Perampanel: expanding therapeutic options for patients with medically refractory secondary generalized convulsive seizures.

To evaluate the efficacy of adjunctive, once-daily perampanel against secondarily generalized (SG) seizures in three Phase III trials (studies 304, 305, and 306) and their extension (study 307). The Phase III studies enrolled patients (≥ 12 years) with uncontrolled partial-onset seizures despite treatment with 1-3 concomitant antiepileptic drugs. Patients completing the core Phase III studies were eligible for the extension study. Endpoints included median percent change in SG seizure frequency, 50% responder (proportion of patients achieving a ≥ 50% reduction in SG seizure frequency), 75% response, and seizure-freedom rates. In total, 1480 patients were randomized and treated in the three perampanel Phase III trials. At baseline, 71.9% of placebo-treated and 68.4% of perampanel-treated patients had a history of SG seizures. In the individual core Phase III studies, perampanel (4-12 mg) reduced seizure frequency and improved responder rates. Consistent with this, in pooled analyses of the Phase III data, the median percent change in SG seizure frequency was -48.6%, -62.9%, and -53.3% with perampanel 4, 8, and 12 mg, respectively, vs -19.4% with placebo; 50% responder rates were 49.3%, 60.5%, and 53.7% vs 37.0% with placebo. More perampanel-treated patients had ≥ 75% reductions in SG seizure frequency, and seizure-freedom rates improved, compared with placebo. Improvements in seizure frequency and responder rate were maintained during the extension study. Perampanel consistently demonstrated efficacy against SG seizures when assessed using various endpoints. Furthermore, reductions in seizure frequency and improvements in responder rate were sustained with long-term perampanel treatment.

Steady-state carbamazepine pharmacokinetics following oral and stable-labeled intravenous administration in epilepsy patients: effects of race and sex.

Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half-life in patients at steady state have not been determined. We developed an intravenous, stable-labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety-two patients received a 100-mg infusion of SL-carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography-mass spectrometry, and concentration-time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half-life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.

Phenytoin half-life and clearance during maintenance therapy in adults and elderly patients with epilepsy.

BACKGROUND: Phenytoin (PHT) is widely used to treat epilepsy in elderly patients, but information on its pharmacokinetics in this population is limited. OBJECTIVE: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen. METHODS: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model. RESULTS: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours. CONCLUSIONS: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients' sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2-3 weeks.

Trends in antiepileptic drug prescribing for older patients with new-onset epilepsy: 2000-2004.

BACKGROUND: Newer antiepileptic drugs (AEDs) have been shown to be equally efficacious as older seizure medications but with fewer neurotoxic and systemic side effects in the elderly. A growing body of clinical recommendations based on systematic literature review and expert opinion advocate the use of the newer agents and avoidance of phenobarbital and phenytoin. This study sought to determine if changes in practice occurred between 2000 and 2004--a time during which evidence and recommendations became increasingly available. METHODS: National data from the Veterans Health Administration (VA; inpatient, outpatient, pharmacy) from 1998 to 2004 and Medicare data (1999-2004) were used to identify patients 66 years and older with new-onset epilepsy. Initial AED was the first AED received from the VA. AEDs were categorized into four groups: phenobarbital, phenytoin, standard (carbamazepine, valproate), and new (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate). RESULTS: We found a small reduction in use of phenytoin (70.6% to 66.1%) and phenobarbital (3.2% to 1.9%). Use of new AEDs increased significantly from 12.9% to 19.8%, due primarily to use of lamotrigine, levetiracetam, and topiramate. CONCLUSIONS: Despite a growing list of clinical recommendations and guidelines, phenytoin was the most commonly used antiepileptic drug, and there was little change in its use for elderly patients over 5 years. Research further exploring physician and health care system factors associated with change (or lack thereof) will provide better insight into the impact of clinical recommendations on practice.

New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.

OBJECTIVE: To determine the relative tolerability and efficacy of two newer antiepileptic drugs, lamotrigine (LTG) and gabapentin (GBP), as compared to carbamazepine (CBZ) in older patients with epilepsy. METHODS: This was an 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 mg/day. The primary outcome measure was retention in trial for 12 months. RESULTS: Mean age was 72 years. The most common etiology was cerebral infarction. Patients had multiple medical conditions and took an average of seven comedications. Mean plasma levels at 6 weeks were as follows: GBP 8.67 +/- 4.83 microg/mL, LTG 2.87 +/- 1.60 microg/mL, CBZ 6.79 +/- 2.92 microg/mL. They remained stable throughout the trial. Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% (p = 0.0002). Significant paired comparisons: LTG vs CBZ: p < 0.0001; GBP vs CBZ: p = 0.008. Terminations for adverse events: LTG 12.1%, GBP 21.6%, CBZ 31% (p = 0.001). Significant paired comparisons: LTG vs CBZ: p < 0.0001; LTG vs GBP: p = 0.015. There were no significant differences in seizure free rate at 12 months. CONCLUSIONS: The main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.

