Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of carisbamate (CRS), an investigational drug, as adjunctive treatment for partial-onset seizures in adults. METHODS: A randomized, double-blind, placebo-controlled, multicenter, dose-ranging study was conducted in 12 countries. Patients counted seizures during an 8-week baseline period, and then, if eligible, entered a double-blind phase consisting of a 4-week dose-titration period (target CRS doses: 100, 300, 800, or 1,600 mg/d or placebo in two divided doses) and a 12-week maintenance period. The primary efficacy variable was percent reduction in partial-onset seizure frequency during the double-blind phase compared with pretreatment baseline. Safety data and responder rates were also assessed. RESULTS: Five hundred thirty-seven patients were randomized, and 82% completed the study. In the intent-to-treat population (n = 533), CRS at doses of > or =300 mg/d (p < or = 0.006) reduced the frequency of partial-onset seizures vs placebo: 6% (placebo) vs 24% (300 mg/d), 21% (800 mg/d), and 29% (1,600 mg/d) for CRS. Adverse events consisted primarily of CNS effects, and led to discontinuation of drug in 8% of the placebo group vs 5% (100 mg/d), 6% (300 mg/d), 12% (800 mg/d), and 19% (1,600 mg/d) of the CRS groups. CONCLUSIONS: Carisbamate at doses of 300, 800, and 1,600 mg/d was effective as adjunctive therapy for reducing the frequency of partial-onset seizures.

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.

Nonfocal generalized tonic-clonic seizures: response during long-term topiramate treatment. Topiramate YTC/YTCE Study Group.

PURPOSE: A total of 131 adults and children (mean age, 27 years; range, 3-59 years) with generalized tonic-clonic seizures (GTCS) of nonfocal origin resistant to other antiepileptic drugs (AEDs) were treated with open-label topiramate (TPM) after completing double-blind placebo-controlled trials. RESULTS: The mean duration of open-label TPM treatment was 387 days (range, 14-909 days); the mean TPM dose was 7 mg/kg/day (range, 1-16 mg/kg/day). At the last study visit, the frequency of GTCS was reduced > or =50% from baseline in 63% of patients and by > or =75% in 44%. Among patients treated > or =6 months, 16% were GTCS free > or =6 months despite a pretreatment seizure frequency of one GTCS/week (median). Treatment with TPM was being continued in 82% of patients (n = 107) at the last visit. During treatment periods of up to 2.5 years, 11 (8%) patients discontinued TPM because of adverse events and seven (5%) because of inadequate seizure control. CONCLUSIONS: TPM therapy was well tolerated, and seizure control was maintained with long-term, open-label therapy in patients with GTCS, leading to prolonged seizure-free intervals in some patients with seizures previously resistant to AED therapy.

An open-label study of repeated use of diazepam rectal gel (Diastat) for episodes of acute breakthrough seizures and clusters: safety, efficacy, and tolerance. North American Diastat Group.

PURPOSE: To assess safety of diazepam rectal gel (DZPRG) for control of acute seizures in epilepsy patients and to evaluate tolerance with repeated use of DZPRG at intervals of > or =5 days. METHODS: Subjects were persons with epilepsy, age 2 years or older, with seizure clusters or prolonged seizures. Onset of a treatable episode was defined; caregivers were trained to administer DZPRG and to monitor respiration, seizures, and adverse effects (AEs). DZPRG was dispensed in a single-use, prefilled syringe; dosage was determined by age and weight. Maximal use was > or =5-day intervals, < or =5 times/month. After use, caregivers returned data booklets and syringe. Caregivers and physicians completed global ratings yearly. RESULTS: In 149 subjects treated, 77% of 1,578 administrations resulted in seizure freedom for the next 12 h. One hundred twenty-five received two or more treatments (two to 78; median, 8), 0.03-4.3/month (median, 0.4). To evaluate tolerance, subjects with two or more episodes were divided into low (two to seven episodes) and high use (eight to 78 episodes treated). There was no difference in proportion seizure free 12 h after the first administration versus last administration, for either infrequent or frequent administration. Sedation occurred in 17%, attributed to DZPRG in 9%. No respiratory depression was attributable to DZPRG. Three subjects withdrew because of AEs attributable to (agitation) or possibly attributable to DZPRG (chest pain, rash). Five subjects withdrew because of AEs unrelated to DZPRG. Caregiver and physician global ratings were highly positive at both 12 and 24 months. CONCLUSIONS: DZPRG is safe and effective in children and adults with epilepsy with breakthrough seizures. Neither tolerance nor significant medication-related AEs were seen with repeated DZPRG administration at intervals > or =5 days.

