Poster

Long-Term Safety and Tolerability of Lacosamide for Partial-Onset Seizures

Boston, MA—The purpose of this study, presented as a poster at the annual AES meeting, was to examine the long-term safety of lacosamide (LCM) for partial-onset seizures based on all available data from Phase II-III double-blind and open-label extension trials. William Rosenfeld, MD, of the Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, MO, and colleagues found that long-term LCM treatment was generally well tolerated in their analysis of 1327 patients exposed to LCM during double-blind or open-label extension trials, with the incidence of treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory and ECG findings similar to those reported with short-term, double-blind use.

Researchers analyzed pooled data for patients treated with LCM in completed double-blind trials and corresponding ongoing open-label extension trials. Data from the double-blind and open-label trials were included for those patients who received LCM in double-blind trials. Data from the transition period at the end of the double-blind trials and from open-label trials were used for those patients who were given placebo in double-blind trials. LCM exposure was relative to the first dose and was based on all available data (double-blind and open-label extension) from visits completed as of an interim analysis cut-off of April 7, 2008. Safety analyses included the following: TEAEs; ECGs; vital signs; body weight; and clinical laboratory data.

One thousand three hundred twenty-seven patients received at least one dose of LCM, representing 2663 patient-years exposure. The median duration of LCM exposure was 700 days (minimum duration, 1 day; maximum duration, 2437 days). The most common modal dose (dose used for the longest period of time) was 400 mg/day (n=347, 26.1%), with 85.7% of patients (n=1137) having a modal dose of 200-600 mg/day and 8.4% (n=111) having a modal dose of > 600 to ≤ 800 mg/day. At the time of this interim analysis, 526 patients were still enrolled in LCM clinical trials, and 1211 patients (91.3%) had reported at least one TEAE as of the interim analysis cut-off. The most common TEAEs (≥ 10%) were reported as follows: dizziness (45.6%), headache (20.6%), diplopia (18.5%), nausea (15.3%), nasopharyngitis (14.3%), vomiting (14.1%), fatigue (13.8%), coordination abnormal (12.5%), vision blurred (12.0%), tremor (11.5%), somnolence (11.5%), convulsion (11.4%), and confusion (10.4%).

The overall incidence of TEAEs increased with dose, although the increase was not remarkable, and most TEAEs were mild or moderate in intensity. In general, there were no new types of TEAEs thought to be related to the drug that emerged with chronic therapy. Dizziness (4.7%) was the only adverse event for which maximum intensity was reported as “severe” in > 1% of subjects. The most common TEAEs leading to discontinuation (> 1%) were dizziness (5.3%), vomiting (1.6%), nausea (1.5%), diplopia (1.5%), and coordination abnormal (1.5%). Long-term LCM treatment was not associated with any pattern of change in median or mean measurements for hematology, clinical chemistry, vital sign, or body weight. A small increase in mean PR interval of 5-9 ms was noted on ECGs acquired at various times during LCM exposure; however, this did not appear to be clinically relevant, and there were no reports of higher- (second or third) degree heart block.

Poster

Efficacy and Tolerability of Levetiracetam

Boston, MA— Levetiracetam extended release tablets (Keppra XR) became available in September 2008 for use as an add-on to other antiepileptic treatments for people with partial-onset seizures who are age 16 years and older. There are currently few data regarding the drug’s efficacy and tolerability. Researchers retrospectively analyzed data from the electronic medical records of 20 patients with epilepsy treated with Keppra XR with doses ranging from 500-4000 mg per day in the Neurology clinic at the Scott & White Hospital/Texas A&M Health Science Center, Temple. Results, presented as a poster at the AES annual meeting, revealed that good efficacy and tolerability of Keppra XR was seen in the epilepsy population analyzed. From the limited retrospective analysis, it was also concluded that Keppra XR was found to be effective as monotherapy.

Keppra XR was used as standard once-a-day dosing. The age range of participants was 15-74 years; 12 (60%) were female and eight (40%) were male. Sixteen (80%) patients had partial and four (20%) had generalized epilepsy. Keppra XR was used as monotherapy in 13 (65%) patients, and was used as adjunctive therapy in seven persons (35%). Thirteen (65%) patients were switched from Keppra IR to Keppra XR because of compliance issues and breakthrough seizures on generic levetiracetum. In six patients, 1:1 switch was made. In two patients, the dose was increased to achieve better control of seizures. Improvement was seen with the decreased dose of Keppra XR as compared to Keppra IR in six patients. There was favorable response to Keppra XR in terms of efficacy in 17 (85%) patients. No major side effects were reported; however, Keppra XR was tapered in three (15%) patients (in 1 patient because of increased frequency of seizures, and in the other 2 because of dizziness and mood problems).