Rapid infusion with valproate sodium is well tolerated in patients with epilepsy.

Many IV antiepileptic drugs administered in emergency situations to patients with prolonged seizures have serious adverse effects. For this reason, the authors conducted a multicenter, open-label, prospective, dose-escalation study of IV valproate sodium administered to patients with epilepsy at rates of infusion of up to 6 mg/kg/minute and doses of up to 30 mg/kg. Valproate sodium had no clinically significant negative effects on blood pressure and pulse rate and caused only mild-to-moderate, reversible adverse events.

Safety and tolerance of rapidly infused Depacon. A randomized trial in subjects with epilepsy.

BACKGROUND: Valproate sodium injection (Depacon(R)) is an intravenous form of valproate for use in absence and complex partial seizures when circumstances preclude oral administration. Certain situations may warrant larger and more rapid infusions than permitted by the original labeling. This study evaluated the safety of more rapid infusions. METHODS: Subjects with epilepsy were randomized in a 2:1 ratio to receive up to 15 mg/kg of valproate sodium infused at 3.0 or 1.5 mg/kg/min. Up to four infusions were allowed within 24 h to achieve target plasma valproate concentrations of 50-100 mcg/ml. Primary safety endpoints were the changes in the 5-min and minimum post-first infusion blood pressures (BPs). RESULTS: One hundred twelve subjects were treated, (3.0 mg/kg/min group: n=72, 1.5 mg/kg/min group: n=40). No significant treatment differences were detected for changes in the primary BP endpoints. Two subjects in the 3.0 mg/kg/min group had potentially clinically significant low systolic BP values during the study. Similar proportions of subjects in the two groups reported adverse events during or within 6 h following the first infusion. CONCLUSIONS: Valproate sodium injection dosages up to 15 mg/kg and rates of 1.5 and 3.0 mg/kg/min were well tolerated in this population.

Fosphenytoin: pharmacokinetics and tolerance of intramuscular loading doses.

PURPOSE: Fosphenytoin (FPHT; Cerebyx) is well absorbed when given intramuscularly (IM). All prior pharmacokinetic studies had the first plasma sample obtained 30 min after IM administration. The objectives of this study were to determine the rate and extent of FPHT absorption and to evaluate the tolerability of IM FPHT compared with IM saline. METHODS: This was an open-label, double-blinded study in which patients received 10 mg/kg dose of IM FPHT in one gluteus and IM saline in the other gluteus. Half the patients received saline injection of equal volume to FPHT (up to 19.5 mL); the other half received 2 mL of saline. Neurologic examination, vital signs, PHT blood samples, injection site examination, and subjective pain scores at injection site were obtained before and at timed intervals for 6 h. RESULTS: Total PHT serum concentrations 10 microg/mL were obtained in 5 min in 14.3% of patients and in 26.3% after 10 min. More than half the patients had therapeutic serum concentrations at 30 min; 45.8% of patients reported no pain at either the FPHT or saline injection site. No significant difference in pain was noted between FPHT and saline injection sites at 60 min and thereafter. Early decrease in blood pressure occurred but was not clinically significant. Classic PHT-induced central nervous system (CNS) side effects were evident in one third of patients within 1 h after injection. CONCLUSIONS: (a) IM FPHT is rapidly absorbed (therapeutic levels achieved as early as 5-20 min). (b) IM FPHT is well tolerated by most patients irrespective of injection volume.

Increased seizures after discontinuing carbamazepine: results from the gabapentin monotherapy trial.

Studies in patients with epilepsy undergoing telemetry evaluation for surgery have suggested that discontinuation of carbamazepine (CBZ) is associated with increased seizures. The period of observation in that setting, however, was limited to a few days. The authors reviewed the occurrence of seizures in patients with epilepsy who had all their antiepileptic medications discontinued during an 8-week period, converted to gabapentin monotherapy, and observed for 26 weeks as part of the gabapentin trial #945-082. Two hundred and seventy-five patients were enrolled. Kaplan-Meier estimates of time to exit for all patients showed that 18% of patients previously treated with CBZ completed the study as compared with 30% of the patients receiving other antiepileptic medications. Increase in the frequency of seizures was maximal in the 2 weeks following CBZ discontinuation. Seizures increased both in frequency and severity but no new seizure types were observed. The findings in this study show that removal of CBZ is associated with increased frequency of seizures in patients with a previous history of epilepsy with incompletely controlled seizures. The period of maximal increase was the first 2 weeks after CBZ discontinuation.

Epilepsy in the elderly.

