Alvimopan. Dennis J. Cada, PharmD, FASHP, FASCP (Editor)*; Terri L. Levien, PharmD ; and Danial E. Baker, PharmD, FASHP, FASCP

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1 Hospital Pharmacy Volume 43, Number 10, pp Wolters Kluwer Health, Inc. FORMULARY DRUG REVIEWS Alvimopan Dennis J. Cada, PharmD, FASHP, FASCP (Editor)*; Terri L. Levien, PharmD ; and Danial E. Baker, PharmD, FASHP, FASCP Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing inservices. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and are also available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at The October 2008 monograph topics are on clevidipine butyrate injectable emulsion, tetrabenazine, tenofovir disoproxil fumarate tablets, ferumoxytol, and saxagliptin. The DUE is on clevidipine butyrate injectable emulsion. Generic Name: ALVIMOPAN Proprietary Name: Entereg (Adolor/GlaxoSmithKline) Approval Rating: 1S Therapeutic Class: Selective Opioid Antagonists Similar Drugs: Methylnaltrexone Sound- or Look-Alike Names: Alprazolam INDICATIONS Alvimopan is indicated for acceleration of the time to upper and lower gastrointestinal (GI) recovery following partial large- or small-bowel resection surgery with primary anastomosis. 1 It is only available and approved for shortterm use in hospitalized patients in organizations that are enrolled in the Entereg Access Support and Education (EASE) program. 1 CLINICAL PHARMACOLOGY Ileus is a common postoperative complication following major abdominal surgery. Ileus causes abdominal discomfort, nausea, and vomiting. Restoration of motility in the stomach and small bowel generally occurs within 24 hours and colonic function within 72 hours. Delayed return of GI function and resumption of oral intake are major causes of prolonged hospitalization in some patients. 2-4 Up to 30% of patients undergoing bowel resection will not achieve GI recovery by postoperative day 6. 5 Postoperative ileus has been identified as a serious adverse reaction in 6.1% of patients undergoing bowel resection. 6 The primary causes of ileus are surgical manipulation of the bowel and stimulation of opioid receptors. Stimulation of opioid receptors can occur via endogenous opioid re leased in response to the stress of surgery and/or the use of opioids for the treatment of pain. Administration of opioids for postoperative pain relief can delay postoperative recovery of colonic motility or prolong postoperative ileus. 2 Opioid-induced bowel dysfunction also commonly produces troubling symp toms in patients receiving opioids for the treatment of cancer pain or other chronic pain conditions. 4,7 Opioids cause this effect by 2 methods: inhibiting the release of acetylcholine from the mesenteric plexus and stimulating the muopioid receptor. By inhibiting the release of acetylcholine from the mesenteric plexus, the opioid is able to increase muscle tone and reduce propulsive activity. 2 Stimulation of the mu-opioid receptor results in delayed gastric emptying, increased GI smooth muscle tone, and induced spasm; provokes colic; inhibits propulsive contractions; increases fluid absorption; and decreases GI transit. 7,8 This combined effect results in constipation, bloating, abdominal discomfort, and gastroesophageal reflux. Alvimopan is a potent, selective opioid antagonist with a long dura- *Executive Editor, The Formulary; Clinical Associate Professor of Pharmacotherapy, Drug Information Center, Washington State University, Spokane, Washington; Director, Drug Information Center, and Professor of Pharmacy Practice, College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA The authors indicate no relationships that could be perceived as conflicts of interest. Hospital Pharmacy 819

2 tion of action. 2 It has limited oral absorption and does not cross the blood-brain barrier because of its moderately large zwitterionic form and polarity, and it exerts no opioid agonist effects. 2,8,9 Alvimopan has high affinity for the mu-opioid receptor, lower affinity for the delta-opioid receptor, and lowest affinity for the kappa-opioid receptor. 8,9 Alvimopan is a more potent mu-receptor antagonist than naloxone, and both alvimopan and its primary metabolite have greater mu-opioid-receptor-binding affinity than methylnaltrexone. 9,10 Alvimopan has no affinity for adrenergic, dopaminergic, histaminergic, gamma-aminobutyric acid (GABA) ergic, or muscarinic cholinergic receptors. 4 The dissociation rate of alvimopan from the mu-opioid receptor (half-life, 30 to 44 minutes) is much slower than that of naloxone (half-life, 0.82 minutes) or methylnaltrexone (half-life, 0.46 minutes). 11 In animal models of postoperative ileus, alvimopan improved GI transit when administered before surgery. 12 Alvimopan activity in animal models of postoperative ileus was enhanced by concomitant therapy with an anti-inflammatory agent. 13 In healthy volunteers, administration of intravenous (IV) morphine 0.05 mg/kg prolonged GI transit time from 69 to 103 minutes, an effect prevented by administration of oral alvimopan 4 mg (transit time, 76 minutes; P = 0.004). 