A study of topiramate pharmacokinetics and tolerability in children with epilepsy.

The pharmacokinetic and safety profile of topiramate as adjunctive therapy was assessed in pediatric patients with epilepsy in an open-label, 4-week, single-center study. Six children from each of the following age groups were enrolled: 4-7 years, 8-11 years, and 12-17 years. Patients received topiramate 1 mg/kg/day for 1 week, with subsequent progressive weekly increases in dosage to 3, 6, and then 9 mg/kg/day or 800 mg/day, whichever was less. Topiramate oral plasma clearance (CI/F) was independent of dose, and steady-state plasma concentrations increased in proportion to dose. Weight-normalized topiramate CL/F was higher (P = 0.003) in pediatric patients receiving enzyme-inducing concomitant antiepileptic drugs (AEDs) (mean = 70.1 ml/minute/70 kg) than in those not receiving enzyme-inducing AEDs (mean = 33.1 mL/ minute/kg). Topiramate CL/F in children was approximately 50% greater than that observed in adults regardless of the type of concomitant AED therapy. Thus steady-state plasma topiramate concentrations for the same mg/kg dose will be approximately 33% lower in pediatric patients than in adult patients. The most frequently reported treatment-emergent adverse events considered related to topiramate therapy included anorexia, fatigue, and nervousness, and no patient discontinued therapy. This study indicates that, in children 4-17 years of age, topiramate has linear pharmacokinetics, 50% higher clearance than in adults, and is generally well tolerated.

Treating repetitive seizures with a rectal diazepam formulation: a randomized study. The North American Diastat Study Group.

OBJECTIVE: To evaluate the effectiveness and safety of a single-dose treatment for acute repetitive seizure (ARS) episodes (e.g., clusters) administered in a nonmedical setting by caregivers. BACKGROUND: Patients with epilepsy may experience ARS episodes despite optimal anticonvulsant treatment. Such episodes require rapid treatment as medical emergencies. Typically, the patient is treated in an emergency medical setting with i.v. medication by trained medical personnel. METHODS: The authors undertook a multicenter, randomized, parallel, double-blind study of a single administration of Diastat (diazepam rectal gel) for treating episodes of ARS. ARS episodes and treatment criteria were defined for each patient at the start of the study. Caregivers were taught to determine ARS episode onset, administer a predetermined dose of study medication, monitor outcome, count respirations, and record seizures and adverse events. RESULTS: A total of 29 centers enrolled 158 patients, of whom 114 patients had a treated ARS episode (Diastat, n = 56; placebo, n = 58). Diastat treatment reduced median seizure frequency (p = 0.029). More Diastat patients were seizure free post-treatment (Diastat, 55%; placebo, 34%; p = 0.031). Kaplan-Meier analysis of the time to the next seizure favored Diastat treatment (p < 0.007). The most common adverse event was somnolence. CONCLUSION: Administration of a single rectal dose of Diastat was significantly more effective than placebo in reducing the number of seizures following an episode of ARS. Caregivers could administer treatment safely and effectively in a nonmedical setting.

Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy.

PURPOSE: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. METHODS: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-microg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200, and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. RESULTS: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100-400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC(0-24)) values for ethinyl estradiol were 18-30% lower in cycles 2 through 4 compared with cycle 1 (p < or = 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7-33.0% higher (p < or = 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T(max)) values determined during topiramate therapy were not significantly different from those at baseline. CONCLUSIONS: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing > or = 35 microg of ethinyl estradiol.

PIP: The efficacy of combined oral contraceptives (OCs) is diminished in women taking enzyme-inducing anti-epileptic drugs such as phenytoin, phenobarbital, and carbamazepine. In preliminary in vitro studies, a new anti-epileptic drug derived from D-fructose, topiramate, produced no clinically relevant inhibitory effects on the metabolism of such drugs as barbiturates, classic neuroleptics, and tricyclic antidepressants. To assess this new drug, 12 women with documented histories of epilepsy took an OC containing 1 mg norethindrone and 35 mcg ethinyl estradiol as well as topiramate (100-400 mg every 12 hours) for 4 menstrual cycles. Serial blood samples were obtained on day 20 of the 4 cycles. None of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate. Ethinyl estradiol serum levels were reduced by an average of 30% from baseline. The mean area under the concentration-versus-time curve over the 24-hour period values for ethinyl estradiol were 18-30% lower in cycles 2-4 than the baseline cycle and mean oral serum clearance values were 14.7-33.0% higher. This compares favorably with the 40-72% reductions in progestin and estrogen levels recorded in women taking a levonorgestrel-containing OC and enzyme-inducing anti-epileptics. Although topiramate's modest interaction with OCs is not likely to interfere with contraceptive efficacy, the reduction in serum estrogen concentrations has the potential to increase the incidence of breakthrough bleeding, indicating the OC should contain at least 35 mcg of estrogen.