The incidence of epilepsy is high in the elderly. Increasing awareness of this phenomenon has led to a better understanding of the predominant seizure types, their clinical manifestations, and the most appropriate treatment regimens. Carbamazepine, phenytoin, and valproic acid are considered to be first-line antiepileptic drugs (AEDs). However, the newer AEDs gabapentin, lamotrigine, and tiagabine also warrant consideration as first-line agents because of their efficacy and favorable side-effect profiles. This is particularly important because aging produces physical changes in the patient that can increase the likelihood of adverse effects. To select the appropriate drug and dosage for each individual, a variety of issues must be considered. These include age-related changes in body composition and physiology, as well as the pharmacokinetics, routes of administration, drug interactions, adverse-effect profiles, and cost of available agents.

Fosphenytoin and phenytoin in patients with status epilepticus: improved tolerability versus increased costs.

Tonic-clonic status epilepticus (TCSE) is the most common neurological emergency and affects approximately 60000 patients each year in the US. The risk of complications increases substantially as TCSE lasts longer than 60 minutes. Ideally, drugs used to treat this condition should be well tolerated when administered as rapid intravenous infusions and should not interfere with patients' state of consciousness or cardiovascular and respiratory functions. Because of its efficacy, absence of sedation or respiratory suppression, intravenous phenytoin has largely replaced phenobarbital (phenobarbitone) as the second agent of choice (following the administration of a benzodiazepine) in the treatment of TCSE. While the efficacy of phenytoin in the treatment of acute seizures and TCSE is well established, the parenteral formulation of phenytoin has several inherent shortcomings which compromise its tolerability and limit the rate of administration. Intravenous phenytoin has been associated with fatal haemodynamic complications and serious reactions at the injection site including skin necrosis and amputation of extremities. Fosphenytoin, a phenytoin prodrug, has the same pharmacological properties as phenytoin but none of the injection site and cardiac rhythm complications of intravenous infusions of phenytoin. While fosphenytoin costs more than intravenous phenytoin, treating the acute and chronic complications of TCSE itself, and the complications of intravenous phenytoin can also be costly. All other factors being equal, there is no doubt that fosphenytoin is better tolerated and can be delivered faster than intravenous phenytoin; 2 measures that clearly improve outcome in patients with TCSE. The tolerability of intramuscular fosphenytoin also extends its use to clinical situations where prompt administration of a nondepressing anticonvulsant is indicated but secure intravenous access and cardiac monitoring are not available, such as treatment of seizures by rescue squads in the field and serial seizures in the institutionalised, elderly and other patients with intractable epilepsy.

New developments in the treatment of epilepsy.

Epilepsy is a medical disorder that presents with single or clustered seizures. There are several new drugs that effectively treat epilepsy with few side effects, and treatments of children, women, and the elderly are discussed. In the special population of children, there is a strong emphasis on the cognitive and behavioral benefits of specific therapies. In the population of epileptic women, seizures most often occur at the start of puberty and menarche, and worsen periodically with each menstrual cycle. Relief of symptoms often occurs at menopause, but a possibility of exacerbation also exists. Women with epilepsy often battle a fear of becoming pregnant. This is a fallacy which must be widely dispelled, as the risk is less than supposed. Among the elderly, epilepsy often presents after trauma, particularly stroke, and the incidence is three times greater for those over 60 years of age than the general population. Due to various conditions specific to the elderly, misdiagnosis is common. The greatest challenge in treating the elderly is adverse side effects.

Guidelines for nonemergency use of parenteral phenytoin products: proceedings of an expert panel consensus process. Panel on Nonemergency Use of Parenteral Phenytoin Products.

This document summarizes the proceedings of an expert panel consensus process addressing the nonemergency use of parenteral phenytoin products for management of seizures in pediatric and adult patients. The algorithm and consensus statements developed by the expert panel emphasize strategies for lowering the probability of adverse events associated with the use of parenteral phenytoin products. Specific patient characteristics are defined to guide administration and monitoring of parenteral phenytoin therapy. The algorithm provides a decision pathway for the selection of the product and the route of administration of phenytoin sodium or fosphenytoin sodium after it has been determined that a parenteral phenytoin product is appropriate. Key factors covered in the algorithm include a list of patient characteristics and considerations necessary to prevent parenteral phenytoin adverse effects during selection of administration route and recommendations for monitoring of parenteral phenytoin therapy once it has been initiated. Situations requiring rapid attainment of high phenytoin concentrations, such as in the management of acute seizures, are not addressed in these guidelines.

Restraining patients and shoulder dislocations during seizures.