8 In another study enrolling healthy volunteers, oral alvimopan 3 mg 3 times daily negated the transit effects of oral morphine 30 mg administered twice daily. 9 Similarly, oral alvimopan 2.4 mg completely prevented loperamide-induced in - creases in transit time. 9 Orally administered alvimopan does not affect morphine analgesia or pupil constriction. 8 PHARMACOKINETICS Following oral administration, peak alvimopan plasma concentrations are reached in approximately 2 hours. 1 The absolute oral bioavailability is estimated as 6% (range, 1% to 19%). 1 A high-fat meal reduces both the extent and rate of absorption. 1 In nonsurgical subjects, food decreased absorption rate by 54% and alvimopan bioavailability by 18%. 14 Patients who underwent surgery had an 80% reduction in absorption rate in both the fasted and fed states. 14 Bioavailability of the primary metabolite, ADL , was 40% greater in patients who underwent surgery and fasted than in those who did not have surgery. 14 In clinical trials of postoperative ileus, the first dose was administered in the fasting state and subsequent doses were given without regard to food. 1 Concentrations of alvimopan and the metabolite were increased about 1.9- and 1.4-fold, respectively, in patients with postoperative ileus compared with healthy volunteers. 1 Alvimopan does not penetrate the central nervous system. 8 The primary metabolite, ADL , is formed in the GI tract and then absorbed systemically. The rate of metabolite formation is limited by the rate of transit of alvimopan to the GI tract. 14 Concentrations of ADL exceed those of alvimopan. 10 Renal clearance accounts for approximately 35% of total clearance. 1 The terminal phase half-life of alvimopan ranges from 10 to 17 hours; the terminal halflife of the metabolite ranges from 10 to 18 hours. 1 Alvimopan plasma concentrations may be increased 10-fold in patients with severe hepatic function impairment. 1 Bioavailability and clearance are reduced with age; alvimopan concentrations are 35% higher in elderly patients. 14 Concentrations of alvimopan are not altered, and dosage adjustments based on age are not necessary. 1 Alvimopan pharmacokinetics are not affected by weight, gender, or renal function. 14 Alvimopan metabolite exposure increases 2- to 5-fold in patients with moderate to severe renal function impairment. 1 Alvimopan concentrations are not affected by race; however, the alvimopan metabolite concentrations are 43% lower in patients who are black and 82% lower in those who are Hispanic, compared with those who are white. 14 Clinical importance is not expected of these differences in surgical patients, and dosage adjustments based on race are not advised. 1 COMPARATIVE EFFICACY Postoperative Ileus Alvimopan was evaluated using a randomized, placebo-controlled, single-center study enrolling 79 patients 18 to 78 years of age scheduled to undergo major abdominal surgery. Patients received alvimopan 1 or 6 mg or placebo 2 hours before surgery and then twice daily until the first bowel movement, until discharge from the hospital, or for a maximum of 7 days. Randomization was stratified by type of surgery. The power analysis (95%) indicated that enrollment of 26 patients per group was required. Data were available for 78 patients (26 in each treatment group) who re ceived study treatment and un - derwent surgery (15 patients underwent partial colectomy, 63 underwent total abdominal hysterectomy). All subjects received opioids for postoperative pain relief using patient-controlled, IV morphine or meperidine. Diet and activity were advanced as tolerated. The average number of doses administered was 6 in the placebo group, 820 Volume 43, October 2008

3 5.2 in the alvimopan 1 mg group, and 5.3 in the alvimopan 6 mg group. Patients in the alvimopan 6 mg group experienced faster recovery of GI function than those in the placebo group. The median time to first passage of flatus was reduced from 70 to 49 hours (P = 0.03); the median time to first bowel movement was reduced from 111 to 70 hours (P = 0.01); and the median time until patients were ready for discharge was reduced from 91 to 68 hours (P = 0.03). Consumption of solids (92 vs 59 hours; P < 0.001) and actual hospital discharge (100 vs 71 hours; P < 0.001) also occurred sooner in patients treated with alvimopan 6 mg. In addition, nausea occurred less frequently in the alvimopan 6 mg group, with 27% of patients in the 6 mg group reporting a visual-analog nausea score of more than 20 (scale, 1 to 100) compared with 63% of patients treated with placebo and 67% of those in the alvimopan 1 mg group (P = 0.003). Vomiting occurred in 23% of patients in the placebo group, 26% of patients in the 1 mg group, and none of the patients in the 6 mg group. Results in the group treated with alvimopan 1 mg did not differ from those in the placebo group. Use of opioids decreased with time and was similar in the 3 groups. 