Poster

KONQUEST: Keppra versus Older Antiepileptic Drugs and Neuropsychiatric, Neurocognitive, and Quality-of-Life Outcomes in Treatment of Epilepsy as Substitution Monotherapy

Boston, MA—Epilepsy, a chronic condition, has complex effects on a person’s social, vocational, and psychological function. Newer antiepileptic drugs (AEDs) such as levetiracetam (LEV) have been proposed to be better tolerated than older drugs such as carbamazepine (CBZ) and sodium valproate (VPA), therefore potentially improving quality of life. This study, presented as a poster at the AES annual meeting, tested medical and psychosocial outcomes from treatment with LEV as compared with two standard older drugs, CBZ and VPA, used as substitution monotherapy. Researchers concluded that tolerability, adverse effects, psychological symptomatology, and quality of life all improve with substitution monotherapy at 3 months. This effect is similar with LEV as with the established AEDs (CBZ and VPA).

Participants of KONQUEST, a randomized, open-label study, were recruited from outpatient clinics in an Australian Center. Patients with partial epilepsy on monotherapy with an older AED who had failed treatment (either due to lack of efficacy or due to adverse effects) were invited to participate. Participants taking phenytoin (PHT) or CBZ were randomized to either LEV or VPA, and participants taking VPA were randomized to either LEV or CBZ. Balanced randomization was used based on Hospital Anxiety Depression Scale (HADS) anxiety scores. Assessments were performed at baseline, 3, and 12 months using validated questionnaires for seizure control, anxiety and depression (HADS), psychiatric distress (Symptom Checklist 90 - SCL 90), Quality of Life in Epilepsy (QOLIE 89), adverse effects (Liverpool Adverse Effects Profile [LAEP]), and a computerized neuropsychological assessment tool (IntegNeuro). Outcome analysis was performed on the basis of intention to treat.

One hundred six patients were enrolled, with 98 satisfactorily completing their 3-month visit: 51 in the LEV group and 47 in the older AED group (randomized to VPA, n=26; or CBZ, n=21). There were significant improvements across all assessments, including LAEP scores (P < 0.05), QOLIE 89 scores (P < 0.001), SCL 90 scores (P < 0.05), and HADS scores (P < 0.05), over the 3-month period regardless of the treatment groups. No significant differences were observed between the two groups. A similar proportion of patients in both groups experienced recurrent seizures (approximately 33%).

American Academy of Pain Medicine 2010 Annual Meeting

Safety and Efficacy of Topical Diclofenac Sodium 1% Gel in Seniors and Younger Patients with Hand Osteoarthritis

San Antonio, TX—Roy D. Altman, MD, University of California-Los Angeles, and colleagues examined the safety and efficacy of diclofenac sodium 1% gel (DSG) in patients age < 65 and ≥ 65 years with hand osteoarthritis (OA). Results, presented at the annual AAPM meeting, revealed that DSG was effective and generally well tolerated for hand OA, regardless of patient age.

Three hundred eighty-five adults with radiographically verified hand OA were randomized to double-blind treatment with DSG (n=198) or placebo (n=187), 2 g to each hand 4 times daily for 8 weeks. OA pain intensity (100-mm visual analog scale), Australian/Canadian Osteoarthritis Hand Index (AUSCAN) score, and global rating of disease (GRD) at 4 and 6 weeks were the primary outcomes. Efficacy outcomes were compared by patient age (< 65 yr vs ≥ 65 yr) using analysis of variance (ANOVA). Researchers recorded all adverse events (AEs).

Participants randomized to DSG experienced improvements relative to baseline at weeks 4 and 6, in OA pain intensity (42%, 46%), total AUSCAN score (35%, 38%), and GRD (36%, 40%). These improvements were significantly superior to those experienced by patients randomized to placebo for OA pain intensity and total AUSCAN score (P ≤ 0.02) at weeks 4 and 6, but for GRD only at week 6 (P = 0.02). Efficacy differences (DSG vs placebo) between patients age < 65 years (DSG, n=109; placebo n=100) versus ≥ 65 years (DSG, n=89; placebo n=87) were not statistically significant. Application-site reactions were more common with DSG versus placebo for patients age < 65 years (4% vs 1%) and ≥ 65 years (5% vs 3%). Researchers reported that no gastrointestinal bleeding or serious treatment-related AEs occurred.

Funding was provided by Endo Pharmaceuticals Inc.

Changes in Opioid Use and Economic Outcomes Among Diabetic Peripheral Neuropathic Pain Patients Treated with Duloxetine Versus Other Therapies

San Antonio, TX—Patients with continuous duloxetine-treated diabetic peripheral neuropathic pain (DPNP) appeared to have reduced opioid use and lower overall healthcare costs, as concluded in an abstract presented at the annual AAPM meeting. This exploratory analysis by Kimberly Fraser, BA, Abt Bio-Pharma Solutions, Inc, Lexington, MA, and colleagues examined changes in opioid use and healthcare costs among commercially-insured patients with DPNP who initiated duloxetine versus other standard of care (SOC) medications (tricyclic antidepressants, venlafaxine, gabapentin, pregabalin).

Administrative claims data were analyzed for patients with DPNP age 18-64 years who initiated duloxetine or SOC between 3/1/2005 and 12/31/2005. Initiation was defined as no pill coverage in the previous 90 days for the same medication. All patients had opioids dispensed in the prior 90 days. Medication possession ratio (MPR) measured medication compliance. Participants were classified as either “continuous” (MPR ≥ 80%) users or “non-continuous” (MPR < 80%) users. Over the 12 months pre- and post-index periods, total opioid days, number of opioid prescriptions dispensed, and cumulative morphine equivalents were examined. In order to assess the changes (pre-index minus post-index) in opioid use (total, short-acting vs long-acting) and healthcare costs, multivariate regressions were performed.