We describe 3 patients whose shoulders dislocated as the movements of the arm were restricted during a generalized tonic clonic seizure over an 18-month period. The first patient had both shoulders dislocated when observers sat on his arms during the convulsion. The second patient had a convulsion while in a forced lateral decubitus position and dislocated the shoulder on that side. The third patient dislocated the shoulder and fractured the acromion as she was held by her arms in a chair during a convulsion. Despite the large number of patients with refractory epilepsy under our care, no cases of spontaneous shoulder dislocation occurred during that period of time.

Skin eruption with gabapentin in a patient with repeated AED-induced Stevens-Johnson's syndrome.

Skin eruptions have been reported with the use of all antiepileptic drugs and there is a significant risk of cross-reactivity between these agents in causing serious eruptions such as Stevens-Johnson's syndrome. Gabepentin is usually considered a safe agent for patients with a previous history of drug allergies and there have been no cases of skin eruption reported to the gabapentin post marketing surveillance. We report a patient who had severe Stevens-Johnson's syndrome induced by phenytoin and later by carbamazepine. Subsequent use of gabapentin also resulted in a skin eruption which was limited to the lower extremities but without systemic or mucosal involvement. This case suggests that patients with a strong history of drug-induced idiosyncratic reactions may experience such reactions to gabapentin as well.

A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy.

UNLABELLED: Gabapentin (GBP) is a non-metabolized antiepileptic drug that is eliminated by renal excretion and displays saturable, dose dependent absorption. The recommended dosing schedule for GBP is t.i.d. At large daily doses, oral bioavailability (F) may be improved by giving the daily dose more frequently. OBJECTIVE: To evaluate whether switching GBP dosage regimen from t.i.d. to q.i.d. results in increased oral bioavailability. METHODS: This study consisted of two parts; a computer simulated pharmacokinetic model and a clinical pharmacokinetic study in nine adult epileptic patients receiving 3600 mg/day and 11 receiving 4800 mg/day. All patients were evaluated during both t.i.d. and q.i.d. regimens. F were determined by calculation of percent of dose excreted unchanged using steady-state 24-h urine collections and were compared using a paired t-test. RESULTS: At 3600 mg/day, mean F following t.i.d. and q.i.d. dosing were 38.7+/-22.1% and 40.0+/-18.9%, respectively (P=0.738). At 4800 mg/day, mean F following t.i.d. and q.i.d. dosing were 29.2+/-16.2% and 35.6+/-17.6%, respectively (P=0.006). DISCUSSION: Good agreement was observed between values from this study and predicted values based on the pharmacokinetic model. Improved GBP F at doses of 3600 mg/day was not achieved with more frequent drug administration, and thus is not warranted. At 4800 mg/day, a 22% increase in F was observed with more frequent drug dosing. CONCLUSION: GBP F may be significantly increased by q.i.d. versus t.i.d. dosing, depending upon dose level. This increase in F however must be balanced against the inconvenience of more frequent dosing. Therapeutic drug level monitoring may aid in the evaluation of such pharmacokinetic maneuvers.

Surgical correction of scoliosis in patients with generalized seizures. Risk of vertebral body fracture.

STUDY DESIGN: A retrospective evaluation of the outcome of surgical management of progressive scoliosis in institutionalized patients with frequent, uncontrolled, generalized tonic clonic seizures. OBJECTIVES: To determine the safety and stability of internal fixation devices in patients with progressive scoliosis and intractable seizures. SUMMARY OF BACKGROUND DATA: Progressive scoliosis is a common problem in severely disabled patients. It has been the belief among some spine physicians that the coexistence of intractable seizures with progressive scoliosis is a contraindication for surgery, because most of the thoracic and lumbar spine is fixed and "unyielding" after internal fixations, increasing the risk of vertebral fractures. There have been reports of fracture of fixation devices, particularly Harrington rods, under conditions of massive trauma or mechanical stress, such as seizures. METHODS: The authors reviewed the outcome of six profoundly retarded institutionalized patients with a history of intractable seizures who underwent internal fixation of the spine between 1984 and 1987 because of progressive scoliosis. Seizure types and frequency of convulsion were obtained from the institutional charts. Follow-up radiographs of the spine obtained at 1, 3, and 6 months after the surgery and once a year thereafter were reviewed by the radiologist and orthopedic surgeon with special attention paid to fractures, stability of the fusion, and integrity of the instrumentation. RESULTS: Six patients underwent spinal fusion with internal spinal fixation, four patients with Harrington rods and two with Luque rods. All patients had refractory tonic clonic seizures ranging from 11 to 80 generalized tonic clonic convulsions per year for the 10-year follow-up period after surgery. There were no fractures, subluxation, or pseudoarthrosis of the fused vertebrae or the vertebral bodies adjacent to the fusion. There were no fractures of the instrumentation. CONCLUSIONS: The authors' findings suggest that when appropriate fusion is attained, the use of internal fixation devices is not contraindicated in the management of progressive scoliosis in patients with intractable seizures.