2 Alvimopan was also evaluated in a double-blind, placebo-controlled, multicenter study enrolling 451 patients scheduled to undergo large bowel resection (67.5%) or simple (21.6%) or radical (7.1%) hysterectomy. Patients were randomized for receipt of alvimopan 6 or 12 mg or placebo at least 2 hours before sur - gery and then twice daily until hospital discharge or for up to 7 days. Opioids for postoperative pain management were administered as IV, patient-controlled analgesia; nonsteroidal anti-inflammatory drug (NSAID) use for postoperative pain management was not permitted. The mean number of doses administered was 8.5 in the placebo group, 7.8 in the 6 mg group, and 7.7 in the 12 mg group. Mean patient age was 58 years; 67% were female and 83% were white. The primary study end point was recovery of GI function (a composite measure of the time to recovery of both upper and lower GI function as defined by time to tolerability of solid foods and time to first flatus or first bowel movement [GI3]). The 6 mg dose was more effective than the placebo based on the primary study end point (14.1 hour reduction compared with placebo; hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.13 to 1.85; P = 0.003), whereas the difference in the 12 mg group was not significant (7.5 hours reduction; HR, 1.28; 95% CI, 0.99 to 1.64; P = 0.059). GI3 recovery was achieved by the fourth day postoperation in 65.2% of patients in the alvimopan 6 mg group compared with 50.3% of those treated with placebo. Mean time to toleration of solid food and first bowel movement (GI2) was reduced 15.2 hours in the 6 mg group (HR, 1.46; 95% CI, 1.11 to 1.93; P = 0.007) and 10.5 hours in the 12 mg group (HR, 1.31; 95% CI, 0.99 to 1.73; P = 0.057). Mean times to written hospital discharge order were 14.1 hours sooner in the 6 mg group (HR, 1.5; 95% CI, 1.18 to 1.9; P < 0.001) and 7.5 hours sooner in the 12 mg group (not significant) compared with placebo. 15 Alvimopan was further assessed in a double-blind, placebo-controlled, multicenter study enrolling 510 patients scheduled to undergo small or large bowel resection (96%) or radical hysterectomy (4%). Patients were randomized for receipt of alvimopan 6 or 12 mg or placebo at least 2 hours before surgery and then twice daily until hospital discharge or for up to 7 days. Opioids for postoperative pain management were administered as IV, patientcontrolled analgesia. The modified intent-to-treat population included 469 patients (395 large bowel resections, 56 small bowel resections, and 18 hysterectomies). Mean patient age was 60.5 years; 50% were women and 87% were white. The mean duration of therapy was 5.1 days in the placebo group and 5.3 days in the alvimopan groups. Time to GI3 recovery was reduced 15 hours in the 6 mg group (HR, 1.28; 95% CI, 1 to 1.64; P < 0.05) and 22 hours in the 12 mg group (HR, 1.54; 95% CI, 1.21 to 1.96; P < 0.001) compared with placebo. Mean times to GI2 recovery were also reduced by 20 hours in the 6 mg group (HR, 1.38; 95% CI, 1.07 to 1.79; P = 0.013) and 28 hours in the 12 mg group (HR, 1.67; 95% CI, 1.3 to 2.15; P < 0.001) compared with placebo. Mean times to written hospital discharge order were 13 hours sooner in the 6 mg group (not significant) and 20 hours sooner in the 12 mg group (HR, 1.42; 95% CI, 1.12 to 1.79; P = 0.003) compared with a mean of 6 days with placebo. 16 Another alvimopan study was a double-blind, placebo-controlled, multicenter study enrolling 519 patients scheduled to undergo simple hysterectomy and receive opioids for pain relief. Patients were randomized for receipt of placebo (106 patients) or alvimopan 12 mg (413 patients) at least 2 hours before surgery and then twice daily for 7 days on an inpatient or outpatient basis. Mean patient age was approximately 43 years; more than 75% of the patient population was white. Postoperative opioid pain management was delivered by patient-controlled analgesia. Safety was the primary study end point, Hospital Pharmacy 821

4 with return of GI function as a secondary end point. Time to GI2 recovery was reduced 20.2 hours with alvimopan compared with placebo (95% CI, 26.5 to 13.9 hours). The time to first bowel movement was reduced 22.2 hours with alvimopan compared with placebo (95% CI, 28.7 to 15.8 hours; HR, 2.33; P < 0.001). There were no differences in time to GI3 recovery, toleration of first solid food, or written hospital discharge order. 