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GW Pharmaceuticals’ formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox‐Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open‐label, fixed‐sequence, drug‐drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady‐state pharmacokinetics of clobazam (and N‐desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7‐hydroxy‐cannabidiol [7‐OH‐CBD] and 7‐carboxy‐cannabidiol [7‐COOH‐CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [Cmax] and area under the concentration‐time curve [AUC], 1.2‐fold), N‐desmethylclobazam exposure increased (Cmax and AUC, 3.4‐fold), stiripentol exposure increased slightly (Cmax, 1.3‐fold; AUC, 1.6‐fold), while no clinically relevant effect on valproate exposure was observed. Concomitant clobazam with cannabidiol increased 7‐OH‐CBD exposure (Cmax, 1.7‐fold; AUC, 1.5‐fold), without notable 7‐COOH‐CBD or cannabidiol increases. Stiripentol decreased 7‐OH‐CBD exposure by 29% and 7‐COOH‐CBD exposure by 13%. There was no effect of valproate on cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.

To review the effects of naltrexone on withdrawal-related adverse events (AEs) and euphoria-related effects, and the relationship between plasma naltrexone concentrations and withdrawal across EMBEDA (MSN; extended-release morphine sulfate with sequestered naltrexone) studies.Five studies in pain patients and a safety review summarizing AE reports during the first year following approval of MSN were assessed for withdrawal reports. Three of these studies also assessed Clinical Opiate Withdrawal Scale (COWS) scores. Plasma naltrexone concentrations of MSN-treated individuals were summarized. Abuse potential was assessed in four studies in non-dependent recreational opioid users.Withdrawal AEs occurred in 13/1781 patients across five MSN studies, and 25/182 cases involving withdrawal were reported in the safety review. In three of these studies, 11/964 patients experienced moderate withdrawal (COWS score = 13-24) and 1/964 patients experienced moderately severe withdrawal (score = 28); all were either non-compliant with study drug, had undetectable plasma naltrexone concentrations, or were tapering to placebo. In ≥89% of plasma naltrexone concentration samples from patients who took MSN (n = 166), naltrexone was below the limit of quantification (4.0 pg/mL). In four studies with non-dependent recreational opioid users (n = 118), crushed MSN was associated with significantly lower scores of drug liking, high, and take drug again than crushed morphine sulfate (p ≤ 0.005).When taken intact as directed, naltrexone in MSN does not precipitate withdrawal. However, when MSN is crushed, naltrexone mitigates, but does not eliminate, the euphorigenic effects of crushed morphine sulfate.

Rationale Treatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential. Methods This was a single-dose, randomized, double-blind, double-dummy, placebo- and active-controlled crossover trial. The abuse potential of single oral doses of plant-derived pharmaceutical formulations of highly purified CBD (Epidiolex®; 750 mg, 1500 mg, and 4500 mg) was compared with that of single oral doses of alprazolam (2 mg), dronabinol (10 mg and 30 mg), and placebo in healthy recreational polydrug users. The primary endpoint to assess abuse potential was the maximum effect (Emax) on Drug-Liking visual analog scale (VAS). Other measurements included Emax on Overall Drug-Liking VAS, Take Drug Again VAS, positive and negative effects, other subjective effects, and Drug Similarity VAS. Cognitive and psychomotor functions were assessed using the Divided Attention Test, the Hopkins Verbal Learning Test—Revised, and the Digit–Symbol Substitution Task. Pharmacokinetic parameters were determined for CBD and its major metabolites. Standard safety measures and adverse events were assessed. Principal results Of 95 eligible subjects, 43 qualified for the treatment phase, received at least 1 dose of investigational medicinal product, and were included in safety assessments; 35 subjects were included in the pharmacodynamic analysis. Subjects receiving alprazolam and dronabinol had significantly higher Drug-Liking Emax (P 18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS Emax values compared with all doses of CBD (P ≤ 0.004). In contrast to alprazolam, CBD administration had no observable effect on cognitive/psychomotor tests. Pharmacokinetic parameters for CBD in this trial were consistent with previous studies. The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported. Conclusion Administration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were significantly lower than those observed with alprazolam and dronabinol.

Rationale The rationale of this study was to assess occurrence of withdrawal symptoms induced by abrupt cessation of cannabidiol (CBD) after prolonged administration in healthy volunteers. Methods Thirty volunteers were randomized to receive 750 mg of a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL; Epidiolex® in the United States and Epidyolex® in Europe) twice daily (b.i.d.) for 4 weeks (Part 1) followed by 2 weeks of 750 mg b.i.d. CBD (Part 2, Arm 1) or matched placebo (Part 2, Arm 2). All volunteers completed the Cannabis Withdrawal Scale (CWS) and the 20-item Penn Physician Withdrawal Checklist (PWC-20) on days − 1, 21, 28, 31, 35, 42, and at follow-up. Results Median CWS and PWC-20 scores slightly decreased from Part 1 to Part 2. Median CWS scores ranged from 0.0 to 4.0 (out of a possible 190) in Arm 1 and 0.0 to 0.5 in Arm 2. Median PWC-20 scores were 0.0 (out of a possible 60) in both arms. Twenty-nine (97%) volunteers in Part 1 reported all-causality treatment-emergent adverse events (AEs); the most commonly reported was diarrhea (63%). In Part 2, Arm 1, 6 (67%) volunteers reported all-causality AEs; the most commonly reported was diarrhea (44%). In Part 2, Arm 2, 9 (75%) volunteers reported all-causality AEs; the most commonly reported was headache (58%). Nine volunteers withdrew because of AEs in Part 1; 1 withdrew in Part 2, Arm 2, because of an AE that began in Part 1. Four severe AEs were reported in Part 1; the remainder were mild or moderate. No serious AEs were reported. Conclusion In healthy volunteers, no evidence of withdrawal syndrome was found with abrupt discontinuation of short-term treatment with CBD.

