topiramate and Liver-Diseases

Topiramate, a sulfamate-substituted monosaccharide, is a new antiepileptic drug (AED) approved as adjunctive therapy for partial-onset seizures in adults. Topiramate is rapidly absorbed, has linear pharmacokinetics, minimal protein binding and a long half-life facilitating a twice-daily dosage regimen. Topiramate has little effect on the plasma concentrations of other AEDs with the exception of phenytoin, concentrations of which may increase in some patients when topiramate is added to the therapy. Topiramate metabolism is increased when administered with carbamazepine or phenytoin. In the absence of enzyme-inducing AEDs, topiramate is eliminated primarily by renal excretion, with 50 to 80% of a dose excreted as unchanged topiramate. In 6 double-blind, placebo-controlled trials, topiramate was shown to be well tolerated and effective as adjunctive therapy for partial-onset seizures in adults. Topiramate consistently reduced seizures across all patient groups defined by age, gender and baseline seizure frequency. Adverse effects were generally mild-to-moderate CNS-related effects and often resolved spontaneously or with slowing of topiramate titration and/or reduction of the dosage of concomitant AEDs. Clinical studies are currently evaluating the effectiveness and safety of topiramate as monotherapy and adjunctive therapy in children with partial seizures, in patients with Lennox-Gastaut syndrome and in patients with generalised tonic-clonic seizures of non-focal onset. Preliminary findings suggest that topiramate has a broad spectrum of clinical use.

Topics: Adult; Aged; Anticonvulsants; Child; Drug Interactions; Epilepsy; Fructose; Humans; Kidney Diseases; Liver Diseases; Topiramate

Topiramate is primarily renally excreted. Chronic renal and hepatic impairment can affect the clearance of topiramate. Therefore, the objective was to establish dosage guidelines for topiramate in chronic renal impairment, end-stage renal disease (ESRD) undergoing hemodialysis, or chronic hepatic impairment patients.. In 3 separate open-label, parallel group studies (n=5-7/group), in patients with mild-moderate and severe renal impairment (based on creatinine clearance), ESRD requiring hemodialysis, or moderate-severe hepatic impairment (based on Child-Pugh classification) and matching healthy participants, pharmacokinetics of a single oral 100mg topiramate was determined.. Compared with healthy controls, overall exposure (AUC0-∞) for topiramate was higher in mild-moderate (85%) and severe renal impairment (117%), consistent with significantly (p<0.05) lower apparent total body clearance (CL/F) and renal clearance (CLR), leading to longer elimination half-life. Both CLR and CL/F of topiramate correlated well with renal function. CL/F was comparable in ESRD and severe renal impairment. Half of usual starting and maintenance dose is recommended in moderate-severe renal impairment patients, and those with ESRD. Hemodialysis effectively removed plasma topiramate with mean dialysis clearance approximately 12-fold greater than CL/F (123.5 mL/min versus 10.8 mL/min). Compared with healthy matched, patients with moderate-severe hepatic impairment exhibited small increase (29%) in topiramate peak plasma concentrations and AUC0-∞ values, consistent with lower CL/F (26%). Topiramate was generally well tolerated.. Half of usual dose is recommended for moderate-severe renal impairment and ESRD. Supplemental dose may be required during hemodialysis. Dose adjustments might not be required in moderate-severe hepatic impairments; however, the small sample size limits generalization.

Topics: Adult; Aged; Aging; Anticonvulsants; Creatine; Female; Fructose; Humans; Kidney Failure, Chronic; Liver Diseases; Male; Middle Aged; Renal Dialysis; Severity of Illness Index; Topiramate

We present three children with severe therapy-refractory epilepsy who tolerated valproate (VPA) well in various combinations with other antiepileptic drugs (AEDs) but developed typical VPA side effects in combination with topiramate (TPM).. The clinical symptoms began with apathy in all three children; two of them also had hypothermia. Furthermore all children had elevated blood ammonia levels, one child in combination with increased liver transaminases and one with thrombocytopenia.. All children recovered completely after discontinuation of VPA or TPM.. TPM seems likely to enhance the risk of side effects usually attributed to VPA and not described in TPM monotherapy. Our case reports suggest that possible adverse effects of VPA should be given particular attention when VPA is combined with TPM.

Topics: Affective Symptoms; Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Hypothermia; Infant; Liver; Liver Diseases; Male; Risk Factors; Thrombocytopenia; Topiramate; Transaminases; Valproic Acid