Antiepileptic Drugs: All Ages

Abstract

EpilepsiaVolume 46, Issue s8 p. 205-222 Free Access Antiepileptic Drugs: All Ages First published: 19 October 2005 https://doi.org/10.1111/j.1528-1167.2005.460801_19.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract 1 E. Andermann, 1 F. Andermann, 2 P. Meyvisch, 2 A. Vandendriessche, and 2 J. Schiemann Delgado ( 1 Montreal Neurological Hospital & Institute, McGill University, Montreal, QC, Canada ; and 2 Clinical, UCB SA, Pharma Sector, Braine l'Alleud, Belgium ) Rationale: The purpose of this trial was to evaluate the efficacy and safety of levetiracetam (LEV) 3000 mg/d (b.i.d.) in patients with idiopathic generalised epilepsy experiencing myoclonic seizures. Methods: In this multicentre, placebo-controlled, double-blind trial, patients who were poorly controlled on one antiepileptic drug (AED) were randomised 1:1, LEV versus placebo. To be eligible, patients had to experience at least 8 days with myoclonic seizures during the 8-week prospective baseline. The 16-week treatment period was composed of a 4-week titration period followed by a 12-week stable dose evaluation period. Seizures were reported by the patients on diaries, myoclonic seizures and absence seizures being reported as days with seizures, while primary generalised tonic-clonic (PGTC) seizures were counted individually. The primary efficacy endpoint was the responder rate (≥50% reduction in days with myoclonic seizures during the treatment period versus baseline). Results: 122 patients, aged 12–65 years, 113 with juvenile myoclonic epilepsy and 9 with juvenile absence epilepsy, were randomised. 60 LEV patients and 60 placebo patients were evaluable for efficacy and safety. The responder rate for myoclonic seizures was 58.3% with LEV versus 23.3% with placebo (p = 0.0002). As a secondary analysis, for all seizure types, the median difference between groups in the percent reduction from baseline was obtained and compared using the Wilcoxon Mann Whitney test. The median difference in percent reduction in seizure days per week for all seizure types was 38.08 (LEV, n = 60; placebo, n = 60; p < 0.0001); for myoclonic seizures, it was 36.55 (LEV, n = 60; placebo, n = 60; p < 0.0001); and for absence seizures, it was 0 (LEV, n = 19; placebo, n = 17; p = not significant). The median difference in percent reduction in seizure frequency per week for PGTC seizures was 30.35 (LEV, n = 15; placebo, n = 18; p = not significant). LEV also demonstrated a good tolerability profile. Conclusions: LEV is highly efficacious and well tolerated in the treatment of refractory patients with idiopathic generalised epilepsy. LEV decreases the number of days with myoclonic seizures in a statistically and clinically significant manner. No significant difference was observed for absence and PGTC seizures. (Supported by funds from UCB.) 1 Dora B. Arevalo, 1 Juan R. Osorio, 1 Josue Medina, and 2 Reyna M. Duron ( 1 Centro de Salud de Opoa, Secretary of Health, Copan, Honduras ; and 2 Neurology Training Program, National Autonomous University of Honduras, Tegucigalpa, Honduras ) Rationale: Injuries associated to epileptic seizures are increasingly recognized in Honduras, where epilepsy is highly prevalent. Our goal was to determine the profile and outcome of epilepsy patients who suffer burns associated to seizures. Methods: A prospective study was performed at the Surgery Services in a rural hospital of West Honduras (Copan City) and the University Hospital at Tegucigalpa City from January 2002 to March of 2005. Demographic data, treatment status and characteristics of burns were evaluated. Results: During the study period, 24 patients with epilepsy were admitted because of burns (71% women and 29% men). The average age was 33 years old (range 11–64). Most burns occurred with hot liquids; 71% of them were grade II and 29% were grade III. All patients reported tonic-clonic seizures during the accident; most were partial secondarily generalized seizures. Sixty-two percent of patients were not under antiepileptic treatment because of discipline and financial issues and 38% were taking treatment but had uncontrolled seizures. There were no fatal cases during the admission time. All patients had aesthetic consequences. Conclusions: This study shows the impact of uncontrolled epileptic seizures in Honduras. Patients suffer these kind of accidents because of non-compliance and problems accessing antiepileptic treatments. There is need for strategies to prevent these and other kinds of accidents in patients with epilepsy in Honduras. 