To compare the results of two open-label primary care-based studies that examined investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion relative to patient self-reports and urine drug tests (UDTs).Risk assessment data from two open-label, multicenter, primary care-based US studies in patients with chronic pain were compared.In one study (n = 1487), 54.4% of patients were at moderate, 24.8% at high, and 20.8% at low risk based on patients' self-reports at baseline on the Screener and Opioid Assessment for Patients with Pain®-Revised questionnaire. Investigators assigned 1.3% of patients as high risk despite 5.0% self-reporting prior illicit drug use and 15.3% with positive UDT(s) for an illicit drug at baseline. In the second study (n = 684), few patients were considered by investigators to be at high risk for misuse (1.6%), abuse (1.8%), or diversion (1.0%). However, 10.4% of patients reported prior illicit drug use; 23.4% had at least one abnormal baseline UDT; 60% of 537 patients reported on the Self-Reported Misuse, Abuse, and Diversion questionnaire they took more opioids than prescribed; and 10.9% reported chewing/crushing opioids in the past. Of patients completing the Current Opioid Misuse Measure, 40.6% were classified as having aberrant behaviors.A comparison of risk assessment across two studies indicates a tendency for investigators to assess patients as lower risk for opioid-related aberrant behaviors despite a significant proportion self-reporting aberrant behavior and/or presenting with illicit UDTs. These consistent findings underline the importance of appropriate implementation of objective measures and self-reporting tools when evaluating risk in patients.www.clinicaltrials.gov identifiers: NCT00640042 and NCT01179191.

The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.

Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690.Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.GW Pharmaceuticals.

Objective: To evaluate the long-term safety of oxycodone-hydrochloride and sequestered naltrexone-hydrochloride (ALO-02) administered for up to 12 months. Design: Open-label, single-arm safety study. Setting: Thirty-two US research centers (ClinicalTrials.gov identifier NCT01428583). Patients: Three hundred ninety-five adults (opioid experienced and opioid naive) with moderate-to-severe chronic noncancer pain (CNCP). Interventions: Open-label, oral ALO-02 capsules, daily dose ranging from 20 to 160 mg oxycodone for up to 12 months. Main outcome measures: Number and type of adverse events (AEs) and drug-related AEs, including assessments of withdrawal (Clinical Opiate Withdrawal Scale; COWS), pharmacokinetics, efficacy, and aberrant behaviors (Current Opioid Misuse Measure). Results: A total of 193 (48.9 percent) patients received ALO-02 for ≥ 181 days and 105 (26.6 percent) patients for ≥ 361 days. The most common treatment-emergent AEs were nausea (25.3 percent), constipation (21.3 percent), vomiting (13.9 percent), and headache (11.6 percent). The most common drug-related AEs were constipation (18.0 percent), nausea (14.9 percent), somnolence (8.4 percent), fatigue (6.8 percent), dizziness (5.6 percent), and vomiting (5.1 percent). A majority of patients (86.6 percent) had a maximum COWS total score below the level for mild withdrawal symptoms at every visit throughout the study. Pain severity scores as measured by the short Form of the Brief Pain Inventory (BPI-SF) decreased over time. Conclusions: Repeat dosing of ALO-02 for up to 12 months is safe and well tolerated in a CNCP population of both opioid-experienced and opioid-naive patients. ALO-02 demonstrated a safety profile consistent with extended-release opioids and the expected analgesic efficacy. The addition of sequestered naltrexone had no significant clinical effect on patients when taken as directed.

Objectives To compare the pharmacodynamic effects, including self-reports of “drug liking” and “high,” of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules (MSN), crushed morphine sulfate controlled-release (CR) tablets, and placebo in an abuse potential study. Design Randomized, double-blind, placebo-controlled, three-way crossover study. Setting Single-center. Subjects Nondependent recreational opioid users. Interventions Orally administered crushed MSN (120-mg morphine sulfate and 4.8-mg naltrexone hydrochloride), crushed 120-mg morphine sulfate CR, and placebo. Outcome Measures Subjective ratings (100-point visual analog scales) of positive drug effects (drug liking, high, good effects, take drug again, and overall drug liking), any effects, and negative effects (bad effects, feel sick, nausea, sleepy, and dizzy), along with pupillometry, pharmacokinetic (PK), and safety assessments. Results Crushed morphine sulfate CR significantly increased ratings of all positive subjective measures relative to placebo (P

Objective: To evaluate whether intact or crushed doses of an extended-release formulation of morphine sulfate surrounding an inner core of sequestered naltrexone (MSN) induces signs and symptoms of withdrawal in opioid-dependent patients. Design: Randomized, double-blind, two-way crossover study. Setting: Single center. Patients: Fourteen patients with chronic moderate-to-severe noncancer pain receiving opioids were enrolled into the study; six completed the maintenance and treatment phases prior to early study discontinuation for issues with manufacturing; eight discontinued: adverse effects (4), noncompliance (1), patient decision (1), study termination (2). Interventions: Patients were titrated to a stable dose of MSN (ranging from 30/1.2 to 100/4.0 mg of morphine/naltrexone) that was used in the single-dose crossover evaluation of crushed and intact MSN. Main outcome measures: Clinical Opiate Withdrawal Scale (COWS). Results: Clinically significant withdrawal (COWS ≥ 13) was observed with rapid onset (≥ 0.8 hours postdose) in three patients (50 percent) following treatment with crushed MSN at the highest doses administered of ≥ 60/2.4 mg. Although naltrexone exposure was negligible following exposure to intact MSN, increasing plasma levels of naltrexone and 6-β-naltrexol were associated with COWS score ≥ 13 in patients who received crushed MSN. COWS ≥ 13 was observed in one patient receiving intact MSN without quantifiable naltrexone concentrations. Conclusion: Crushing the MSN capsule may precipitate moderate-to-severe signs and symptoms of opioid withdrawal in opioid-dependent individuals. The negligible exposure to naltrexone following exposure to intact MSN supports that intact capsules may be taken safely without precipitating withdrawal in opioid-dependent individuals.