17 Alvimopan was also assessed in a randomized, double-blind, placebocontrolled, multicenter study en - rolling 666 patients who were scheduled to undergo surgery for partial small/large bowel resection (68%) or simple (14.6%) or radical (17.4%) hysterectomy. Patients were randomized for receipt of alvimopan 6 or 12 mg or placebo 2 hours before surgery, then twice daily until hospital discharge or for a maximum of 7 days. Patients received IV, patient-controlled analgesia with opioids for postoperative pain. Study data were assessed with a modified intent-to-treat analysis including 615 patients. Mean pa - tient age was 57 years; patient population was 63% women and 76.8% white. For the primary study end point, time to GI3 recovery, no difference was observed between the alvimopan groups and the placebo group (7.5 hours sooner; HR, 1.2; 95% CI, 0.98 to 1.47) (P = 0.08 for the 6 mg dose and 9.9 hours sooner; HR, 1.24; 95% CI, 1.01 to 1.52) (P = for the 12 mg dose; because of multiple-dose comparison to a single placebo group, a P < would be required for consideration of statistical significance). Mean times to GI2 recovery were reduced 16.4 hours with alvimopan 6 mg (HR, 1.37; 95% CI, 1.09 to 1.74; P = 0.008) and 13.7 hours with alvimopan 12 mg (HR, 1.33; 95% CI, 1.05 to 1.68; P = 0.018). Mean times to written hospital discharge order were 14.2 hours sooner in the 6 mg group (HR, 1.31; 95% CI, 1.07 to 1.59; P = 0.008) and 15.2 hours sooner in the 12 mg group (HR, 1.28; 95% CI, 1.05 to 1.56; P = 0.015) compared with placebo. 18 Results of the 5 previously described studies comparing alvimopan with placebo in the treatment of postoperative ileus were also evaluated in a meta-analysis. 2,15-18 The studies selected for the metaanalysis were published between 2001 and 2006, reported results for a total of 2,195 patients undergoing bowel resection or total abdominal hysterectomy, and had primary end points of a composite measure of GI3 and GI2 recovery. A total of 1,521 patients received alvimopan and 674 received placebo. Improvement in both the GI3 end point (HR, 1.3; 95% CI, 1.16 to 1.45; P < 0.001) and the GI2 end point (HR, 1.61; 95% CI, 1.26 to 2.05; P < 0.001) was observed with alvimopan 12 mg compared with placebo. Im provement was also observed with alvimopan 12 mg in time to solid food (HR, 1.14; 95% CI, 1.01 to 1.3; P < 0.04), time to first bowel movement (HR, 1.74; 95% CI, 1.29 to 2.35; P < 0.001), and time to discharge readiness (HR, 1.26; 95% CI, 1.13 to 1.4; P < 0.001). Similar results were also observed for the comparison of alvimopan 6 mg with placebo. No difference between alvimopan and placebo was ob - served in the incidence of treatmentemergent adverse reactions or in patient postoperative pain scores. 19 In a pooled analysis from the same 5 studies, alvimopan 12 mg was reported as accelerating GI3 recovery by 12 hours and GI2 recovery by 17 hours compared with placebo. The 12 mg dose was associated with GI3 and GI2 recovery across demographic subgroups, including patients younger than 65 years of age, patients 65 years of age and older, and patients 75 years of age and older; patients who were female and male; and patients who were white and nonwhite. 20 Pooled results from 3 of the studies were also reported. 15,16,18,21 In this pooled analysis, GI3 recovery also occurred more rapidly in the alvimopan groups (6 mg: HR, 1.28; P < 0.001; 12 mg: HR, 1.38; P < 0.001). GI3 recovery was accelerated at both doses in men but only at the 12 mg dose in women. Similarly, GI3 recovery was accelerated at both doses in patients younger than 65 years of age but only at the 12 mg dose in patients 65 years of age and older. The time to written hospital discharge order was reduced by 16 hours in the 6 mg group and 18 hours in the 12 mg group (P < for both). At both doses, patients treated with alvimopan had less postoperative nasogastric tube insertion, fewer hospital readmissions, less prolongation of hospital stay or readmission, and less postoperative ileus as a serious adverse reaction. 21 Alvimopan 6 and 12 mg was also compared with placebo in 911 adult patients undergoing open abdominal surgery in a randomized, double-blind study. Patients received alvimopan or placebo 2 hours before surgery and twice daily following surgery until hospital discharge or for a maximum of 7 days. Opioids for postoperative pain management were administered as IV, patient-controlled analgesia or intramuscular injections; use of NSAIDs was also permitted. Only the 741 bowel resection patients were included in the final analysis. Mean patient age was 62 to 65 years; 45% were women and approximately 98% were white. The mean duration of treatment 822 Volume 43, October 2008

5 Table 1. Mean G12 Recovery (Hours) in Patients Who Underwent Bowel Resection and Who Were Treated With Alvimopan Versus Placebo 1 Study Number Alvimopan 12 mg Placebo Treatment Difference HR (95% CI) (1.293 to 1.816) (1.256 to 2.102) (1.057 to 1.764) (1.035 to 1.894) (1.07 to 1.575) CI = confidence interval; GI2 = mean time to toleration of solid food and first bowel movement; HR = hazard ratio. was 6.5 days in both alvimopan groups and 6.4 days in the placebo group. The mean time to GI3 recovery was reduced by 8.5 hours in the alvimopan 6 mg group and 4.8 hours in the 12 mg group compared with placebo, but the differences were not significant. The mean time to GI2 recovery was reduced 14.3 hours in the alvimopan 6 mg group (P < 0.001) and 10.7 hours in the 12 mg group (P = 0.008) compared with placebo. 