Rajesh C. Sachdeo

Topiramate Monotherapy for Partial Onset Seizures

Summary: Purpose: Evaluation of topiramate (TPM) as monotherapy in patients with uncontrolled partial onset seizures.

Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy.

Summary: Purpose: We studied the steady‐state pharmacokinetic profile of topiramate (TPM) as a function of dose and the effects of comedication with carbamazepine (CBZ).

Oxcarbazepine monotherapy for partial-onset seizures A multicenter, double-blind, clinical trial

Objective: To evaluate the safety and efficacy of oxcarbazepine (OXC) 2,400 mg/day versus OXC 300 mg/day monotherapy in patients with medically refractory partial epilepsy. Background: OXC is primarily metabolized by reductase enzymes and, consequently, has a low propensity to inhibit or induce oxidative enzymes and a minimal potential for drug–drug interactions. The efficacy of OXC as monotherapy was shown in several comparative trials in patients with newly diagnosed epilepsy and in hospitalized patients undergoing evaluation for epilepsy surgery. Methods: A multicenter, double-blind, randomized, parallel-group trial design was chosen to assess the antiepileptic efficacy of OXC as monotherapy in a refractory epilepsy patient population. Outpatients aged 12 years or older with inadequately controlled partial seizures, with or without secondarily generalized seizures, were enrolled. Patients finished the trial by completing the double-blind phase or by meeting one of four predefined exit criteria: a twofold increase in partial seizure frequency in any 28-day period relative to baseline; a twofold increase in the highest consecutive 2-day partial seizure frequency relative to baseline; occurrence of a single generalized seizure if none occurred during the 6 months prior to randomization; or prolongation or worsening of generalized seizure duration or frequency requiring intervention. Adverse events (AEs), vital signs, and clinical laboratory tests were evaluated. Results: The percentage of patients meeting one of the exit criteria was significantly lower (p < 0.0001) for the OXC 2400 mg/day group (14/34; 41%) than the OXC 300 mg/day group (42/45; 93%). In addition, there was a significant difference in time to exit in favor of the OXC 2400 mg/day group (p = 0.0001). In the intent-to-treat analysis, 12% of patients in the OXC 2400 mg/day group were seizure-free compared with none in the 300 mg/day group. OXC was well-tolerated, with dizziness, fatigue, somnolence, and nausea being the most frequent AEs. Most of these AEs were transient and rated as mild to moderate in intensity. Conclusion: OXC is safe and effective in the treatment of patients with partial epilepsy previously receiving treatment with other antiepileptic drugs. The results of this trial are consistent with previous monotherapy trials with OXC.

Effects of oxcarbazepine on sodium concentration and water handling

Oxcarbazepine, a keto‐analogue of carbamazepine, was recently approved in the United States for the treatment of seizures of partial onset. Some patients treated with oxcarbazepine showed the development of hyponatremia, which in most instances was asymptomatic. Understanding the mechanisms by which oxcarbazepine can lead to a reduction of serum sodium levels could have therapeutic implications for the few patients in whom symptomatic hyponatremia develops. In this study, we evaluated sodium and water handling in patients with epilepsy and in healthy subjects titrated over 3 weeks to a maximum daily oxcarbazepine dose of 2,400mg. All subjects were evaluated in a hospital setting after an overnight fast and after an acute water‐load test performed before oxcarbazepine exposure and after maintenance on the medication for 3 weeks. Before oxcarbazepine exposure, the percentage of water load excreted was normal as both groups excreted more than 80% of the administered water load. After the intake of oxcarbazepine, the water load resulted in a reduction of the serum sodium and free water clearance without a concomitant increase in the arginine vasopressin serum levels. Most subjects in both groups failed to excrete 80% or more of the water load, suggesting that the effect of oxcarbazepine is physiological. We found that, after the water load, serum sodium and free water clearance were diminished in both groups without a concomitant increase in the arginine vasopressin serum levels. These findings indicate that oxcarbazepine‐induced hyponatremia is not attributable to the syndrome of inappropriate secretion of antidiuretic hormone. Possible mechanisms include a direct effect of oxcarbazepine on the renal collecting tubules or an enhancement of their responsiveness to circulating antidiuretic hormone.

Topiramate and Phenytoin Pharmacokinetics During Repetitive Monotherapy and Combination Therapy to Epileptic Patients

Summary: u2002Purpose: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment.