Objective. To evaluate the abuse potential of ALO-02, an abuse-deterrent formulation comprising pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. Design. Randomized, double-blind, placebo-/active-controlled, 6-way crossover study, with naloxone challenge, drug discrimination, and treatment phases. Subjects. Nondependent, recreational opioid users. Methods. Oral administration of crushed and intact ALO-02, crushed immediate-release (IR) oxycodone, and placebo. Primary endpoints were Drug Liking and High measured on visual analog scales and reported as maximum effect (Emax) and area-under-the-effect-curve from 0 to 2 hours (AUE0-2h). Other pharmacodynamic, pharmacokinetic and safety assessments were included. Results. Drug Liking and High (Emax) for crushed oxycodone IR 40 mg were significantly higher compared with placebo, confirming study validity ( P

In a pilot placebo-controlled study, low dosages of 0.5-2mg/24h rotigotine showed a dose-dependent beneficial effect in restless legs syndrome (RLS) patients.Efficacy and safety of the dopamine agonist rotigotine, formulated as a once-daily transdermal system (patch), was investigated for five fixed dosages and compared to placebo in patients with idiopathic RLS in a double-blind, randomized, parallel-group, multicenter, six-week dose-finding trial. Primary efficacy measure was the total score of the International RLS Severity Scale (IRLS); in addition, the RLS-6 scales and the Clinical Global Impressions (CGI) were administered.Of 371 enrolled patients, 341 patients (mean age 58+/-10years, 67% females) were randomized. The IRLS total score improved between baseline and end of the six-week treatment period by -10.6 (0.5mg/24h rotigotine; patch area 2.5cm2), -15.1 (1mg/24h; 5cm2), -15.7 (2mg/24h; 10cm2), -17.5 (3mg/24h; 15cm2), and -14.8 (4mg/24h, 20cm2) as compared to placebo (-9.2). The hierarchical statistical test procedure demonstrated superiority of rotigotine over placebo for 4mg/24h, 3mg/24h, 2mg/24h, and 1mg/24h, with p-values of 0.0013,0.0001, 0.0003, and 0.0004, respectively. Only the 0.5mg/24h dose was not different compared to placebo (p=0.2338). The CGI and the RLS-6 severity items supported the efficacy of the rotigotine doses beyond 0.5mg/24h. The most frequent side effects were application site reactions and nausea and tended to be more frequent with higher doses.This dose-finding trial identified the range for a maintenance dose of rotigotine from 1mg/24h to 3mg/24h. The lowest dose was ineffective and, with the highest dose, no additional benefit was observed.

ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2 h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2 h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2 h , 27.1 vs 136.4, respectively; n = 28; P

Impulsive aggressive behavior is common in psychiatric disorders and accounts for significant morbidity and mortality. However, little systematic treatment data exist from placebo-controlled trials for this symptom domain. This was a multicenter, randomized, double-blind, placebo-controlled study in which outpatients with a score of > or =15 on the Aggression scale of the Overt Aggression Scale-Modified (OAS-M) and who fulfilled DSM-IV criteria for Cluster B personality disorder (n=96), intermittent explosive disorder (n=116), or post-traumatic stress disorder (n=34) were randomized to divalproex sodium or placebo for 12 weeks duration. Based on average OAS-M Aggression scores over the last 4 weeks of treatment, a treatment effect was not observed in the intent-to-treat data set (combined across the three psychiatric disorders), but was observed in both intent-to-treat and evaluable data sets for patients with Cluster B personality disorders. In the Cluster B evaluable data set, statistically significant treatment differences favoring divalproex were also observed for component items of the OAS-M Aggression score, including verbal assault and assault against objects, as well as OAS-M Irritability score, and Clinical Global Impression (CGI)-Severity at multiple time points throughout the study. No treatment group difference was noted for overall premature discontinuation rate; however, across psychiatric diagnoses, 21 (17%) patients in the divalproex group prematurely discontinued because of an adverse event, as compared to 4 (3%) patients in the placebo group (p

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.

Background: Valproate sodium injection (Depacon®) 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.

Background: This study compared the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. Method: This randomized, 12-week, double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and randomly assigned to treatment with divalproex or olanzapine. After an inpatient period of up to 21 days, subjects were followed as outpatients. Dose adjustment was permitted during the inpatient period. Efficacy was assessed using change from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint was change from baseline in weight. Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs. Results: 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomly assigned to treatment. No significant differences between groups were found for any efficacy variable for change from baseline to day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine (p = .210). A significantly (p

Summary: Purpose: To determine whether an increased risk of status epilepticus (SE) and complex partial status epilepticus (CPSE) is associated with tiagabine (TGB) therapy. Methods: Thirteen cases in which an EEG, performed on patients with altered mental status taking TGB, was reported to demonstrate spike-and-wave discharges (SWDs) were reviewed by a panel of experts. In addition, all cases of suspected SE from TGB clinical trials were reviewed. The occurrence of SE in four epidemiologic cohorts from Rochester, Minnesota, Turku, Finland, Bronx, New York, and New Haven, Connecticut was analyzed as an external comparison. Results: Review of the 13 cases with reported SWDs found that the majority had had prior EEGs with similar findings, and only three were thought to have electrographic evidence of SE. There was no difference in the frequency of SE or CPSE in the placebo-controlled clinical trials between the TGB-treated (1.0% SE, 0.8% CPSE) and placebo-treated (1.5% SE, 1.5% CPSE) groups. The 5% frequency of SE and 3% frequency of CPSE in the TGB-treated patients in the long-term safety studies, which included 2,248 patients, were very similar to the rates of occurrence of SE and CPSE in the four external cohorts. The major risk factor for the occurrence of SE and CPSE in all groups was a prior episode of SE (p < 0.0001). Conclusions: Over a 3-year period, SE will occur in 5–10% of patients with epilepsy not in remission. At highest risk are those who have had a prior episode of SE. Treatment with TGB in recommended doses does not increase the risk of SE in patients with partial seizures.