22 Although the GI2 end point is more objective than the GI3 end point, in this study, the GI3 end point was the primary end point like in many of the other the alvimopan clinical trials. The approved labeling for alvimopan contains a summary of the mean GI2 recovery data from 5 of the clinical trials in bowel resection patients. These results can be found in Table 1. Opioid-Induced Bowel Dysfunction Alvimopan was assessed in a study enrolling 67 patients receiving opioid therapy for chronic pain and 34 patients receiving methadone for opioid addiction. All patients were receiving stable opioid doses and experiencing symptoms of opioidinduced bowel dysfunction, primarily constipation. Opioid products used by these patients included hydrocodone and acetaminophen, oxycodone and acetaminophen, codeine and acetaminophen, fentanyl, extended-release oral morphine, extended-release oxycodone, tramadol, meperidine, propoxy - phene, and methadone. The first 75 patients received a single dose of placebo or alvimopan 0.5, 1.5, or 3 mg. The next 26 patients were enrolled in a progressive dosing study in which patients received placebo for 4 days or increasing doses of alvimopan 0.5, 1.5, 3, and 4.5 mg once daily over 4 days. In the single-dose study, dose-related increases in the incidence of bowel movements and increases in stool weight occurred within 12 hours of alvimopan dosing. The incidence of hard, dry stool and moderate to severe straining was also reduced with alvimopan. Maximum re - sponses were seen within 4 hours at the 3 mg dose and 7 hours at the 0.5 mg dose. In the 4-day study, mean stool weight increased in the alvimopan group until the third day, presumably as a result of elimination of retained constipation-related stool. 9 In another randomized, doubleblind study, alvimopan 0.5 and 1 mg were compared with placebo in 168 patients with opioid-induced bowel dysfunction who were receiving chronic opioid therapy for nonmalignant pain (148 patients) or opioid dependence (20 patients). The mean duration of opioid use exceeded 8 years; median morphine equivalent daily doses were 85 to 120 mg (daily dose range, 10 to 1,500 mg). Patients received placebo (54 patients) or alvimopan 0.5 (58 patients) or 1 mg (56 patients) once daily in the morning for 21 days in conjunction with their prestudy medications and bowel regimens. The primary outcome was the proportion of patients having at least 1 bowel movement within 8 hours of study drug administration on each day during the 21-day treatment period. Averaged over the treatment period, 54% of patients in the alvimopan 1 mg group, 43% in the alvimopan 6 mg group, and 29% in the placebo group had a bowel movement within 8 hours after dosing (P < 0.001). The median time to first bowel movement after the initial dose was 3 hours in the 1 mg group, 7 hours in the 0.5 mg group, and 21 hours in the placebo group (P < for 1 mg vs placebo). Mean weekly bowel movement frequency only differed from placebo in the 1 mg group after 1 and 2 weeks of treatment. At the third week, the weekly frequency of bowel movements had increased from a mean of 3.8 to 5.5 in the placebo group, from 4 to 5.2 in the 0.5 mg group, and from 4 to 6.4 in the 1 mg group (difference between groups not significant). Cramping, diarrhea, flatulence, nausea, and vomiting occurred more frequently in the 1 mg group, and more patients in this group dis- Hospital Pharmacy 823

6 continued treatment because of adverse reactions (11% in the 1 mg group, 3% in the 0.5 mg group, and 2% in the placebo group). 23 Alvimopan was also evaluated in a randomized, double-blind, placebo-controlled, dose-finding study enrolling 522 patients with noncancer pain and opioid-induced bowel dysfunction. Enrolled pa - tients reported less than 3 spontaneous bowel movements per week with more than 25% of bowel movements accompanied by a sensation of incomplete evacuation, straining, or lumpy, hard stools and required analgesia equivalent to at least 30 mg of oral morphine daily. Patients were receiving chronic opioid treatment for a mean of 6.2 to 7.8 years and were on their current opioid for a mean of 2.5 to 2.7 years. Patients received alvimopan 0.5 mg twice daily (130 patients), 1 mg once daily (133 patients), 1 mg twice daily (130 patients), or placebo (129 patients) for 6 weeks. Over the first 3 weeks, there was an increase in mean weekly spontaneous bowel movements of 1.71 (95% CI, 0.83 to 2.58) in the 0.5 mg twice-daily group, 1.64 (95% CI, 0.88 to 2.4) in the 1 mg oncedaily group, and 2.52 (95% CI, 1.4 to 3.64) in the 1 mg twice-daily group compared with placebo (P < 0.001). Results were maintained over the 6 weeks of treatment. On the first day of treatment, 31% of patients in the alvimopan groups had a spontaneous bowel movement compared with 18% of patients in the placebo group (P < 0.05). The percentage of patients with an increase in spontaneous bowel movements to at least 3 per week improved from 2% to 63% in the 0.5 mg twice-daily group, from 5% to 63% in the 1 mg once-daily group, and from 3% to 68% in the 1 mg twice-daily group, compared with an increase from 2% to 39% in the placebo group (P < vs placebo for all alvimopan groups). Abdominal pain and diarrhea were more common in the 1 mg once- or twice-daily dosage groups. 