Pharmacy & Therapeutics - October 2008 - (Page 580)

DRUG FORECAST continued from page 574 recovery of GI function, as determined by the surgeon. In all five studies, treatment with alvimopan significantly accelerated the time to recovery of GI function, compared with placebo, by 10.7 to 26.1 hours, as measured by a composite endpoint of toleration of solid food and first bowel movement. GI recovery began approximately 48 hours postoperatively. In addition, patients receiving alvimopan were discharged 13 to 21 hours sooner than those in the placebo group. The use of alvimopan did not reverse opioid analgesia in any of the studies. Adverse events reported with alvimopan (n = 1,650), compared with placebo (n = 1,365), in nine placebo-controlled studies in surgical patients included constipation (9.7% vs. 7.6%), flatulence (8.7% vs. 7.7%), hypokalemia (6.9% vs. 7.5%), dyspepsia (5.9% vs. 4.8%), anemia (5.4% for both), urinar y retention (3.5% vs. 2.3%), and back pain (3.4% vs. 2.6%, respectively). Figure 1 Chemical structure of alvimopan (Entereg). (Data from package insert.6) moderately large molecular weight and low lipophilicity, alvimopan does not cross the blood–brain barrier. Alvimopan has one major metabolite (ADL 08-0011), and its terminal half-life ranges from 10 to 18 hours, similar to that of the parent drug. This metabolite is a result of intestinal rather than hepatic metabolism. High-fat meals decrease the extent and rate of alvimopan absorption; however, the clinical significance is unknown. The drug’s pharmacokinetics is not affected by the patient’s age or sex; therefore, no dosage adjustments are needed. Approximately 2% of the administered dose is excreted in the urine as the unchanged drug. Renal clearance of alvimopan accounts for approximately 30% of total plasma clearance. Biliary secretion is the primary pathway for alvimopan elimination; there is no evidence that hepatic metabolism plays a significant role in further elimination. In a study designed to evaluate potential effects on cardiac conduction, alvimopan did not cause clinically significant prolongation of the corrected QT interval (QTc) at doses up to 24 mg twice daily for seven days. The potential for QTc effects at higher doses has not been studied.6,7 • Patients were randomly assigned to receive alvimopan oral capsules or placebo. • The initial dose was administered preoperatively. • Subsequent doses were given twice daily beginning on postoperative day one until postoperative day seven or until hospital discharge. • Patients who were taking preoperative chronic opioids or who were scheduled to have laparoscopic surgery or epidural anesthesia were excluded. For all studies, the primary efficacy endpoint was the time to recover y of both upper and lower GI tract motility following surgery. In the four POI studies,8–11 the time to recovery of the upper and lower GI tracts was a three-component composite endpoint called GI-3. GI-3 was defined as the time from the end of surgery to the time of recovery of the upper GI tract (toleration of solid food) and the lower GI tract (i.e., the first flatus or the first bowel movement, whichever occurred first). In the one POI efficacy study,12 the time to recovery of the upper and lower GI tracts was a twocomponent composite endpoint called GI-2. GI-2 was defined as the time from the end of surgery to the time of recovery of the upper GI tract (i.e., toleration of solid food) and the lower GI tract (the first bowel movement). Secondary efficacy endpoints included the following measurements of length of hospital stay (LOS): • the discharge order written (DOW), defined as the time from the end of surgery to the time that the hospital discharge order was written • ready, defined as the time from the end of surgery to the time ready for hospital discharge based solely on CHRONIC OPIOID-INDUCED BOWEL DYSFUNCTION Paulson et al.13 Paulson et al. reported results of a phase 3 randomized, placebo-controlled study involving 168 patients with opioidinduced bowel function, defined as fewer than three bowel movements per week. These patients had been receiving opioid analgesic therapy (the equivalent of at least 10 mg/day of oral morphine) for at least one month for nonmalignant pain or opioid dependence. Patients were randomly assigned to receive a single daily dose of alvimopan 0.5 or 1 mg or placebo for 21 days. The average percentage of patients having at least one bowel movement within eight hours after receiving the study drug each day during the 21-day treatment period was significantly higher with alvimopan 1 mg (54%) and 0.5 mg (43%) than with placebo (29%) (P < 0.001). The effect of alvimopan appeared to be dose-related. The median time to the first bowel movement was significantly shorter after the first dose of alvimopan 1 mg compared with placebo (3 hours vs. 21 hours, respectively; P < 0.001). The median time to the first bowel movement was also shorter after the first dose of alvimopan 0.5 mg (7 hours), but this dif- CLINICAL TRIALS POI Studies8–12 The FDA’s approval of alvimopan was based on the results of five multicenter, randomized, double-blind, parallel-group, placebo-controlled studies (four in the U.S. and one in Europe). The trials enrolled more than 2,000 adults undergoing partial large-bowel or small-bowel resection with primary anastomosis or total abdominal hysterectomy under general anesthesia. All five efficacy trials had the following common design features: 580 P&T® • October 2008 • Vol. 33 No. 10

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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