Summary: Purpose: Patients with drug-resistant epilepsy have a higher incidence of psychiatric problems and possibly greater intolerance to antiepileptic drugs (AEDs) than do other patients with epilepsy. Concern has been raised that γ-aminobutyric acid (GABA)ergic drugs may be associated with treatment-emergent psychosis. Tiagabine (TGB; Gabitril), a new AED that blocks synaptic GABA uptake, was developed in trials of drug-resistant patients with epilepsy. We conducted ad hoc analyses of adverse events, drug intolerance, and treatment response to evaluate the association between TGB treatment and psychosis and whether psychiatric history might be predictive of tolerance or effectiveness of this GABAergic drug. Methods: Data were analyzed from two multicenter, randomized, double-blind, placebo-controlled trials of add-on TGB therapy (32 or 56 mg daily) in 554 adolescents and adults with complex partial seizures (CPSs). After an 8- or 12-week baseline phase, double-blind treatment consisted of a 4-week titration period (with TGB dose gradually increased to 32 or 56 mg daily) and an 8- or 12-week fixed-dose period. Adverse events commonly associated with psychosis were evaluated. Treatment intolerance and effectiveness (≥50% reduction in CPS rate) were compared among patients with and without psychiatric histories. Results: Psychotic symptoms (hallucinations) were observed in three (0.8%) of 356 TGB-treated patients and none of 198 placebo-treated patients (p = 0.556, NS). Statistical analysis showed no interaction between psychiatric history and drug intolerance or treatment outcome. Conclusions: TGB administration appears to carry no significant increased risk of treatment-emergent psychosis. Psychiatric history was not predictive of the tolerance or effectiveness of the drug.

Valproate formulations, divalproex sodium extended-release (ER) and the traditional divalproex sodium delayed-release (DR) formulations, are not bioequivalent. This study evaluated if ER QD regimens with 14 and 20% higher daily doses were equivalent to the corresponding DR BID regimens with respect to exposure (AUC) while achieving lower maximum concentration (C(max)) and higher minimum concentration (C(min)) values. This was a Phase I, multiple-dose, fasting, randomized, open-label, crossover design study in healthy adult volunteers (n=36). The two crossover comparisons of unequal total daily doses were: 1000 mg ER versus 875 mg DR and 1500 mg ER versus 1250 mg DR. For each of 14 and 20% higher ER versus DR dose comparisons, the ER and DR regimens were equivalent with respect to AUC. Furthermore, the ER formulation achieved a lower C(max) central value and a higher C(min) mean than the corresponding values for the DR formulation. The mean peak-to-trough fluctuations of valproic acid plasma concentrations were 42-48% lower for the ER formulation compared with the DR. The higher ER doses were as well tolerated as DR, with a small number of adverse events that were non-serious in nature and mild in intensity. Therefore, increasing the once-daily ER dose 14-20% while converting from a total daily DR dose given twice-daily results in equivalent exposure with lower C(max) and higher C(min) values.

Summary Objective Part 1 of this phase III study was a randomized, double-blind, parallel-group, placebo-controlled, multicenter study of caregiver administered diazepam auto-injector (AI) in subjects with acute repetitive seizures (ARS) and demonstrated that diazepam AI was well-tolerated and significantly more effective than placebo AI in delaying the time to next seizure or rescue. Part 2 of this study, presented herein, was an open-label continuation to assess the long-term safety and effectiveness of diazepam AI for the treatment of ARS. Methods Of the 234 subjects randomized in part 1, 161 continued into part 2 and were provided open-label diazepam AI. Effectiveness measures were time to next seizure or rescue, number of subsequent rescues by type (rescue medication, emergency room visit, or other medical care), and number of subsequent seizures during the 12-h follow-up period. Safety data (adverse events and respirations

Objective: The aim of this study was to assess the efficacy, tolerability, and safety of divalproex sodium in the treatment of elderly patients with dementia who exhibited manic symptoms. Methods: This 6-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled elderly nursing home residents with dementia and secondary mania, as distinct from the actual manic episodes that might be associated with bipolar disorder. Patients were randomly assigned to receive placebo or divalproex sodium at a starting dose of 125 mg BID, followed by daily titration in increments of 125 mg/d up to a target dosage of 20 mg/kg/d (maximum dosage of 30 mg/kg/d). Efficacy was assessed using the Bech-Rafaelsen Mania Scale (BRMS), the Cohen-Mansfield Agitation Inventory (CMAI), the Brief Psychiatric Rating Scale (BPRS), and the severity of illness and improvement scales of the Clinical Global Impressions (CGI). Because of a disproportionate number of withdrawals due to somnolence in the active-treatment group, the study was terminated prior to full enrollment. Results: A total of 172 patients were enrolled; 87 received divalproex sodium and 85 received placebo. Forty (46%) divalproex sodium-treated and 60 (71%) placebo-treated patients completed the study. There was no appreciable difference between drug and placebo groups in scores on the BRMS, the primary outcome measure. Scores on the CMAI, however, showed significant improvement in the divalproex sodium-treated group compared with the placebo group ( P P = 0.035). Nineteen divalproex sodium—treated patients (22%) and 3 placebo-treated patients (4%) withdrew from the study because of adverse events ( P P = 0.027 for somnolence; P = 0.029 for thrombocytopenia) with divalproex sodium use than with placebo. Conclusions: Divalproex sodium did not improve signs and symptoms of mania associated with dementia in this sample of nursing-home residents, but did improve symptoms of agitation. Further study of divalproex sodium for agitation, at lower doses and a slower titration rate, is needed to define the optimal regimen for this drug in elderly, medically compromised populations.