24 CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS Contraindications Alvimopan is contraindicated in patients who have received therapeutic doses of opioids for more than 7 consecutive days before administration of alvimopan. 1 A potential contraindication to alvimopan therapy is a known hypersensitivity reaction to alvimopan or any of its product ingredients (polyethylene glycol). Warnings and Precautions A higher incidence of myocardial infarctions was observed in patients treated with alvimopan 0.5 mg twice daily compared with placebo in a 12-month study of pa - tients with chronic pain and opioidinduced bowel dysfunction. Most myocardial infarctions occurred between 1 and 4 months after initiation of treatment. A causal relationship has not been established. An increased incidence of myocardial infarction has not been observed in other alvimopan studies, including those assessing alvimopan 12 mg twice daily for up to 7 days. 1 Increased sensitivity to the effects of alvimopan is expected in patients recently exposed to opioids, and these patients may experience a higher incidence of abdominal pain, diarrhea, nausea, and vomiting. Patients receiving more than 3 doses of an opioid within the week before surgery were not included in the postoperative ileus trials; alvimopan should be used with caution in such patients. 1 Alvimopan use is not recommended in patients with severe hepatic function impairment or end-stage renal disease. 1 Dosage adjustments are not necessary in patients with mild to moderate hepatic function impairment or mild to severe renal function impairment; however, such patients should be monitored for adverse reactions (eg, cramping, diarrhea, GI pain) that may indicate increased levels of alvimopan or its metabolite. 1 Alvimopan use is also not recommended in patients undergoing surgery for correction of complete bowel obstruction. 1 Alvimopan is in pregnancy category B. No evidence of impaired fertility or harm to the fetus has been observed in animal studies. Alvimopan should be used in pregnancy only if clearly needed. 1 Alvimopan and its metabolite are detected in the milk of lactating rats. It is not known whether alvimopan is excreted in human milk. Caution is advised if alvimopan is administered to a woman who is breast-feeding. 1 The safety and effectiveness of alvimopan have not been established in children. 1 ADVERSE REACTIONS The most common adverse reactions (see Table 2) observed in patients undergoing bowel resection were anemia, back pain, dyspepsia, hypo - kalemia, and urinary retention. 1 Other adverse reactions ob served in alvimopan studies have included abdominal pain, diarrhea, flatulence, hypotension, nausea, ner vousness, polyuria, pruritus, and vomiting. Adverse reactions were gen er ally of a similar nature and incidence in the placebo- and alvimopan-treatment groups. 9,15,16,18,22,25,26 In a pooled analysis, alvimopan 12 mg was associated with a lower incidence of nausea, postoperative ileus, pruritus, and vomiting as treatment-emergent adverse reactions compared with placebo Volume 43, October 2008

7 Table 2. Most Common Treatment-Emergent Adverse Reactions With Alvimopan Versus Placebo 1 Adverse Reactions Patients Who Underwent All Patients Who Bowel Resection Underwent Surgery Placebo (n = 986) Alvimopan (n = 999) Placebo (n = 1,365) Alvimopan (n = 1,650) Hypokalemia 8.5% 9.5% 7.5% 6.9% Dyspepsia 4.6% 7% 4.8% 5.9% Anemia 4.2% 5.2% 5.4% 5.4% Constipation 3.9% 4% 7.6% 9.7% Back pain 1.7% 3.3% 2.6% 3.4% Urinary retention 2.1% 3.2% 2.3% 3.5% Flatulence 4.5% 3.1% 7.7% 8.7% In patients on chronic opioid therapy, a 3 mg dose was associated with cramps, diarrhea, and loose stools, which were attributed to a localized opioid withdrawal. 9 Alvimopan is contraindicated in pa - tients on chronic opioid therapy. 1 DRUG INTERACTIONS Alvimopan and its metabolite are substrates for P-glycoprotein; however, pharmacokinetic analysis does not reveal evidence of any interaction with mild to moderate P-glycoprotein inhibitors. Clinical studies of coadministration of alvimopan with strong P-glycoprotein inhibitors (eg, amiodarone, bepridil, cyclosporine, diltiazem, itraconazole, quinidine, quinine, spironolactone, verapamil) have not been conducted. 1 Alvimopan is not a CYP450 enzyme substrate and, therefore, likely will not be the subject of interactions with CYP enzyme inducers or inhibitors. 1 Alvimopan and its metabolite also have not been observed as being inhibitors or inducers of CYP en - zymes or P-glycoprotein. 1 Concentrations of the alvimopan metabolite are 49% lower in the presence of acid blockers and 81% lower in patients receiving preoperative antibiotics. 