity, and reduced visual acuity) have been reported.

All patients should undergo comprehensive ophthalmological examinations at baseline and at least every six months, which should include visual acuity, slit-lamp examination, dilated fundus photography, and macular OCT imaging. If retinal pigment changes, vitelliform maculopathy or vision changes are detected, treatment with Trobalt should only be continued after a careful re-assessment of the balance of benefits and risks. If continued, the patient should be monitored more closely.

Skin disorders

Pigment changes (discolouration) of the skin, lips or nails have been reported in long-term clinical studies with retigabine, sometimes but not always in conjunction with pigment changes of ocular tissues (see above paragraph and section 4.8). In patients who develop these changes, treatment with Trobalt should only be continued after a careful re-assessment of the balance of benefits and risks.

Urinary retention

Urinary 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 interval

A 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 disorders

Confusional 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 risk

Suicidal 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 medicinal products 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 retigabine.

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 seizures

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 (see section 4.2).

Laboratory tests

Retigabine has been shown to interfere with clinical laboratory assays of both serum and urine bilirubin, which can result in falsely elevated readings.

Interaction studies have only been performed in adults.

Other antiepileptic medicinal products

In vitro data indicated a low potential for interaction with other antiepileptic medicinal products (see section 5.2). The drug interaction potential was, therefore, evaluated 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 medicinal products:

• 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 medicinal products 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 digoxin

Data 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.

Based on a study conducted in healthy volunteers, therapeutic doses of retigabine (600-1,200 mg/day) resulted in a minor (8-18%) increase in digoxin AUC following a single oral dose of digoxin. The increase did not appear to be dependent on retigabine dose and is not considered clinically relevant. There was no meaningful change in digoxin C_max. No dose adjustment of digoxin is needed.

Interaction with anaesthetics

Trobalt may increase the duration of anaesthesia induced by some anaesthetics (for example thiopental sodium; see section 5.1).

Interaction with alcohol

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 Trobalt with alcohol.

Oral contraceptives

At retigabine doses of up to 750 mg/day, there was no clinically significant effect of retigabine on the pharmacokinetics of the estrogen (ethinyl estradiol) or progestogen (norethindrone) components of the oral contraceptive pill. In addition, there was no clinically significant effect of the low dose combination oral contraceptive pill on the pharmacokinetics of retigabine.

Pregnancy

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 Trobalt

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 (see section 5.3). 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 (see section 5.3). The clinical significance of this finding is not known.

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

Breastfeeding

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 Trobalt should be made taking into account the benefit of breast-feeding to the child and the benefit of Trobalt 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 (see section 5.3).

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 (see section 4.8). 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 Trobalt 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 (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. 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 national reporting system listed in Appendix V.

Not applicable.