The effects of tiagabine (TGB) on abilities and on adjustment and mood are as yet incompletely understood. These effects were compared with those of phenytoin (PHT) and carbamazepine (CBZ) in an add-on study. Patients included in the analysis were adults with uncontrolled partial seizures who at study entry were on CBZ alone (n=153) or on PHT alone (n=124). Of the patients receiving CBZ, 82 were randomized to add-on TGB and 71 were randomized to add-on PHT during the double-blind period. Of the patients receiving PHT, 58 were randomized to add-on TGB and 66 were randomized to add-on CBZ. Eight tests of mental abilities and three of mood and adjustment were given prior to assignment of add-on treatment and after up to 16 weeks of add-on treatment. For the baseline CBZ group, analyses were done to search for differential changes from baseline in the test scores of the add-on TGB and add-on PHT groups, and for the baseline PHT group in the add-on TGB and add-on CBZ groups. In the baseline CBZ group, no differences in test scores were found between PHT and TGB. In the baseline PHT group for the area of abilities, patients treated with TGB had improved verbal fluency, as well as quicker responses on a test of perceptual/motor speed compared with patients treated with CBZ. For the baseline PHT group in the area of adjustment and mood, patients treated with TGB reported less positive mood and more financial concerns compared to patients treated with CBZ. Overall, add-on TGB showed few or no differences in comparison with add-on CBZ and add-on PHT.

This study was designed to determine the highest tiagabine dosage that could be administered as monotherapy to patients with complex partial seizures refractory to treatment with other antiepileptic drugs (AEDs) without unacceptable adverse events. Thirty-one patients, 18–47 years of age, participated at three sites. During a 3-week initiation phase, tiagabine was started and the dosage increased while concomitant AED dosage was reduced. During a 7-week dose-evaluation phase, dosage was adjusted until the maximum tolerated dosage was reached. During the dose termination phase, patients tolerating the drug entered a long-term open-label study of tiagabine monotherapy. Of 31 patients, 19 converted to monotherapy; in 12 cases, monotherapy was tolerated well enough to be continued for 7 weeks. Of the 12 nonconverters, seven left during the initiation phase due to adverse events and five due to inadequate seizure control. Most events were mildly or moderately severe and were associated with the central nervous system. Plasma tiagabine concentrations were similar in both converters and nonconverters. Conversion to tiagabine monotherapy was accomplished in most patients with difficult-to-control seizures when previous AED monotherapy was replaced in under 4 weeks. The ideal dosage appeared to be approximately 38 mg/day given in three divided doses.

Summary: Purpose: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy. Methods: In all, 2,147 plasma samples from 5 1 1 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach. Results: The patients’ average (+SD) weight and age were 73.8 + 20.7 kg and 32.1 k 12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 Llh, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (1 2.8 Lh). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates. Conclusions: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables. Key Words: Population-TiagabinePharmacokinetics-Epilepsy . Tiagabine [TGB: (R)-N-(4,4-di(3-methyl-2-thienyl)but-3-enyl-nipecotic acid], is a potent and selective inhibitor of y-aminobutyric acid (GABA) uptake. TGB, a nipecotic acid derivative discovered by Novo-Nordisk A/S (Bagsvaerd, Denmark), was recently approved in the United States as adjunctive therapy in the treatment of partial seizures.

This single-center, open-label study examined the safety and potential effect of tiagabine on valproate pharmacokinetics under steady-state conditions. Twelve adult patients with seizures controlled by an individualized fixed dosage of valproate participated in the study. On day 1, the pharmacokinetics of valproic acid were determined. On days 2 through 14, tiagabine was titrated from 8 to 24 mg/d (or the maximum tolerated dose up to 24 mg/d), and the patients continued to take their usual fixed dosage of valproate. Valproic acid pharmacokinetics were assessed again on day 14. The mean maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC0-tau ) for valproic acid were reduced approximately 10% and 12%, respectively (p < or = 0.05), when valproate and tiagabine were administered concomitantly, compared with the mean values when valproate was administered alone. The concomitant administration of these drugs was generally well tolerated. Ten patients reported treatment-emergent adverse events during the study, the most common of which was dizziness(n = 8). Only one patient experienced events that were considered to be severe. There were no clinically important effects on laboratory values, vital signs, or physical exam findings. The small decreases in mean valproic acid Cmax and AUC0-tau observed during the concomitant administration of tiagabine and valproate are probably of limited clinical importance, given the broad therapeutic range of valproate (50-100 microg/mL).

Summary: Purpose: We evaluated the dose-related impacts of tiagabine (TGB) on cognition and mood in a monotherapy study. Methods: Patients were 123 adults with uncontrolled partial seizures, each treated with a single currently available antiepileptic drug (AED) for management of clinical epilepsy. They completed a battery of neuropsychological tests during an 8 week prospective baseline period and once again at the end of the 12-week fixed-dose period (or earlier if they dropped out of the study). Sixty-six patients were randomized to 6 mg/day TGB and 57 were randomized to 36 mg/day TGB. Results: Few changes in either abilities or adjustment and mood were noted when all patients were considered as a single group. However, analysis of both dose and attainment of TGB monotherapy showed that patients receiving TGB monotherapy did best, improving particularly in the areas of adjustment and mood with low-dose TGB and in the area of abilities with high-dose TGB. Patients who did not attain monotherapy showed no change except that the high-dose group did not perform as well on measures of mood and adjustment. Baseline AED and changes in seizure control did not affect the results. Conclusions: Patients attainment of TGB monotherapy was associated with their achievement of positive changes of varying degree on psychological tests. Failure to attain TGB monotherapy was associated with no changes on the tests except in patients receiving high-dose TGB where it appeared that some alterations in mood might have been avoided if a slower titration schedule had been used.

