There will be a formal scientific poster session convened
Thursday, September 6 at 12:30 pm.
Bioequivalence of Buccal and Sublingual Administration of Fentanyl Buccal Tablet: A Randomized, Open-Label, Single-Dose, Crossover Study
Mona Darwish, Mary Kirby, John Jiang, Philmore Robertson, William Tracewell
Cephalon, Inc., Frazer, PA
PURPOSE: Fentanyl buccal tablet (FBT) is designed to provide rapid-onset analgesia by enhancing fentanyl absorption across the buccal mucosa. We assessed the bioequivalence of FBT placed buccally vs sublingually in healthy adults to explore administration options.
METHODS: Subjects were randomized to treatment with one 400-µg tablet placed buccally (above a molar tooth between the upper gum and cheek) or sublingually, with a ≥7-day washout between doses. Naltrexone was administered to minimize opioid effects. Plasma fentanyl was measured through 72 hours postdose. Peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC0-∞), time to Cmax (tmax), and AUC from time 0 to median buccal tmax (AUC0-tmax') were recorded. Bioequivalence was declared if the 90% CIs of the treatment ratios (sublingual/buccal) for AUC0-∞ and Cmax were within the range 0.80-1.25. Tablet residue was inspected at 15 and 30 minutes. The study protocol was approved by an IRB and subjects provided written informed consent.
RESULTS: Ninety subjects were enrolled; 78 completed the study (mean age, 27 years). The plasma concentration-time curves were nearly identical after buccal and sublingual administration of FBT. Mean Cmax values for FBT administered buccally vs sublingually were 0.97 vs 0.85 ng/mL (ratiosublingual/buccal = 0.87; 90% CI = 0.82, 0.92). Mean AUC0-∞ values were 6.22 vs 5.88 ng•h/mL (ratiosublingual/buccal = 0.95; 90% CI = 0.90, 0.99). The CIs of the ratios showed that buccal and sublingual administration were bioequivalent. Median values for tmax and mean values for AUC0-tmax' were also similar following buccal and sublingual administration. Adverse events (AEs) in these naltrexone-blocked, nonopioid-tolerant healthy subjects were mild and included headache, nausea, dizziness, and fatigue, with no meaningful between-treatment differences. Application-site AEs occurred in 12% and 5% of subjects following buccal and sublingual administration, respectively. Fewer subjects had FBT residue at 15 and 30 minutes after sublingual administration (2% and 1%, respectively) than after buccal administration (36% and 15%).
CONCLUSION: FBT administered buccally and sublingually provided bioequivalent pharmacokinetic profiles in healthy subjects. These findings may expand administration options for patients who need or prefer an alternative to buccal administration.
Disclosure: M. Darwish, M. Kirby, J. Jiang, W. Tracewell, and P. Robertson are employees of Cephalon, Inc.
The Safety and Efficacy of Duloxetine Hydrochloride for the Treatment of Fibromyalgia: Results from a 6-month Randomized, Double-Blind, Placebo-Controlled, Fixed-Dosed Trial
Madelaine Wohlreich1, Jon Russell2, Philip Mease3, Timothy Smith4, Daniel Kajdasz1, Daniel Walker1, Amy Chappell1
1) Eli Lilly and Company, Indianapolis, IN 2) University of Texas Health Science Center, San Antonio, TX 3) University of Washington School of Medicine, Seattle, WA 4) Mercy Health Research, Chesterfield, MO
OBJECTIVES: The primary objective was to determine whether treatment with duloxetine [DLX] 120 mg/d for 3 months was effective in reducing pain severity in patients with fibromyalgia syndrome [FMS].
METHODS: DLX60 mg/d, DLX120 mg/d, and placebo [PBO] were compared during 6 months of treatment in adults with American College of Rheumatology-defined primary FMS. Coprimary efficacy measures included the Brief Pain Inventory Average Pain Score [APS], and the Patient’s Global Impressions of Improvement [PGI-I] questionnaire. Safety and tolerability were assessed.
RESULTS: At 3 months, patients treated with DLX120 mg/d showed greater improvement in change from baseline in APS score [-2.31 vs -1.38, P<.001] and endpoint PGI-I score [2.89 vs 3.39, P=.004] vs PBO-treated patients. At 6 months, the DLX120 mg/d group still exhibited greater improvement in APS change [-2.25 vs -1.42, P=.003] and PGI-I [2.93 vs 3.37, P=.012]. The DLX60 mg/d group showed significant improvement compared with PBO on both measures at 3 months and on APS change at 6 months. At 6 months, response, defined as ≥50% reduction from baseline in APS, was greater with DLX120 mg/d [35.9%, P≤.01] and DLX60 mg/d [32.6%, P≤.05] vs PBO [21.6%]. DLX was similarly efficacious in patients with [N=122] or without [N=375] major depressive disorder [MDD] with regard to both co-primaries. Discontinuation rates over 6 months were similar among the groups (DLX60 mg/d 45.3%, DLX120 mg/d 46.3%, PBO 50.0%). Adverse event-related discontinuation was significantly higher in the DLX120 mg/d [25.9%, P=.003] but not in the DLX60 mg/d [15.3%, P=.400] group compared with the PBO (11.8%) group.