14 Pharmacokinetics of alvimopan are not affected, and the impact on the metabolite is not anticipated as being clinically important. 1 DOSING The recommended dose to accelerate GI recovery is 12 mg administered 30 minutes to 5 hours before surgery, followed by 12 mg twice daily beginning the day after surgery for a maximum of 7 days or until discharge. Patients should not receive more than 15 doses. 1 No dosage adjustments are necessary in elderly patients, patients with mild to moderate hepatic function impairment (Child-Pugh class A and B), or patients with mild to severe renal function impairment. 1 PRODUCT AVAILABILITY AND STORAGE Alvimopan received approval from the US Food and Drug Administration (FDA) in May Approval of alvimopan required an FDA-sanctioned risk evaluation and mitigation strategy. This requirement was met with the EASE Program ( ; http: // Alvimopan is only available to hospitals that enroll in the EASE program. To enroll in the program, a hospital must acknowledge the following 1 : hospital staff who prescribe, dispense, or administer alvimopan have been provided educational materials describing the need to limit use to short-term, inpatient use; patients will not receive more than 15 doses of alvimopan; alvimopan will not be dispensed to patients after they have been discharged from the hospital. Alvimopan is available as 12 mg capsules in unit-dose packs of 30 capsules. It should be stored at room temperature (25 C; 77 F), with excursions permitted between 15 and 30 C (59 and 86 F). 1 CONCLUSION Alvimopan is the first agent approved specifically for acceleration of GI recovery following bowel resection. Because of an increased incidence of myocardial infarction observed in a long-term study in patients receiving chronic opioid therapy, alvimopan is only available through a limited distribution program. Alvimopan use must be limited to short-term inpatient use in registered hospitals. In clinical trials, alvimopan accelerated time to GI recovery in patients who underwent bowel resection. Alvimopan therapy was well tolerated in this population; adverse cardiovascular reactions were not observed with this use. REFERENCES 1. Entereg [package insert]. Research Triangle Park, NC: GlaxoSmithKline; May Hospital Pharmacy 825

8 2. Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001;345(13): Steinbrook RA. An opioid antagonist for postoperative ileus. N Engl J Med. 2001;345(13): Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003; 63(7): Delaney CP, Senagore AJ, Viscusi ER, et al. Postoperative upper and lower gastrointestinal recovery and gastrointestinal morbidity in patients undergoing bowel resection: pooled analysis of placebo data from 3 randomized controlled trials. Am J Surg. 2006;191(3): Wolff BG, Viscusi ER, Delaney CP, Du W, Techner L. Patterns of gastrointestinal recovery after bowel resection and total abdominal hysterectomy: pooled results from the placebo arms of alvimopan phase III North American clinical trials. J Am Coll Surg. 2007; 205(1): Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182(5A) (suppl):11s-18s. 8. Liu SS, Hodgson PS, Carpenter RL, Fricke JR Jr. ADL , a trans-3,4- dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther. 2001; 69(1): Schmidt WK. Alvimopan (ADL ) is a novel peripheral opioid antagonist. Am J Surg. 2001;182(5A)(suppl): 27S-38S. 10. Beattie DT, Cheruvu M, Mai N, et al. The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL and methylnaltrexone. Naunyn Schmiede - bergs Arch Pharmacol. 2007;375(3): Cassel JA, Daubert JD, DeHaven RN. [(3)H]Alvimopan binding to the micro opioid receptor: comparative binding kinetics of opioid antagonists. Eur J Pharmacol. 2005;520(1-3): Fukuda H, Suenaga K, Tsuchida D, et al. The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats. Brain Res. 2006;1102(1): Schmidt J, Stoffels B, Nazir A, Dehaven-Hudkins DL, Bauer AJ. Alvimopan and COX-2 inhibition reverse opioid and inflammatory components of postoperative ileus. Neurogastroenterol Motil. 2008;20(6): Foss JF, Fisher DM, Schmith VD. Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials. Clin Pharmacol Ther. 2008;83(5): Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48(6): Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240(4): Herzog TJ, Coleman RL, Guerrieri JP Jr, et al. A double-blind, randomized, placebo-controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy. Am J Obstet Gynecol. 2006;195(2): Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20(3):537]. Surg Endosc. 2006;20(1): Tan EK, Cornish J, Darzi AW, Tekkis PP. Meta-analysis: alvimopan vs placebo in the treatment of post-operative ileus. Aliment Pharmacol Ther. 2007;25(1): Senagore AJ, Bauer JJ, Du W, Techner L. Alvimopan accelerates gastrointestinal recovery after bowel resection regardless of age, gender, race, or concomitant medication use. Surgery. 