We report an open-label study of 25 children with complex partial seizures that assessed the pharmacokinetics and safety of a single dose of approximately 0.1 mg/kg tiagabine. The children received their usual individualized regimen of one concomitant antiepilepsy drug (AED) throughout the study. Seventeen children were receiving an inducing AED (carbamazepine or phenytoin); eight were receiving valproate. Tiagabine was well tolerated. Dose-normalized Cmax was higher in children taking valproate (18.2 +/- 5.0 ng/mL/mg) than in the induced children (14.8 +/- 6.9 ng/mL/mg), but the difference was not statistically significant. Dose-normalized area under the plasma concentration-time curve from time zero to infinite time was significantly higher (p = 0.002) in children taking valproate (176.5 +/- 54.7 ng.hr/mL/mg) than in induced children (92.4 +/- 56.7 ng.hr/mL/mg). Similarly, oral clearance in the children taking valproate (96 +/- 39 mL/min) was half that of the induced children (207 +/- 91 mL/min). Half-life in children taking valproate (5.7 hr) was almost twice that for the induced children (3.2 hr), and the elimination rate constant was significantly lower (p0.02) for the children taking valproate than for the induced children. Volume of distribution was similar in the children taking valproate (52 +/- 9 L) and the induced children (59 +/- 29 L). This is consistent with observations in adults taking tiagabine with inducing AEDs or valproate. Exploratory regressions on these data in children and previous data in adults showed fairly strong relationships between body size and tiagabine clearance and volume of distribution, with body size explaining about 40 to 50% of the variability. When adjusted per kg body weight, clearance and volume were greater in children than adults. When adjusted per m2 body surface area, clearance and volume were more similar in adults and children.

Purpose A diazepam auto‐injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS (ClinicalTrials.gov identifier NCT00319501). Methods In this phase III, randomized, double‐blind, parallel‐group, placebo‐controlled, multicenter study, subjects with epilepsy on a stable antiepileptic drug regimen who required intermittent medical intervention to control ARS were randomized 1:1 to the placebo AI or the diazepam AI group. Subjects were stratified according to age (2–5, 6–11, ≥12 years). Dose (5, 10, 15, or 20 mg) was based on age and weight. A single dose of study medication was dispensed to be administered by caregivers in an outpatient setting when required. The primary end point was time to next seizure or rescue from 15 min to 12 h postdose. Secondary end points included rescue medication use, number of seizures postdose, caregiver and physician treatment assessments, and safety measures. Key findings Of 234 subjects randomized, 81/110 in the placebo AI group and 82/124 in the diazepam AI group were included in the intent‐to‐treat analysis. Baseline characteristics were similar for both groups. Time to next seizure or rescue was significantly longer in the diazepam AI group compared with the placebo AI group, with a hazard ratio of 0.55 (95% confidence interval [CI] 0.34–0.88; p = 0.012) for diazepam AI versus placebo AI, adjusted for age group. The 25th percentile for time to the next seizure or rescue was 1.18 h (95% CI 0.38–2.03) for placebo AI and 2.70 h (95% CI 0.48–11.42) for diazepam AI; the median was 5.9 h for placebo AI and was inestimable for diazepam AI due to the low number of events experienced by subjects in that group. The proportion of subjects using rescue medication postdose was 30% (24/81) placebo AI versus 17% (14/82) diazepam AI (p = 0.066). An event (seizure or rescue) occurred in 55.6% of subjects in the placebo AI group and 35.4% in the diazepam AI group. The number of seizures experienced during the 12‐h postdose period was significantly lower for diazepam AI (median 0.0) compared with placebo AI (median 1.0; p = 0.010). Treatment‐emergent adverse events (TEAEs) were reported in 44% (35/79) of subjects in the placebo AI group and 42% (34/81) in the diazepam AI group. The most common TEAEs reported were injection site pain (15% placebo AI, 17% diazepam AI) and injection site hemorrhage (6% placebo AI, 5% diazepam AI). Significance The diazepam AI was significantly more effective than placebo AI at delaying the next seizure or rescue. Secondary efficacy end points were generally supportive of the primary outcome. Diazepam AI administered by trained caregivers was effective for the treatment of ARS and was well tolerated, with a safety profile similar to placebo.

Background Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here. Methods Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography. Results Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h). Conclusions Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.

Bioequivalence is an important component of the development of AEDs. Development of new formulations after the original testing of any drug requires demonstration that the compounds are therapeutically equivalent and additional efficacy studies may not be required. Extended-release formulations may reduce toxicity with a lower maximum blood concentration (C(max)) and improve efficacy with a higher minimum blood concentration (C(min)). Obtaining an equivalent area under the curve (AUC) while slowing the gastrointestinal transit and avoiding food effects and dose dumping among a population with epilepsy with individual variability requires extensive engineering of the formulation. The development of extended release divalproex (Depakote ER) is used as an example of the challenges of this phase of drug development. Other routes of administration discussed are rectal preparations, nasal formulations, and intravenous infusions. These newer formulations may offer better patient care and more efficient development.

Rotigotine is a new dopamine agonist with transdermal patch formulation for the treatment of Parkinson disease. The aim of this study was to investigate safety and efficacy of rotigotine in patients with early-stage Parkinson disease. In this open-label, dose-escalation, safety and efficacy study, 31 patients in the early stages of idiopathic Parkinson disease received rotigotine to a maximum of 18.0 mg/day. Of the 29 patients who completed the 28-day treatment phase, 24 were maintained at the maximum dose level. The drug was well tolerated, and skin reactions were mild. A statistically significant improvement in UPDRS I, II, and III scores was observed from baseline to end of treatment for the 29 subjects who completed the trial. Mean improvement (+/- standard deviation) was -0.41 +/- 0.78 on UPDRS I (P = 0.0078), -2.76 +/- 3.31 on UPDRS II (P = 0.0001), and -4.62 +/- 5.32 on UPDRS III (P < 0.0001). When results were stratified by maximum dose achieved, significant improvements were seen on all 3 subscores for patients achieving the maximum dose. These data suggest that rotigotine is a safe, well-tolerated, and effective treatment for early-stage Parkinson disease.

Background Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex. Method In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. Results The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters. Conclusion These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.

Background Divalproex sodium is a mood stabilizer used in the United States for the treatment of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical antipsychotic, was approved for the treatment of acute mania. This study compares the clinical, health-related quality of life (HRQL), and economic outcomes of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. Method This 12-week, double-blind, double-dummy, randomized clinical trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for an acute manic episode recruited from 21 U.S. clinical centers. Subjects were randomly assigned to treatment with either divalproex or olanzapine and were followed in hospital for up to 21 days. If after 21 days clinical improvements (based on the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects showing clinical improvement were treated for up to 12 weeks. HRQL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and costs were collected over the 12-week study. Results A total of 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed beyond 21 days. No statistically significant differences between the treatment groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week outpatient medical costs were significantly lower for the divalproex-treated group (541 US dollars) compared with the olanzapine-treated group (1080 US dollars) (p =.004). There was no significant difference in total medical costs between the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars; p =.88). Conclusion Divalproex is associated with lower 12-week outpatient costs compared with olanzapine. Divalproex and olanzapine have similar short-term effects on clinical or HRQL outcomes in bipolar disorder subjects.