1 Jacci L. Bainbridge ( 1 Neurology, University of Colorado Health Sciences Center, Denver, CO ) Rationale: In this study data relating to seizure count/frequency were obtained from subjects switched from immediate-release carbamazepine (IR-CBZ) to an equal total daily dose of Carbatrol® extended-release capsules (CBZ-ERC) at a minimum of 400 mg/d. Methods: At baseline, eligible and enrolled subjects were switched from their current IR-CBZ product to an equal total daily dose of CBZ-ERC. Grounds for exclusion from this multicenter study included: known history of generalized tonic-clonic status epilepticus or epilepsy syndromes that may potentially worsen with carbamazepine treatment, progressive neurological disorder, receiving more than 1 additional antiepileptic drug or any type of neuroleptic drug, or CBZ-ERC treatment within 90 days of study screening. Data from 453 patients with epilepsy were collected. Seizure count assessment via seizure diary was performed at baseline (month 0), month 2, and endpoint, while assessment of seizure count at months 1 and 3 were communicated by telephone. Results: Overall mean monthly seizure count (all patients) was significantly decreased both at month 3 and at end point when compared to baseline (P= .05). Conclusions: Monthly seizure count was significantly reduced in patients switched from IR-CBZ to CBZ-ERC at comparable doses. These data support CBZ-ERC as an effective formulation to deliver carbamazepine to the patient with epilepsy. Carbatrol is registered in the United States Patent and Trademark Office. (Supported by Shire.) 1 Steffen Baltes, 1 Heidrun Potschka, and 1 Wolfgang Löscher ( 1 Department of Pharmacology,Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany ) Rationale: The overexpression of multidrug transporters (MDTs) in the blood-brain barrier (BBB), particularly of P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated proteins (MRPs, ABCC), is discussed to be involved in pharmacoresistance to antiepileptic drugs (AEDs). It has been demonstrated that this overexpression is correlated with seizure severity and duration. This MDT overexpression may hamper a successful treatment of status epilepticus (SE). Our previous studies revealed that the brain access of several AEDs (e.g. phenytoin and phenobarbital) may be limited by MDTs. Other studies indicate that MRPs are involved in the efflux of valproic acid (VPA) at the BBB. However, VPA is known to be often efficacious in treatment of patients with SE resistant to benzodiazepines or phenytoin. As well as for SE as with regard to chronic treatment of epilepsy, the aim of the study presented here was to investigate whether P-gp or in particular MRP2 is involved in VPA transport at the BBB. Methods: We performed in vitro transport assays with cell lines overexpressing P-gp or MRP2, respectively, and we performed brain microdialysis experiments in rats applying two strategies to demonstrate MDT function. Verapamil and probenecid were used to inhibit MDTs in normal rats. Furthermore brain access of VPA was compared between mutant rats lacking MRP2 and wildtype rats of the background strain. Results: No significant in vitro transport of VPA nor any significant impact of MDTs on extracellular brain levels in rats could be found. VPA was the first AED we investigated so far passing this variety of tests without any indication of transport by P-gp or MRP2. Conclusions: The lack of P-gp and MRP2 to limit the brain access of VPA would provide an explanation for the efficacy of VPA especially in SE patients that are resistant to other AEDs. Currently, we investigate a potential impact of MDTs on intracellular VPA brain concentration. (Supported by Deutsche Forschungsgemeinschaft (Bonn, Germany) and Desitin Arzneimittel GmbH (Hamburg,Germany).) 