Oxcarbazepine for Treatment of Partial Epilepsy: A Review and Recommendations for Clinical Use

Recent trials and extensive postmarketing use confirm the efficacy and safety of oxcarbazepine (OXC) as a first-line treatment for adults and children with simple partial seizures, complex partial seizures, and partial seizures evolving to secondarily generalized seizures. OXC undergoes reductive metabolism at its keto moiety to form 10-hydroxy-10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (MHD), which is glucuronidated and excreted in the urine, with minimal involvement of the hepatic cytochrome P450-dependent enzymes. OXC has some drug interactions, and does not require titration, allowing for better tolerability. Titration for monotherapy and adjunctive therapy of OXC could begin at 150 mg/day and be increased by 150 mg every 2-3 days until the target dose of 900-1200 mg/day is reached. If necessary, one can go faster and start with up to 600 mg/day and titrate with weekly increments up to 600 mg/day if necessary for seizure control. Conversion to monotherapy can be done overnight or gradually. For gradual conversion, use the recommended titration of OXC and withdraw the baseline antiepileptic drugs gradually by 25%, starting at Day 14 or earlier in case of baseline tolerability issues. Consider reducing the dose of the primary antiepileptic drug during adjunctive therapy in case of adverse events or increase the dose of OXC in case of incomplete seizure control. In children OXC should be started at 8-10 mg/kg/day in two or three divided doses. If clinically indicated the dose can then be increased by 10 mg/kg/day in weekly intervals with final doses up to 30-46 mg/kg/day. Dose adjustment may be necessary in very young children (age 2-5 years) and in patients with renal dysfunction, based on renal clearance. However no adjustment of OXC dose is needed in patients with mild to moderate hepatic dysfunction. OXC has a number of advantages which include rapid titration, no need for safety monitoring (except for uncommon and mostly asymptomatic hyponatremia), a low potential for drug-drug interactions (except for those possibly impairing the effectiveness of oral contraceptives and increasing the serum concentration of phenytoin), a rash rate of less than 5%, similar efficacy and similar or better tolerability and safety compared with first-generation antiepileptic drugs. OXC is a valuable alternative to current treatment options.

Sustained Efficacy and Long‐term Safety of Oxcarbazepine: One‐year Open‐label Extension of a Study in Refractory Partial Epilepsy

Summary:u2002 Purpose: To evaluate the long‐term efficacy, tolerability, and safety of oxcarbazepine (OXC) in medically refractory partial epilepsy.

Tolerability and Pharmacokinetics of Monotherapy Felbamate Doses of 1,200–6,000 mg/day in Subjects with Epilepsy

: Purpose: Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200–6,000 mg/day were assessed in two open‐label studies with similar designs.

Amelioration of erectile dysfunction following a switch from carbamazepine to oxcarbazepine: recent clinical experience

ABSTRACT Oxcarbazepine is an antiepileptic drug (AED) indicated for use as monotherapy and add-on therapy in adults and children 4 years of age and older. Despite being structurally related to carbamazepine, oxcarbazepine differs substantially in its pharmacokinetic and safety profile; oxcarbazepine has a much lower risk of pharmacokinetic drug–drug interactions than carbamazepine. Carbamazepine has also been shown to induce the hepatic synthesis of sex hormone-binding globulin, thus reducing free serum testosterone levels and possibly causing erectile dysfunction (ED) in some men; these effects have not been observed with oxcarbazepine. This paper provides a discussion of recent clinical experience with men who presented in private clinical practice with complaints of ED while being treated with carbamazepine for seizure disorders. The four illustrative case studies presented in this report suggest that switching AED treatment from carbamazepine to oxcarbazepine in men with epilepsy can reduce the ED side effects observed with carbamazepine.

Topiramate efficacy in infancy

Topiramate is a sulfamate-substituted monosaccharide that has demonstrated efficacy as an antiepileptic drug in adults with partial onset seizures. Experience in children has been limited, but early reports have supported its safety and effectiveness in children as young as 2 years of age. In two infants ages 12 and 9 months, respectively, with partial seizures, the authors report excellent efficacy with good tolerability at doses up to 7.7 mg/kg. Although long-term safety and possible adverse sequelae have not been fully established in children, topiramate may represent an option for infants with high seizure frequency unresponsive to standard antiepileptic drugs.