Summary: Purpose: Acute pancreatitis has been associated with a number of medications, including valproate (VPA). Valproate-coincident pancreatitis is uncommon and is usually associated with other risk factors; however, the United States Food and Drug Administration has issued a box warning for risk of acute pancreatitis with VPA products. We reviewed cases of pancreatitis in VPA-treated patients from the clinical database of VPA/divalproex trials and compared the incidence of elevated amylase levels between VPA- and placebo-treated patients. Methods: Report rates of acute pancreatitis coincident with VPA use in 34 clinical trials were calculated. Incidence rates of amylase elevations above the normal range in three clinical placebo-controlled migraine trials were compared between VPA- and placebo-treated patients. Results: Among 3,007 VPA-treated patients in 34 clinical trials, two reports of pancreatitis were considered by investigators to be probably related to VPA. Both patients recovered. Similar rates of amylase elevations were observed in VPA- (5.9%) and placebo-treated (6.1%) patients in the three migraine headache trials. Conclusions: VPA-coincident acute pancreatitis is uncommon and idiosyncratic. Checking amylase levels in the absence of other clinical signs and symptoms provides little value for predicting pancreatitis. Physicians should be guided by clinical symptoms of pancreatitis to identify cases.

Purpose: To compare the safety and efficacy of two formulations of divalproex, extended-release divalproex versus the original divalproex tablet, in adolescent and adult patients with epilepsy. Methods: Eligible patients were between the ages of 12 and 65 years with primary generalized epilepsy, which was controlled over the month prior to study enrollment with divalproex or valproic acid 1000 mg to 2000 mg/day. The patients were well-controlled; 39 of 43 (91%) had no seizures in the previous year. Patients were randomized to receive 84 days of either divalproex two times a day (b.i.d.)/three times a day (t.i.d.) or extended-release divalproex qd and then (crossed over to) 84 days of the comparator formulation. During the two treatment periods, patients received the same daily dose equivalent of divalproex as was taken during the month prior to study entry. The clinical status of patients was evaluated at a screening visit and at four subsequent visits conducted every 42 days. Results: There was no statistically significant difference between the formulation groups for seizure control rate (95% [41/43] for divalproex and 93% [40/43] for extended-release divalproex). Likewise, the formulation groups were similar based on the incidence of treatment-related adverse events. The most frequently reported (≤11.4% for either formulation) treatment-related adverse events were asthenia, tremor, nausea, and dizziness. Conclusions: Extended-release divalproex was similar to divalproex for the treatment of well-controlled, primary generalized epilepsy in terms of overall safety and efficacy parameters.

Summary: Combinations of tiagabine (TGB), carbamazepine (CBZ), and phenytoin (PHT) were compared for their impact on health-related quality of life (HRQOL) and adverse effects related to treatment efficacy for people with frequent complex partial seizures. Two independent, randomized, double-blind clinical trials for efficacy and safety were conducted simultaneously with treatment groups: CBZ+PHT versus CBZ+TGB, and PHT+CBZ versus PHT+TGB. Treatment was initiated at week 0 and continued through week 16. HRQOL was evaluated with the QOLIE-89. Treatment success was defined as ≥50% reduction in complex partial seizures. Among patients who achieved a ≥50% reduction in seizures, addition of TGB to baseline PHT enhanced patient perceptions of attention/concentration (13%; p = 0.002), memory (17%; p = 0.042), and language subscales (22%; p = 0.004). Addition of CBZ to PHT led to positive change in the work/driving/social relations subscale (14%; p = 0.004). These improvements were significantly different only between visits, not between the two treatment groups. Seizure worry subscale scores showed improvement among all treatment groups and was probably related to participation in the clinical trial. These exploratory analyses suggest a possible early positive effect of TGB on patient-perceived cognitive domains using the QOLIE-89. These findings are limited by the small sample size and could be related to reduction in seizures.

Changes in body weight were evaluated in 349 patients from a study comparing efficacy of add-on therapy with tiagabine (TGB), carbamazepine (CBZ) or phenytoin (PHT). TGB add-on therapy showed no significant weight changes when added to either PHT or CBZ. CBZ add-on therapy showed a significant percentage weight gain of a mean body increase of 1.5% (P = 0.002). Adjunctive TGB therapy had no significant effect on total body weight, while adjunctive CBZ therapy was associated with weight gain.

Two single-center, open-label studies examined the potential effects of tiagabine on the pharmacokinetics and safety of carbamazepine and phenytoin at steady state. Twelve adult patients with seizures controlled by an individualized fixed dosage of antiepilepsy medication (carbamazepine or phenytoin) participated in each study. On day 1, the pharmacokinetics of the baseline antiepilepsy drug were determined. On days 2 through 18, tiagabine was titrated from 8 to 48 mg/d (or the maximum tolerated dose up to 48 mg/d), and the usual fixed dosage of carbamazepine or phenytoin was continued. The pharmacokinetic assessment was repeated on day 18. There were no statistically significant differences in carbamazepine, carbamazepine epoxide, and phenytoin pharmacokinetic parameters when either drug was administered alone or in combination with tiagabine. In each study, 11 of 12 patients (92%) experienced treatment-emergent adverse events after tiagabine was added. The most frequent adverse events were dizziness, headache, difficulty concentrating, drowsiness, and tremor. Most symptoms were mild or moderate in severity and resolved without further treatment, although tiagabine dosage reductions were required by 4 patients in the carbamazepine study and by 3 patients in the phenytoin study. There were no clinically important effects on physical examination or neurologic test results, laboratory values, or vital signs. The results suggest that addition of tiagabine to a fixed regimen of either carbamazepine or phenytoin is generally well tolerated and that carbamazepine and phenytoin steady-state pharmacokinetics are unaffected by the addition of tiagabine.