1 Victor Biton, 2 Rajesh Sachdeo, 3 William Rosenfeld, 4 Steven Schachter, 5 Carlos Perdomo, and 5 Santiago Arroyo ( 1 Clinical Trials, Inc., Little Rock, AR ; 2 St. Peter's University Hospital, New Brunswick, NJ ; 3 Comprehensive Epilepsy Care Center for Children and Adults, St. Luke's Hosptial, St. Louis, MO ; 4 Beth Israel Deaconess Medical Center, Boston, MA ; and 5 Eisai Global Clinical Development, Ridgefield Park, NJ ) Rationale: Rufinamide, a structurally novel antiepileptic drug (AED) under investigation, demonstrates broad-spectrum anticonvulsant activity in animal models. The efficacy and safety of rufinamide (800 mg/d) as adjunctive therapy was evaluated for patients with inadequately controlled primary generalized tonic-clonic (GTC) seizures. Methods: This multicenter, double-blind, placebo-controlled study of rufinamide (initiated and maintained at 800 mg/d, BID) consisted of a 56-day baseline phase and a 140-day double-blind phase. The study was open to patients ≥4 years of age with a diagnosis of inadequately controlled primary GTC seizures who were treated with 1 or 2 concomitant, fixed-dosage AEDs. To be randomized, patients had to have experienced at least 3 GTC seizures during the baseline phase, with at least 1 occurrence during each 28-day baseline period. The primary efficacy end point was the percent change from baseline in GTC seizure frequency per 28 days. Adverse events (AEs) and laboratory measures for patients receiving any amount of study drug were used to assess safety. Results: A total of 153 patients were randomized and received at least one dose of study drug: rufinamide, n = 78; placebo, n = 75. Mean age of treated patients was 29.3 years (range, 4–63 y) and the median number of GTC seizures per 28 days during baseline was 3.5 (range, 1.5–84) and 4.0 (range, 1.5–74) for the rufinamide and placebo groups, respectively. The primary efficacy variable did not show a significant difference between rufinamide (median reduction, 36.4%) and placebo (25.6%; p = 0.633). Sixty-four patients (82.1%) in the rufinamide group and 61 placebo patients (81.3%) experienced at least 1 AE. Nonfatal serious AEs were reported by 7 rufinamide-treated and 4 placebo patients, but none were considered related to the study drug. Three patients in each treatment group discontinued due to AEs and 1 placebo patient died. Adverse events (reported by ≥10% of patients) in the rufinamide group versus placebo were headache (21.8% vs 22.7%), somnolence (16.7% vs 13.3%), nausea (16.7% vs 8.0%), dizziness (12.8% vs 10.7%), and vomiting (10.3% vs 6.7%). No treatment-emergent and clinically relevant alterations were seen in laboratory parameters. Conclusions: A greater median reduction in GTC seizure frequency was seen in rufinamide-treated patients compared to those receiving placebo, but the difference was not statistically significant. Safety assessments were comparable between treatment groups. (Supported by Eisai Inc.) 1 Victor Biton, 2 Alain Vuong, 2 Susan Kerls, 2 Anne Hammer, and 2 John Messenheimer ( 1 Arkansas Epilepsy Program, Arkansas Epilepsy Program, Little Rock, AR ; and 2 Neurology, GlaxoSmithKline, Research Triangle Park, NC ) Rationale: In the US, LAMICTAL® (lamotrigine, LTG) is indicated for partial seizures with or without secondarily generalization in children and adults, and for the generalized seizures associated with Lennox-Gastaut syndrome. This abstract reports efficacy, including time to onset, and tolerability results from a study with LTG as adjunctive therapy in patients with primary generalized tonic-clonic seizures (PGTCS). Methods: LTG-naïve patients (≥ 2 years, ≥ 13 kg) with inadequately controlled PGTCS, receiving a stable regimen of 1 or 2 AED(s) and an electroencephalogram (EEG) with evidence of generalized epileptiform discharges or no evidence of interictal expression of partial seizures were enrolled in a randomized, double-blind, placebo-controlled, parallel-group trial. Patients having ≥ 3 PGTCS over an 8-week Baseline were randomized (1:1) to receive either LTG or placebo (PBO). The treatment period consisted of an Escalation phase (12 weeks for patients 2–12 years, 7 weeks for patients > 12 years) and a Maintenance phase (12 weeks). Results: Of 184 patients enrolled, 117 were randomized and received LTG or PBO. LTG group: n = 58, 50% male, median age = 27 years (range = 2–53), 50% with 1 concurrent AED, most common concurrent AED: valproate = 41%, phenytoin = 31%, topiramate = 21%, median PGTCS during Baseline = 2.4. PBO group: n = 59, 56% male, median age = 25 years (range = 2–55), 59% with 1 concurrent AED, most common concurrent AED: valproate = 47%, phenytoin = 22%, topiramate = 12%, median PGTCS during Baseline = 2.9. In the overall population the median percent decreases from Baseline in PGTCS were 56% and 30% (p = 0.036) 5 weeks after treatment initiation with LTG and