Comparison of the steady-state pharmacokinetics of topiramate and valproate in patients with epilepsy during monotherapy and concomitant therapy.

PURPOSE: The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions. METHODS: After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy. RESULTS: All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for > or = 2 weeks without VPA. TPM plasma peak concentration (C(max)) and area under the concentration-versus-time curve during a 12-h dosing interval (AUC(0-12)) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy. TPM oral and renal clearances (n = 8) were 25.9 +/- 4.6 and 11.6 +/- 3.2 ml/min during TPM monotherapy and were 29.8 +/- 4.2 and 12.4 +/- 2.7 ml/min during VPA concomitant therapy. VPA AUC(0-12) decreased (11.3%; n = 10) with the addition of TPM 400 mg every 12 h. VPA oral clearance was 12.8 +/- 4.1 ml/min during monotherapy and was 13.8 +/- 4.0, 14.1 +/- 3.9, and 14.5 +/- 5.2 ml/min during coadministration of TPM 100, 200, and 400 mg every 12 h, respectively. Cognitive dysfunction, observed in some patients receiving high doses of VPA with TPM, reversed or improved with VPA dose reduction and discontinuation. The lower-than-normal prestudy platelet count measured in one patient increased to normal levels when VPA was discontinued. CONCLUSIONS: Because changes in TPM and VPA pharmacokinetics were small, it is unlikely that their concomitant use will have a significant impact on the clinical condition of the patient.

Long-term experience with topiramate as adjunctive therapy and as monotherapy in patients with partial onset seizures: retrospective survey of open-label treatment.

Because initial studies of new antiepileptic drugs (AEDs) are add-on trials in refractory patient populations, their effectiveness as monotherapy is usually not apparent until relatively later in their development programs. The novel AED topiramate (TPM) has been found efficacious as adjunctive therapy in controlled, randomized trials in adults with partial onset seizures. We report a retrospective analysis of TPM as AED monotherapy in 214 patients from five centers who received TPM in investigational trials. Of this total, 136 (64%) were still receiving TPM at the time of the analysis, with a mean treatment duration of 2.5 years. One-third of the patients have been successfully converted to TPM monotherapy, and 62% of those converted have been seizure-free for at least 3 months. The results of this analysis suggest that TPM may prove to be a valuable new AED for both monotherapy and add-on therapy in partial onset epilepsy.

Topiramate: a review of preclinical, pharmacokinetic, and clinical data.

The antiepileptic drug (AED) topiramate is a monosaccharide derivative with a sulfamate functionality. It modulates voltage-dependent sodium conductance, potentiates gamma-aminobutyric acid-evoked currents, and blocks the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of the glutamate receptor. Topiramate is rapidly absorbed and has linear, proportional, steady-state pharmacokinetics. It has no known clinically significant effect on plasma levels of carbamazepine, valproic acid, or phenobarbital, although it may increase plasma concentrations of phenytoin in some patients. When topiramate is used with hepatic enzyme-inducing AEDs, its plasma concentrations are approximately 50% lower than when it is administered alone. The efficacy of topiramate 200 to 1000 mg/d administered in two divided doses as adjunctive therapy for partial-onset seizures was investigated in five double-masked, placebo-controlled trials. The median percentage reduction in average monthly seizure frequency from baseline was 12% for placebo, compared with 30% for the 200-mg/d group and 48% for the 400-mg/d group. At a dosage of 400 mg/d, a seizure reduction of 75% or greater was seen in 22% of topiramate patients, compared with 7% of those receiving placebo; up to 9% of topiramate patients, compared with none of those receiving placebo, became seizure free. Although little additional efficacy was seen at dosages of 600, 800, and 1000 mg/d, dosing should be individualized, because some patients may respond to higher dosages. When topiramate is combined with other AEDs, the most common side effects at dosages of 200 to 400 mg/d are somnolence, dizziness, ataxia, psychomotor slowing, hesitant speech, and wordfinding difficulties. Most patients who experienced adverse events during the first 8 weeks of the trials no longer experienced them by their last visit. Although there was a 1.5% incidence of renal stones that may be associated with carbonic anhydrase inhibition, more than 75% of patients experiencing a stone continued on therapy.