We reviewed the clinical safety of tiagabine HCl (TGB), a selective CNS GABA uptake inhibitor, in nearly 3100 patients from 53 separate clinical trials. TGB was found to have no clinically important effect upon hepatic metabolic processes, serum concentrations of concomitant antiepileptic drugs (AEDs), laboratory values, or important interactions with any common non-AEDs. Adverse effects were usually mild and involved the nervous system. TGB is safe and well-tolerated as add-on therapy for the treatment of partial seizures.

Summary Vigabatrin (VGB) prevents seizures by irreversible inhibition of γ-aminobutyric acid (GABA) transaminase and a resulting increase in GABA levels. We evaluated the cognitive and quality-of-life (QOL) effects of VGB in a double-blinded, add-on, placebo-controlled, parallel group dose-response study of patients with focal epilepsy whose complex partial seizures (CPS) were difficult to control. In a single investigation, patients were randomly assigned to placebo (n = 40), 1 g VGB (n = 36), 3 g VGB (n = 38), or 6 g VGB (n = 32), treated for 12 weeks after a 6-week dose escalation period, and tested at the end of the baseline period and at the end of the treatment period with eight cognitive measures and three tests of mood and adjustment. The patient groups were highly similar at study entry. Results at the end of the study showed substantial relief from seizures. The Digit Cancellation Test showed decreases in performance with increasing doses of VGB. Performance on no other test showed any decrement with increasing dosage. Relief from seizures was not associated with changes on the psychological tests. VGB is a useful antiepileptic drug (AED) that has little impact on tests of either cognitive abilities or QOL, even at a high dose.

Unbalanced Statistical Analysis of Combined Divalproex and Antipsychotic Therapy for Schizophrenia

To determine the efficacy and tolerability of tiagabine, a new antiepileptic drug (AED) that inhibits gamma-aminobutyric acid (GABA) uptake, at 3 dose levels vs placebo as adjunctive therapy in patients with intractable complex partial seizures (CPS).Randomized, double-blind, placebo-controlled study with a parallel-group, add-on design, starting with a 12-week unblinded baseline phase followed by a 20-week double-blind treatment phase.Twenty-one US medical centers.Patients (N = 297) aged 12 to 77 years, previously diagnosed as having CPS and receiving stable regimens of 1 to 3 hepatic enzyme-inducing AEDs; divalproex sodium or valproic acid was allowed in combination with any of these drugs.Placebo or tiagabine 4 times a day at 16, 32, or 56 mg daily.Median change in 4-week CPS frequency and adverse events.Median decreases in 4-week CPS frequency for the 32-mg (-2.2) and 56-mg (-2.8) tiagabine groups were significantly greater than for the placebo (-0.7) group (P = .03 and P.03, respectively); 20% and 29% of patients in the 32- and 56-mg groups had a 50% or greater reduction in the frequency of CPS vs 4% in the placebo group (P = .002 and P.001, respectively). Adverse effects were similar for placebo and tiagabine except for a significantly greater incidence of dizziness in the 32-mg tiagabine group, tremor in the 32- and 56-mg groups, abnormal thinking (usually mental lethargy or difficulty concentrating) in the 56-mg group, and depressed mood in the 16- and 56-mg groups.Tiagabine is efficacious and well tolerated as adjunctive therapy for CPS; there is a clear dose-response relationship.

Objective: To evaluate the efficacy and safety of 2 regimens of tiagabine as add-on therapy for patients with complex partial seizures (CPSs) that are refractory to other treatment. Design: Randomized, double-blind, placebocontrolled, add-on, parallel-group trial with an 8-week baseline period, 12-week experimental period (4 weeks of dose titration and 8 weeks of fixed-dose therapy), and 4-week termination period. Setting: Twenty-six centers throughout the United States. Patients: Three hundred fifty-one patients were enrolled, 318 were entered in the double-blind period, and 271 completed the study. Interventions: Tiagabine, 16 mg 2 times per day (106 patients); tiagabine, 8 mg 4 times daily (105 patients); and placebo (107 patients). The doses of tiagabine were titrated in 3 steps to the fixed dose. Main Outcome Measure: The median change in the 4-week rate of CPSs from baseline to experimental period. Results: The median change from baseline was −1.6 CPSs per 4 weeks in the group of patients who were given tiagabine 2 times per day, and it was −1.2 CPSs in the group of patients who were given tiagabine 4 times per day ( P =.06 and P =.02, respectively, compared with placebo). The 4-week seizure frequency was reduced by 50% or more in 31% of the patients who were given tiagabine 2 times per day and in 27% of the patients who were given tiagabine 4 times per day vs 10% of the placebo-treated patients ( P ≤.001 for each tiagabine-treated group compared with the placebo group). The most frequent adverse events involved the central nervous system and occurred in comparable proportions in the 3 treatment groups. Similar proportions of patients discontinued the study prematurely for adverse events. Conclusions: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.

We evaluated the psychological effects of the antiepilepsy drug vigabatrin in a randomized multicenter double-blind placebo-controlled parallel group study that compared 3 grams oral vigabatrin with placebo as daily add-on therapy in patients with focal epilepsy whose complex partial seizures were difficult to control. Testing at baseline and after 12 weeks of vigabatrin (n = 83) or placebo (n = 85) used eight measures of cognitive abilities and three of mood and adjustment. The vigabatrin and placebo groups were highly similar at entry into the study. At the end of the study, there were no differences between the vigabatrin and placebo groups on any cognitive variable or on any measure of mood and adjustment. Analysis of the results related to relief from seizures demonstrated only chance findings. In a similar manner, there were no relationships between vigabatrin serum levels at the end of the study and changes on measures of abilities and adjustment. Vigabatrin appears to be a useful antiepilepsy drug with little impact upon tests of either cognitive abilities or quality of life.