PBO, respectively; in patients >12 years, the decreases were 63% and 33% (p = 0.045) 3 weeks after treatment initiation. The median percent decreases from Baseline in PGTCS were 82% and 43% (p = 0.006) during Maintenance, and 66% and 34% (p = 0.006) during the entire treatment phase, for LTG and PBO, respectively. The median PGTCS counts per month were 2.4 and 2.9 during Baseline for LTG and PBO, respectively, 1.0 and 2.3 (p = 0.013) during Escalation, and 0.4 and 1.6 (p = 0.001) during Maintenance, and 0.8 and 2.0 (p = 0.003) during the entire treatment phase. The most common (≥ 5%) drug-related adverse events for LTG and PBO respectively were dizziness: 5% and 2% for LTG and PBO respectively, somnolence: 5% and 2%, and nausea: 5% and 3%. The non-serious rash rate was 3% for both LTG and PBO. No serious rash was reported. Conclusions: The results from this study, combined with the established efficacy and safety of LTG for partial seizures, clearly demonstrate that LTG is a broad spectrum AED which is efficacious and well tolerated in patients with either partial or generalized seizures. (Supported by GlaxoSmithKline.) 1 David Burdette ( 1 Department of Neurology, Henry Ford Hospital, Detroit, MI ) Rationale: This open-label study assessed the efficacy and safety of low-dose zonisamide initiated in combination with concomitant antiepileptic drugs (AEDs). Methods: Patients aged ≥12 years with partial seizures treated with 1 or 2 concomitant AEDs were enrolled in a 4-week screening phase (SP). Patients were required to have ≥1 seizure during the SP to be eligible for the study. Zonisamide was initiated at a dosage of 25 mg/d and increased to a maximum tolerated dosage or 400 mg/d during the titration phase (TP) (Weeks 0–8). Patients then received their maximum tolerated dosage for the maintenance phase (MP) (Weeks 9–12). The primary efficacy measure was seizure frequency per 28 days as recorded in a seizure diary. Secondary efficacy measures were the change in seizure type or duration and in physician and patient global assessments (rated on a 0–100 scale) between Week 0 (baseline) and Week 12. Safety was assessed via reports of adverse events (AEs) and changes in body weight. Results: A total of 243 patients (mean age, 35.7 years; range, 12–85 years) were treated. Median duration of treatment was 84 days (range, 1–162 days); median maximum zonisamide dosage was 400 mg/d (range, 25–800 mg/d). Median seizure frequency decreased by 47.6% from 8.3 (SP) to 4.0 (MP), with 48.5% of patients (95% confidence interval [CI]: 41.4, 55.5) experiencing ≥50% seizure frequency reduction. Median frequencies of simple partial, complex partial, and other seizure types were reduced by 57.1%, 51.0%, and 96.1%, respectively. A ≥50% reduction in frequency of simple partial, complex partial, and other seizure types was observed in 53.2%, 51.0%, and 69.7% of patients, respectively. No change in seizure type or duration was apparent with zonisamide therapy. Patients' global assessment of AED therapy improved significantly from a mean score of 40.7 at baseline to 67.1 (95% CI: 63.1, 70.4) during treatment. Investigator global assessments of AED therapy also improved from a mean of 31.7 at baseline to 64.0 (95% CI: 61.3, 66.8) during treatment. The most frequently reported treatment-emergent AEs (≥10% of patients) included dizziness (17.3%), somnolence (17.3%), headache (14.0%), abnormal thinking (13.2%), asthenia (11.9%), anorexia (11.5%), accidental injury (11.1%), and nausea (10.7%). Thirteen patients (5.3%) experienced serious AEs (SAEs), 4 of whom had SAEs considered to be zonisamide related. Twenty-two patients (9.1%) withdrew from the study for AEs. Mean body weight decreased from baseline by 0.7 kg (95% CI: -1.1, -0.4) and 1.0 kg (95% CI: -1.3, -0.6) in the TP and MP, respectively. Conclusions: This low-dose, slow titration regimen for zonisamide resulted in substantially decreased seizure frequency, and a significant proportion of patients had a ≥50% seizure frequency reduction. Zonisamide was also generally safe and well tolerated. Small but significant decreases in body weight were observed during the study. (Supported by Eisai Inc.) 1 Frances J. Hayes, 2 Paul T. Caldwell, 1 Patrick M. Sluss, 2 Clay R. Warnock, and 2 Jouko I. Isojarvi ( 1 Gynecology, Massachusetts General Hospital, Boston, MA ; and 2 Neurosciences MDC, GlaxoSmithKline, Research Triangle Park, NC ) Rationale: To evaluate the impact of initiating therapy with either valproate (VPA) or lamotrigine (LTG) on body weight and serum lipid levels in women with epilepsy (WWE). Methods: Eligibility criteria for this prospective, randomized, open-label, multicenter study (LAM30007) included age 13–40 years, regular menstrual cycles; no concurrent hormonal medications; no prior LTG or VPA; and either newly diagnosed [<2 weeks prior antiepileptic drug (AED)] or inadequately controlled epilepsy (only 1 chronic AED≥3 months). Subjects were randomized to VPA or LTG and were treated for up to 12 months. Fasting serum lipid levels and body weight were measured at baseline and every three months during the study. To exclude the confounding effect of puberty on the results, a post-hoc analysis was conducted in women who were >2 years post menarche. An Analysis of Covariance model comparing end of study measurements to screen was used, including the screening measurement and group center as covariates. Results: A total of 363 women (177 LTG, 186 VPA) ages 12 to 40 years were evaluated. The mean weight gain in the VPA group was 2.8 kg (SD = 3.35) and 0.2 (SD = 3.90) kg in the LTG group (p < 0.001). Mean serum triglyceride concentrations increased 8.4 mg/dL (SD = 37.5) in women taking VPA, while they decreased slightly in the LTG group (0.2 mg/dL, SD = 36.3, p = 0.019). The serum total cholesterol levels showed a slight decrease in both treatment groups, but there was a mean decrease of 2.6 mg/dL (SD = 10.3) in serum HDL-cholesterol levels in VPA treated women, whereas a slight increase of 0.6 mg/dL (SD = 9.2) was observed during LTG treatment (p = 0.001). Conclusions: This large, multiethnic, prospective, randomized study indicates that VPA is associated with weight gain and unfavorable changes in serum lipid levels in WWE, whereas LTG does not seem to affect body weight or serum lipid levels. (Supported by GlaxoSmithKline.) 1 Michael P. Charlet ( 1 Neurology, Leonard J. Chabert Medical Center, Houma, LA ) Rationale: Optimizing treatment for patients with epilepsy must take into account more than basic seizure control. The assessment of adverse events (AEs) and tolerability are important goals in this population to balance medication dosage and efficacy. Differences in adverse event profile or severity between immediate-release and extended-release formulations of carbamazepine are not clearly defined. In this study, tolerability and safety data was obtained from subjects switched from immediate-release carbamazepine (IR-CBZ) to an equal total daily dose of Carbatrol® extended-release capsules (CBZ-ERC) at a minimum of 400 mg/d. Methods: At baseline, eligible and enrolled subjects were switched from their current IR-CBZ product to an equal total daily dose of CBZ-ERC. Grounds for exclusion from this multicenter open-label study included: known history of generalized tonic-clonic status epilepticus or epilepsy syndromes that may potentially worsen with carbamazepine treatment, progressive neurological disorder, receiving more than 1 additional antiepileptic drug or any type of neuroleptic drug, or CBZ-ERC treatment within 90 days of study screening. Data from 381 patients with epilepsy were collected. Assessments performed at baseline (month 0) and month 3 included adverse event profile (AEP) for adults 18–59 years of age, Hague seizure severity (HASS) and side-effects (HASES) scales for adolescents <18 years of age (filled out by parent or guardian of adolescent study participant), and monitoring of AE occurrence. The AEP is a 19-item questionnaire scored on a scale from 1 (never a problem) to 4 (always or often a problem), and takes into account sedation, dizziness, unsteadiness, concentration difficulty, depression, and double/blurred vision. Results: The AEP (adults) as well as HASES (adolescents) showed significant decreases from baseline to month 3 in overall mean side effect score (P= .0001 and P= .01, respectively). Subscale scores of both questionnaires also showed significant decreases on many variables. HASS showed a decreased total score with a trend toward significance. Most commonly occurring AEs were headache, dizziness, and fatigue. Overall, 78.8% of both patients and parents (of adolescent patients), as well as 86.4% of physicians preferred CBZ-ERC to previous IR-CBZ medications. Patient responses also indicated that compared to 38.7% at baseline (IR-CBZ), 58.6% of patients “strongly agree” that they rarely skip or miss a dose of their medication. Conclusions: Patients with epilepsy switched from IR-CBZ to ERC-CBZ experienced decreased AE occurrence and severity. While 22.1% of study participants reported at least one AE, only 3.3% discontinued due to AE occurrence, and only 3.9% reported AE occurrence as “severe.” These data demonstrate the benefits of ERC-CBZ in terms of safety, tolerability, and preference in a clinical trial setting. (Supported by Shire.) 