Pharmacy & Therapeutics - October 2008 - (Page 582)

DRUG FORECAST the risks. Under REMS, the FDA has restricted the availability of alvimopan to hospitals that have enrolled in the EASE program. This restriction mandates that alvimopan is not to be dispensed to patients after hospital discharge. To enroll in EASE, hospitals must acknowledge that the staf f who prescribe, dispense, and administer alvimopan have been given educational materials about the need to restrict the use of alvimopan to inpatients only and to limit the dosage to 15 doses per patient.6 include prokinetic agents such as metoclopramide (Reglan, Schwarz) and intravenous (IV) er ythromycin. 18,19 Introduced in the 1960s, metoclopramide accelerates gastric emptying and stimulates gastric, pyloric, and small-bowel motor activity, but it has little or no effect on the colon. Despite the drug’s use in the management of POI, there are no data from randomized controlled trials to support this notion. Cheape et al.,20 in a prospectively randomized study, assessed metoclopramide in reducing the duration of ileus after colorectal surgery. One hundred consecutive patients who underwent elective abdominal colorectal surgery were assigned to receive or not to receive metoclopramide. IV metoclopramide was administered every eight hours from the completion of surgery until patients were able to tolerate a diet of solid food. Metoclopramide did not significantly alter the course of POI. In a double-blind controlled study of 60 patients by Jepsen et al., metoclopramide had a negative effect upon the resolution of POI.21 This drug can cause sedation, akathisia (feelings of motor restlessness), and other extrapyramidal reactions.19 Erythromycin, a motilin-receptor agonist, has been used in patients with POI, and some data suggest that it stimulates gastric emptying postoperatively. However, erythromycin lacks activity in the colon. Bonacini et al.22 attempted to determine whether erythromycin shortened the period of POI in a prospective, double-blind, placebo-controlled study of 77 patients. Forty-one patients received IV erythromycin 250 mg every eight hours for nine doses upon admission to the recovery room; 36 patients received placebo. Recorded outcomes included the time (in hours) to the first passage of flatus, the first liquid meal, the first bowel movement, and total LOS. There was no significant difference between groups. The authors concluded that er ythromycin did not seem to alter clinical parameters of GI motility after an abdominal operation.21 Other drugs such as propranolol (Inderal, Wyeth)23 andneostigmine (Prostigmin, ICN)24 have been used to treat POI; however, clinical data showing benefits in accelerating postoperative GI recovery are lacking. Methylnaltrexone (Relistor, Wyeth/ Progenics), another quaternar y muopioid receptor antagonist, was approved in April 2008 for the treatment of opioidinduced constipation in palliative-care patients with insufficient response to laxative therapy. Preliminary results from the two phase 3 trials showed that methylnaltrexone did not achieve the primary endpoint of the study—a reduction in time to recovery of GI function (i.e., the time to the first bowel movement), FUTURE TRENDS AND ONGOING STUDIES16,17 Adolor plans to conduct two pediatric studies of alvimopan to assess GI recovery in (1) newborns zero to one month of age and (2) children one month of age and older, up to 16 years of age who are undergoing bowel resection. The studies will measure population pharmacokinetic parameters, safety, and time to the first tolerated feeding in hospitalized infants zero to one month of age. In patients older than one month of age up to 16 years, the study will measure the time to the first tolerated feeding, pharmacokinetic parameters, the proportion of postoperative days with stool passed while in the hospital, LOS, the need for postoperative nasogastric tube insertion for symptoms of POI, and safety. In July 2008, the FDA lifted the clinical hold on the Investigational New Drug Application (IND) of alvimopan capsules for POI. Adolor and GlaxoSmithKline plan to begin a multicenter, double-blind, placebo-controlled, parallel-group clinical trial of alvimopan to treat POI in patients undergoing radical cystectomy, another population in whom POI is a significant burden, as part of a postmarketing commitment.16,17 As of September 2008, GlaxoSmithKline returned worldwide rights to Adolor related to Entereg for chronic OBD but is retaining the rights to Entereg for POI. The companies will continue to collaborate on developing and marketing Entereg for POI in the U.S. Table 2 Therapy for Postoperative Ileus: Cost Comparison Average Wholesale Price $1,12526 Drug Alvimopan (Entereg) Dosing 12 mg 30 minutes to 5 hours before surgery, followed by 12 mg twice daily for up to 7 days for a maximum of 15 doses 10 mg orally four times daily for 7 days 10 mg IV four times daily for 7 days Metoclopramide (Reglan), generic $4.4227 $11.8027 $15.7927 Erythromycin TRADITIONAL TREATMENT OPTIONS Pharmacological agents for the treatment and prevention of POI include several FDA-approved drugs that have been used on an off-label basis. They 200 mg IV, then 250 mg orally three times daily for 7 days 250 mg orally three times daily for 7 days $5.7927 Data from University of Utah Hospitals & Clinics26 and CardinalHealth.27 582 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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