Conclusions: DLX60 and DLX120 mg/d are efficacious and safe treatment options for pain associated with FMS, whether or not MDD is present.
Funding provided by Eli Lilly and Company and Boehringer Ingelheim
Safety of Duloxetine in Management of Diabetic Peripheral Neuropathic Pain Between Patients With and Without Historical and/or Co-morbid Cardiovascular Conditions
Joachim Wernicke, Apurva Prakash, Daniel Kajdasz, John Houston, Jerry Hall
Eli Lilly and Company, Indianapolis, IN
PURPOSE: Diabetic patients are predisposed to hypertension and other cardiovascular (CV) conditions. Within our DPNP database, we compared the safety and tolerability of duloxetine between patients with and without historical (Hx) or co-morbid CV conditions at study entry.
METHODS: Data were pooled from 3 double-blind, placebo-controlled studies in adult patients with DPNP. Patients were randomized to duloxetine (DLX) 60 mg QD (N=344), 60 mg BID (N=341), or placebo (PBO) (N=339) for 12 weeks. Safety assessments included discontinuation rates, treatment-emergent adverse events (TEAEs), and changes in BP.
RESULTS: Mean age of patients with Hx/co-morbid CV conditions (n=762) was 61.1 yrs and in patients without Hx/co-morbid CV conditions (n=262) was 56.1 yrs. The most common Hx/co-morbid CV conditions were hypertension (65%), coronary artery disease, and myocardial infarction. Other than diabetes medications and antihypertensives, the most common concomitant medications used by all patients included cholesterol-lowering agents, analgesics, and levothyroxine. Rates of discontinuation due to AEs were higher for DLX vs. PBO in both subgroups (13.5% DLX, 6.0% PBO and 14.3% DLX, 3.4% PBO respectively) in patients with and without Hx/co-morbid CV conditions. Rates of CV-related TEAEs in patients with (8.4% DLX; 9.9% PBO) and without (8.6% DLX; 6.0% PBO) Hx/co-morbid CV conditions were similar (p>.1 for tx by subgroup interactions). The effect of DLX vs. PBO on mean changes in SBP and DBP between patients with and without Hx/co-morbid CV conditions was not statistically significant (p>.1 for tx by subgroup interaction). Rates of sustained hypertension were similar between patients with (2.4% DLX; 2.8% PBO) and without (2.9% DLX; 4.7% PBO) Hx/co-morbid CV conditions (p>.1 for tx by subgroup interactions).
CONCLUSION: In this analysis, the safety of duloxetine in patients with DPNP was not significantly different between patients with and without historical or co-morbid CV conditions.
Funding provided by Eli Lilly and Company and Boehringer Ingelheim
Duloxetine as Treatment for Diabetic Peripheral Neuropathic Pain: Results from All Placebo-Controlled Studies
Joachim Wernicke, Michael Robinson, James Martinez, Jerry Hall,
Eli Lilly and Company, Indianapolis, IN
PURPOSE: Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor approved for the management of diabetic peripheral neuropathic pain (DPNP). We present a summary of efficacy results from all placebo-controlled DPNP studies completed for duloxetine.
METHODS: Adult outpatients with symptoms of DPNP (without depression) were studied in three, large, placebo-controlled clinical trials utilizing fixed doses of duloxetine (60mg/d or 120mg/d). University and clinical trial research sites, endocrinologists, neurologists, rheumatologists, primary care, psychiatrists. The primary efficacy measure was the weekly mean score of the 24-hour average pain severity measured by a patient-rated 11-point Likert scale. Safety data were collected. All analyses were done on an intent-to-treat basis. Pooled and individual study results are presented.
RESULTS: Patients treated with duloxetine at doses of 60 or 120mg/d reported significantly greater improvement in mean 24-hour average pain severity compared to placebo. Significant separation from placebo occurred as early as week one, was sustained at each time point throughout the 12-week studies, and was replicated in all studies. In all studies, patients treated with duloxetine 60 or 120mg/day experienced mean improvement from baseline in 24-hour average pain severity that approached or exceeded 30% by 2 weeks of treatment. By 12 weeks of treatment, mean improvement for duloxetine at 60 or 120mg/d approached or exceeded 50%. Duloxetine treatment produced significantly greater improvement than placebo on all patient-rated pain assessments including pain at night and ‘worst pain’. Adverse events most commonly reported in duloxetine-treated patients included nausea, somnolence, dizziness, constipation, dry mouth, hyperhidrosis, and decreased appetite. The majority of patients reported these as mild or moderate in severity and events were more common at higher doses of duloxetine.
CONCLUSIONS: Duloxetine 60 or 120 mg/d provides rapid and substantial relief of neuropathic pain associated with diabetic peripheral neuropathy. Results were replicated in all placebo-controlled studies.
