Pharmacy & Therapeutics - October 2008 - (Page 581)

DRUG FORECAST ference was not statistically significant. Alvimopan was well tolerated; 18 of 54 (33%) of patients in the placebo group, 22 of 58 (38%) of patients in the 0.5-mg group, and 27 of 56 (48%) of patients in the 1-mg group experienced at least one of the most common adverse effects, namely abdominal cramping, nausea, vomiting, diarrhea, and flatulence. Most of these effects were described as transient and mild to moderate in severity, resolving within one week. Alvimopan did not antagonize opioid-induced analgesia. opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan restored GI function and relieved OBD without compromising analgesia. A higher number of myocardial infarctions (MIs) occurred in patients treated with alvimopan (2.6%), compared with placebo patients (1.12%). Five of the MIs occurred at two investigational centers and did not appear to be related to the duration of alvimopan treatment. In this study, most of the MIs occurred between one month and four months after initiation of treatment. This imbalance has not been obser ved in other studies of alvimopan, including studies in patients undergoing bowel-resection surger y who received alvimopan 12 mg twice daily for up to seven days, and a causal relationship with alvimopan has not been established. The study also showed an imbalance in the incidence of neoplasms (2.8% for alvimopan vs. 0.7% for placebo) and in the rate of fractures reported for alvimopan compared with placebo.6 ADVERSE DRUG REACTIONS Patients tolerated alvimopan well. Commonly repor ted adverse ef fects included nausea, vomiting, and abdominal distention. The drug did not appear to reverse opioid analgesia at therapeutic doses.6 However, in patients receiving chronic opioid therapy, the use of alvimopan may precipitate a dose-related, localized, gut-specific withdrawal.6,10 Three randomized, double-blind, placebo-controlled trials enrolled a total of 1,012 patients undergoing bowel re section or radical hysterectomy.10,12,15 Patients were randomly assigned to receive alvimopan 6 mg or placebo two hours before surger y and then twice daily after surgery. In trials by Delaney10 and Wolff,12 the most commonly obser ved treatmentemergent adverse events were nausea, vomiting, and hypotension. Nausea and vomiting occurred in a higher, but not statistically significant, percentage of patients receiving placebo than in those receiving alvimopan 6 mg. There was no difference between the groups in incidence of hypotension. In the Wolff trial,12 serious adverse events considered by the investigators to be related to the study drug were experienced by 1.2% of placebo patients and 3% of patients receiving alvimopan 6 mg. The percentage of patients who dis continued treatment because of adverse events was 2.4% for the alvimopan 6-mg group and 4.2% for the placebo group. In the Taguchi trial,15 nausea and vomiting occurred significantly less often with alvimopan 6 mg. No adverse events were considered to be related to the administration of alvimopan. A phase 3, double-blind, placebo-controlled, 12-month study was designed to evaluate the long-term safety and tolerability of alvimopan 0.5 mg twice daily in patients taking opioids for chronic noncancer pain and experiencing opioidinduced bowel dysfunction (OBD).16 A total of 805 patients were randomly assigned, in a 2:1 fashion; 538 patients received alvimopan, and 267 received placebo. Webster et al.14 Webster et al. explored the efficacy and safety of alvimopan in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD) and sought to identify at least one treatment regimen that would improve OBD. Following a two-week baseline period, 522 subjects were enrolled who reported fewer than three spontaneous bowel movements per week (with 25% or more accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools) and who required analgesia equivalent to oral morphine 30 mg/day or more. Patients were randomly assigned to receive alvimopan 0.5 mg twice daily, 1 mg once daily, 1 mg twice daily, or placebo for six weeks. Compared with placebo, alvimopan showed a statistically and clinically significant increase in the mean weekly frequency of spontaneous bowel movements over the initial three weeks of treatment (the primary endpoint) with 0.5 mg twice daily (+1.71 mean spontaneous bowel movements per week), 1 mg once daily (+1.64), and 1 mg twice daily (+2.52) (P < 0.001 for all comparisons). The increased frequency of spontaneous bowel movements and additional treatment effects (less straining, incomplete evacuation, abdominal bloating or discomfort; more stool consistency; and better appetite) were sustained for more than six weeks. The most commonly reported adverse events (abdominal pain, nausea, and diarrhea) occurred more often in those patients taking higher doses. The 0.5-mg twice-daily regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side-effect profile similar to that of placebo. There was no evidence of USE IN SPECIAL POPULATIONS Alvimopan is classified as a Pregnancy Category B agent.6 DRUG INTERACTIONS The concomitant administration of alvimopan with inducers or inhibitors of cytochrome P450 (CYP) enzymes is unlikely to alter its metabolism because it is not a substrate of CYP enzymes, according to in vitro data. The coadministration of alvimopan does not appear to alter the pharmacokinetics of morphine or its metabolite, morphine-6-glucuronide, when morphine is administered intravenously; dosage adjustments, therefore, are not necessary.6 PRECAUTIONS AND CONTRAINDICATIONS Alvimopan is not recommended for patients with severe hepatic impairment or end-stage renal disease or in patients undergoing surgery to correct complete bowel obstruction. Alvimopan is contraindicated in patients who have been receiving therapeutic doses of opioids for more than seven consecutive days.6 DOSAGE AND ADMINISTRATION As a tablet designed for oral administration, alvimopan should be used only in a hospital setting. The FDA has approved alvimopan with a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the drug’s benefits outweigh Vol. 33 No. 10 • October 2008 • P&T® 581

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - October 2008

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

For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.