One thousand two hundred eighty-one patients were identified (98 duloxetine continuous users, 243 duloxetine non-continuous users, 195 SOC continuous users, and 745 SOC non-continuous users). Results showed that duloxetine non-continuous and SOC (continuous and non-continuous) patients had significantly less reduction on total opioid days (-24.4, -23.7, -18.5, respectively, all P < 0.05) and short-acting hydrocodone use (days, prescriptions, and cumulative morphine equivalents) than duloxetine continuous patients, controlling for demographic and clinical characteristics. In addition, duloxetine non-continuous patients experienced $12,729 (P < 0.05) more total healthcare costs as compared to duloxetine continuous patients.

Funding for this project was provided by Eli Lilly and Company.

Assessment for Opioid-Withdrawal Syndrome in Patients with Chronic Moderate-to-Severe Pain Taking ALO-01 (Morphine Sulfate and Naltrexone Hydrochloride) ER Capsules

San Antonio, TX—Pellets in ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules (EMBEDA™), which are indicated for treatment of chronic moderate-to-severe pain, contain sequestered naltrexone designed for release to mitigate morphine-induced effects if tampered by crushing. In persons taking ALO-01 as intended (whole), trace amounts of naltrexone were found in a small proportion of plasma samples in early-phase single- and multiple-dose trials.

Two phase-III trials, therefore, included assessments to determine whether any patients taking ALO-01 for chronic moderate-to-severe pain experienced opioid-withdrawal syndrome. Results, presented at the annual AAPM meeting, suggest that sequestered naltrexone in ALO-01 taken as directed does not increase risk of opioid withdrawal in patients with chronic moderate-to-severe pain.

Institutional review boards approved the protocol, informed-consent, and recruitment materials before trial initiation. Trial A (N=547): after dose titration, patients (n=344) were randomized to 12-weeks maintenance on ALO-01 or placebo (2-wk taper). Trial B: patients (n=465) took ALO-01 open-label for 12-months. The Clinical Opiate Withdrawal Scale (COWS: 0-48, mild [5-12]; moderate [13-24]; moderately severe [25-36]; severe [> 36]) evaluated opioid withdrawal.

Researchers from King Pharmaceuticals, Inc., found that no patients in either trial taking ALO-01 as directed experienced COWS consistent with moderate or greater withdrawal. In Trial A, one patient after 5-weeks titration had COWS of 16 (moderate withdrawal) after taking fewer doses than instructed; one patient during maintenance had a score of 28 (moderately severe) after abruptly stopping medication. Three patients during taper-to-placebo had scores 13, 23, and 23 (moderate withdrawal). In Trial B, a small proportion of patients had COWS consistent with mild withdrawal at week 4 (n=16, 4.8%) to month 6 (n=3, 1.4%). Five patients had COWS of 13-23, consistent with moderate withdrawal; all did not take medication as directed per study protocol.

This research was supported by King Pharmaceuticals, Inc.

IV Acetaminophen Produces Clinically Meaningful Pain Response and Opioid-Sparing Effect After Major Orthopedic Surgery

San Antonio, TX—After major orthopedic surgery, IV acetaminophen (IV APAP) 1000 mg produced a statistically significant reduction in opioid consumption (33-63% reduction) and significantly reduced the need for opioid rescue, as reported in a study presented at the annual AAPM meeting. IV APAP is currently under review by the FDA.

The efficacy of IV APAP 1000 mg after total hip arthroplasty (THA) or total knee arthroplasty (TKA) was demonstrated in three randomized, double-blind, placebo-controlled studies (total N=231). Three repeated or single-dose studies of IV APAP after THA or TKA were analyzed:

• RC 210 3 002 (IV APAP, N=49; placebo, N=52);
• 136-02-03 (IV APAP, N=30; placebo, N=31); and
• 136-01-03 (IV APAP, 1000 mg N=35; placebo, N=34).

Opioid sparing was defined as ≥ 30% reduction in opioid consumption or avoidance of the need for opioid rescue.

Heather D. Smith, MBA, from Cadence Pharmaceuticals, San Diego, CA, and colleagues revealed that in study RC 210 3 002, mean IV morphine consumption was reduced by 46% during the first 6 hours (9.7 vs 17.8 mg; P = 0.0001) and by 33% over 24 hours (38.3 vs 57.4 mg; P = 0.0007). In studies 136-01-03 and 136-02-03, the mean opioid consumption was reduced by 53% (4.5 vs 9.6 mg) during the 6-hour study period (P = 0.016) and by 63% (1.9 vs 5.1 mg) during the first 4 hours (P = 0.006). In these two studies, 43% and 50% of participants did not require any rescue opioid during the treatment period. As compared to placebo, median time-to-rescue results also were consistent with these data. In all three studies, adverse events were comparable to placebo.

Funding was received from Cadence Pharmaceuticals.