Funding provided by Eli Lilly and Company
The Relationships Between Sleep and Pain in Patients with Diabetic Peripheral Neuropathic Pain: Responses to Treatment with Duloxetine
David Fishbain1, Jerry Hall2, Adam Meyers2, Jill Gonzales2, Virgil Whitmyer 2, Craig Mallinckrodt2
1University of Miami School of Medicine, Miami, FL, 2 Eli Lilly and Company, Indianapolis, IN
PURPOSE: Although the prevalence of sleep problems in patients with chronic pain (CP) is reported to be as high as 70%, the relationships between pain and sleep have not been thoroughly quantified.
METHODS: Data from clinical trials of duloxetine in patients with diabetic peripheral neuropathic pain (DPNP) are used to investigate associations between pain and sleep. Data were pooled from 3 double-blind, randomized, placebo-controlled, 12-week trials of patients with DPNP in which major mood disorders were excluded. Study 1 (N=457) compared duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), and placebo; Studies 2 (N=334) and 3 (N=348) compared duloxetine 60 mg QD and 60 mg BID with placebo. A non-somnolent/nonsedating medications subset of patients (n=923) was constructed by dropping DPNP patients reporting somnolence or on sedating concomitant medications. Efficacy measures included average daily pain severity and average night pain severity, both collected via patient diaries, and the Brief Pain Inventory (BPI) interference items.
RESULTS: The weekly mean scores of the daily pain severity and night pain severity were calculated for Weeks 1-12. BPI was administered at Weeks 4, 8, and 12. At baseline, both daily and night pain severity were positively and significantly correlated with sleep interference (r=0.37 and 0.57, respectively; p<.001). Both doses of duloxetine were significantly superior to placebo in reducing both daily and night pain at Week 1 and at all assessment times thereafter. Placebo response was greater on sleep interference than for either pain measure. Both duloxetine doses were superior to placebo in reducing sleep interference at Weeks 4, 8, and 12. Correlations between changes to endpoint in daily pain and night pain with sleep interference changes were 0.48 and 0.54 for all patients and 0.46 and 0.53 for non-somnolent/nonsedating medication patients, respectively (p<.001).
CONCLUSIONS: Results suggest moderate to strong associations at baseline between daily pain, night pain and sleep interference, as well as between changes in pain (daily and night) and changes in sleep interference. Although causality was not established, these findings suggest improvements in pain will be associated with less interference in sleep.
Funding provided by Eli Lilly and Company
Long-Term Safety of Fentanyl Buccal Tablet for the Treatment of Breakthrough Pain in Opioid-Tolerant Cancer Patients
Sharon Weinstein,1 Rajbala Thakur,2 John Messina,3 Fang Xie,3 Haresh Jhangiani4
1Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; 2University of Rochester Medical Center, Rochester, NY; 3Cephalon, Inc., Frazer, PA; 4Compassionate Cancer Care Medical Group, Fountain Valley, CA
PURPOSE: This long-term, open-label, multicenter study was conducted to evaluate the safety and tolerability of treatment with fentanyl buccal tablet (FBT) to manage breakthrough pain (BTP) in opioid-tolerant patients with chronic cancer pain.
METHODS: Adults taking around-the-clock opioids for persistent pain (intensity ≤7) and experiencing 1-4 BTP episodes/day were maintained at their successful dose from 1 of 2 previous clinical studies (rollover patients, n=120) or titrated to a successful FBT dose (100-800 µg) (treatment-naive patients, n=110; retitrated patients, n=2). Monthly assessments included BTP episodes/day, FBT dose/day, and adverse event (AE) recording. The study protocol was approved by the Independent Ethics Committee or Institutional Review Board for each participating investigator, and written informed consent was obtained from each patient.
RESULTS: 197 patients entered the dose-maintenance phase, including 79 patients who achieved a successful FBT dose during titration. In the dose-maintenance phase, median duration of FBT exposure was 122 days (range, 1-698; 36 patients [18%] had FBT exposure ≥12 months); mean (SE) dose/BTP episode was 554.8±18.6 µg; and the initial successful dose was the same as the ending dose for 136 (69%) patients. In the dose-maintenance phase, discontinuations included 3 patients for lack of efficacy and 71 for AEs. AEs, typical of opioid use and consistent with those observed in short-term studies, included nausea (n=86), vomiting (n=52), and dizziness (n=46). Serious AEs included disease progression (n=62) and pneumonia (n=16); all serious AEs were deemed by investigators to be unrelated to study medication with the exception of drug withdrawal syndrome in one patient.
CONCLUSIONS: FBT was generally safe and well-tolerated in the treatment of BTP in this study, the largest and longest FBT study in patients with cancer to date.
Disclosure: Sharon Weinstein, Rajbala Thakur, and Haresh Jhangiani received funding from Cephalon, Inc. to conduct research on FBT. John Messina and Fang Xie are employees of Cephalon, Inc.
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