Absorption of valproic acid suppositories in human volunteers.

The absorption of valproic acid administered by rectal suppository was studied in six male volunteers. Valproic acid was incorporated into a synthetic lipid base in our pharmacy. Each subject received 500 mg of valproic acid by rectal suppository and 500 mg of oral valproate sodium syrup one week apart; 13 blood samples were drawn to determine serum concentrations over 48 hours after administration of each formulation. Significant differences were evident in the amount absorbed, maximum serum concentration, and time to achieve maximum serum concentration between the oral and rectal formulations. Mean absorption after rectal suppository was 80%. Maximum serum concentration was 43.4 mg/L after oral administration and 29.2 mg/L after rectal suppository. The time to achieve maximum serum concentration was 1.0 hour after oral syrup and 3.1 hours after rectal suppository. Absorption of the rectal suppository was consistent and complete within 3 hours. The use of valproate sodium in rectal suppository form can be a more convenient and satisfactory method of administering valproic acid when the oral route is impossible. Dosage increases may be necessary, and serum concentrations should be monitored.

Adverse behavioral response to clonazepam as a function of Verbal IQ-Performance IQ discrepancy.

Eight of 38 consecutive patients who received clonazepam had significant behavioral side effects. In these 8 patients, the mean absolute IQ discordance between Verbal IQ (VIQ) and Performance IQ (PIQ) was 17.5 points. Thirty of 38 patients had no adverse behavioral side effects while receiving clonazepam. In these 30 patients, the mean absolute VIQ-PIQ discrepancy was 6.5 points. Full neuropsychological testing had been performed on all patients. The only test variable showing a statistically significant difference was the absolute discrepancy between VIQ and PIQ (P less than 0.0001).

Valproic acid loading during intensive monitoring.

Of 35 patients who had generalized tonic-clonic seizures during antiepileptic drug therapy withdrawal, "loading" with valproic acid was effective in limiting these seizures in 32 patients. A loading dose of approximately 12.5 mg/kg was used. This dose resulted in valproic acid levels between 284 and 458 mumol/L (41 and 66 mg/L) 1.5 hours after "loading" in six of the eight patients in whom serum concentrations were measured.

Response of multiple seizure types to corpus callosum section.

Twenty-four patients (16 men, 8 women) underwent corpus callosum section specifically for improvement of control of atonic or tonic seizures that resulted in falls and injuries. All patients suffered from multiple seizure types, including complex partial (CP) and tonic-clonic (TC) seizures, in addition to the tonic or atonic episodes. Preoperative seizure frequency was quantified for all types for 1 year immediately before surgery and for the most recent year since the procedure; average monthly counts were obtained for each seizure type. The period of follow-up since surgery averaged 43 months (range, 23-79 months). Statistically significant improvements were documented, not only for the atonic/tonic seizures (p less than 0.0001) for all patients, but also for TC seizures (17 patients; p less than 0.001) and CP seizures (20 patients; p less than 0.02). Six patients experienced an exacerbation of CP seizures postoperatively, and three developed new simple partial (SP) seizures. In all of the CP group and all three of the SP group, ictal video and EEG features suggested that the new seizures were an aborted expression of the previously generalized seizures. From these data, we conclude that callosotomy is an effective treatment for tonic, atonic, and TC seizures intractable to anticonvulsant medications. Three patients became seizure free. The procedure may also be useful for certain specific subgroups of CP epilepsy, but further studies are required before expanding callosotomy to intractable CP seizures not amenable to focal resection.

Chronic inflammatory polyradiculoneuropathy complicated by factor VIII antibody.

A 66-year-old man with a 45-month course of chronic inflammatory polyradiculoneuropathy developed a coagulopathy due to an antibody to factor VIII. Despite clinical improvement in the neurologic disease at the onset of the coagulation disorder, antibody to peripheral nerve myelin was demonstrated in high titer. Antibodies to factor VIII and peripheral nerve myelin were both of the IgG class, but were immunologically distinct. This previously unreported association lends further credence to a disturbance in immunoregulation in chronic inflammatory polyradiculoneuropathy.