1 Pamela L. Clemens, 1 James C. Cloyd, 2 Robert L. Kriel, and 1 Rory P. Remmel ( 1 Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN ; and 2 Neurology, Hennepin County Medical Center, Minneapolis, MN ) Rationale: Rectal administration of some AEDs is a viable alternative when the oral route is temporarily unavailable. Oxcarbazepine (OXC) is a newer AED that is rapidly converted to a monohydroxy derivative (MHD), the active compound. Our study was designed to characterize the bioavailability and tolerability of OXC suspension (300 mg/5 ml) administered rectally. Methods: This study used a randomized, crossover design in 10 healthy volunteers who were randomized to the order of routes of administration. Subjects fasted the morning of each dose and administered a Fleet's enema before the rectal dose. The rectal dose was mixed with an equal volume of water and administered via a catheter attached to a syringe. A two-week wash-out occurred between doses. Blood was drawn pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours post-dose. The first 2 subjects received 300 mg doses. Following review of concentrations and tolerability, the remaining 8 subjects received 450 mg doses. Side effects were assessed at each sampling timepoint using a self-administered questionnaire with a 5-point rating scale (5 = most severe). Plasma samples were assayed for OXC and MHD using a validated HPLC assay. Lower limit of detection for MHD was 0.01 mcg/ml and 0.015 mcg/ml for OXC. Maximum concentration (Cmax) and time to maximum concentration (tmax) were obtained directly from the plasma concentration-time curves (AUCs). AUCs were determined for both OXC and MHD via non-compartmental analysis using WinNonLin. Relative bioavailability was calculated as (AUCrectal/AUCoral)*100%. AUC and Cmax of MHD following each route of administration were compared using Wilcoxon signed-rank tests. Results: Mean relative bioavailability of MHD was 10.15% (SD 6.73) in the 2 subjects receiving 300 mg doses and 7.77% (SD 5.93) in the 450 mg dose subjects. The MHD Cmax and AUC at the 450 mg dose level differed significantly between routes (p < 0.01). The most common side effects were headache and fatigue; there was no discernable difference between routes. One subject rated discomfort of rectal administration as 3/5, another reported discomfort of oral administration 1/5 due to taste. Most subjects had a few clinical labs outside the normal range, each was considered clinically insignificant. Conclusions: The Cmax and exposure to MHD after rectal administration of OXC suspension are significantly less than after oral administration. It is unlikely that adequate MHD concentrations can be reached by rectally administering diluted OXC suspension. (Supported by Novartis & University of Minnesota.) 1 Michael Collins, and 2 Mary Kay M. Hermanson ( 1 Pharmacy, University of Wisconsin Hospitals, Madison, WI ; and 2 Neurology, University of Wisconsin Hospitals, Madison, WI ) Rationale: In September 2004 the State of Wisconsin Medicaid program mandated a change to generic phenytoin for those patients on brand Dilantin unless there was Federal Medwatch form filed documenting an adverse event. This is in contrast to the previously accepted physician request for dispensing “brand medically necessary.” Other drugs newly included in that list included warfarin, cyslosporine and levothyroxine. Pre and post phenytoin concentrations were measured for eight patients changed from brand Dilantin to Mylan's phenytoin and given the same dose. All patients had a fall in phenytoin concentrations and most required a dose adjustment to attain concentrations between 10–20mcg/ml. Some patients required a dose increase to the extent that the monthly cost for generic exceeded their previous cost for branded product. One patient reported breakthrough seizures during this transition. Widespread complaints to the Medicaid program from