In a single dose study in volunteers with end stage renal disease, the retigabine AUC was increased by approximately 100% relative to healthy volunteers. However, the effect of haemodialysis on retigabine clearance was not adequately eva luated.

Hepatic impairment

In a single dose study, there were no clinically significant effects on retigabine AUC in volunteers with mild hepatic impairment (Child-Pugh score 5 to 6). The retigabine AUC was increased by approximately 50% in volunteers with moderate hepatic impairment (Child-Pugh score 7 to 9) and by approximately 100% in volunteers with severe hepatic impairment (Child-Pugh score >9), relative to healthy volunteers. Adjustment of the Trobalt dose is recommended in patients with moderate or severe hepatic impairment (see section 4.2).

Body weight

In a population pharmacokinetic analysis, retigabine clearance increased with increasing body surface area. However, this increase is not considered to be clinically meaningful, and since retigabine is titrated according to individual patient response and tolerability, dose-adjustments are not required on the basis of body weight.

Elderly (65 years of age and above)

In a single-dose study, retigabine was eliminated more slowly by healthy elderly volunteers (66 to 82 years of age) relative to healthy young adult volunteers, resulting in a higher AUC (approximately 40 to 50%) and longer terminal half-life (30%) (see section 4.2).

Gender

The results of a single dose study showed that in young adult volunteers, retigabine Cmax was approximately 65% higher in females than in males, and in elderly volunteers (66 to 82 years of age), retigabine Cmax was approximately 75% higher in females compared with males. When Cmax was normalized for weight, the values were approximately 30% higher in young females than in males and 40% higher in elderly females compared with males. However, there was no apparent gender difference in weight-normalized clearance, and since retigabine is titrated according to individual patient response and tolerability, dose-adjustments are not required on the basis of gender.

Race

A post-hoc analysis across multiple healthy volunteer studies demonstrated a 20% reduction in retigabine clearance in healthy black volunteers relative to healthy Caucasian volunteers. However, this effect is not considered clinically significant, therefore no adjustment of the Trobalt dose is recommended.

Paediatric population

The pharmacokinetics of retigabine in children and adolescents have not been investigated.

5.3 Preclinical safety data

 Maximum doses in repeat dose toxicity studies were limited by the exaggerated pharmacologic effects of retigabine (including ataxia, hypokinesia and tremor). At no observed effect levels, animal exposure in these studies was generally less than that reached in humans at recommended clinical doses.

Distension of the gall bladder was seen in studies with dogs, but there was no evidence of cholestasis or other signs of gall bladder dysfunction, and bile ejection volume was unchanged. The gall bladder distension in the dog resulted in focal compression of the liver. No signs of gall bladder dysfunction were seen clinically.

Preclinical data reveal no special hazard for