2007;142(4): Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies. Ann Surg. 2007;245(3): Büchler MW, Seiler CM, Monson JR, et al. Clinical trial: alvimopan for the management of postoperative ileus after abdominal surgery: results of an international randomised, double-blind, multicentre, placebo-controlled clinical study [published online ahead of print March 28, 2008]. Aliment Pharmacol Ther. doi: /j x. 23. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction 21-day treatmentrandomized clinical trial. J Pain. 2005;6(3): Webster L, Jansen JP, Peppin J, et al. Alvimopan, a peripherally acting muopioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dosefinding study in subjects taking opioid for chronic non-cancer pain. Pain. 2008;137(2): Adolor Corporation announces topline results in Entereg phase 3 clinical study 308 in postoperative ileus [news release]. Exton, PA: Adolor Corp; January 13, Adolor Corporation. Results from Entereg phase 3 clinical study 14CL308 [slide presentation]. January 13, /NSD/ADLR/presentations/adlr_ pdf. Accessed January 27, FDA approves Entereg to help restore bowel function following surgery [news release]. Rockville, MD: Food and Drug Administration; May 20, /NEW01838.html. Accessed July 9, Volume 43, October 2008

9 Continuing Education Case Study Quiz Goal The goal of this program is to educate the reader about the use of alvimopan in the management of postoperative ileus. Objectives At the completion of this program, the reader will be able to: 1. Describe the pharmacology and pharmacokinetics of alvimopan. 2. Discuss the risks associated with the use of alvimopan. 3. Discuss the potential benefit of alvimopan for an individual patient. 4. Apply information on the use of alvimopan to a case study. Key Words alvimopan, ileus, new drugs, opioid antagonist 1. Alvimopan is approved by the US Food and Drug Administration (FDA) to speed gastrointestinal recovery: A. with short-term use in all patients following partial large- or small-bowel resection surgery. B. with long-term use in all patients following partial large- or small-bowel resection surgery. C. in outpatients following partial large- or small-bowel resection surgery. D. following partial large- or small-bowel resection sur - gery in patients who are in hospitals enrolled in the Entereg Access Support and Education (EASE) program. 2. Alvimopan has a high affinity for: A. adrenergic receptors. B. mu-opioid receptors. C. dopaminergic receptors. D. histaminergic receptors. 3. Following oral administration, peak plasma alvimopan concentrations occur in approximately: A. 0.5 hours. B. 1 hour. C. 1.5 hours. D. 2 hours. 4. The half-life of alvimopan is approximately: A. 1 hour. B. 3 hours. C. 6 hours. D. 14 hours. 5. Alvimopan pharmacokinetics are affected by: A. hepatic impairment. B. weight. C. gender. D. renal function. 6. Alvimopan is contraindicated in: A. patients who received therapeutic doses of opioids for more than 7 consecutive days before administration of alvimopan. B. patients with postoperative acute renal failure. C. patients who are pregnant. D. patients with known sulfonamide allergies. 7. Common adverse reactions reported with alvimopan include: A. blurred vision, constipation, and nausea. B. anemia, hypokalemia, and urinary retention. C. headache, urinary frequency, and abdominal cramping. D. thrombocytopenia, constipation, and orthostatic hypotension. 8. Which of the following was observed in one long-term study of patients treated with alvimopan 0.5 mg twice daily compared to placebo? A. A higher incidence of stroke B. A higher incidence of bleeding C. A higher incidence of death D. A higher incidence of myo - cardial infarction Case History LC is a 75-year-old woman with moderate hepatic cirrhosis and stage II colon cancer. She is currently scheduled to undergo large-bowel resection. Alvimopan therapy has been suggested for LC because she developed a prolonged postoperative ileus following a hysterectomy 10 years ago. She weighs 120 pounds, and her height is 62 inches. Her serum creatinine is 1.2 mg/dl. (Answer questions 9 through 12 and 15 regarding LC s case history.) 9. Which of the following is a concern with alvimopan administration for LC? A. Pupil constriction B. Decreased morphine efficacy C. Potential increase of alvimopan or its metabolite D. Penetration of the central nervous system 10. When should the first alvimopan dose be administered to LC? A. 10 to 12 hours before surgery B. 30 minutes to 5 hours before surgery C. Immediately before surgery D. The day after surgery Hospital Pharmacy 827

10 11. What is the recommended postoperative dose of alvimopan for LC? A. 6 mg twice daily for a max - imum of 7 days B. 12 mg once daily for a maximum of 14 days C. 12 mg twice daily for a maximum of 7 days D. 24 mg once daily for a maximum of 7 days 12. LC s alvimopan dose requires adjustment based on: A. age. B. moderate hepatic impairment. C. renal impairment. D. No dose adjustment is needed. 13. What is the maximum number of alvimopan doses that a patient can receive? A. 2 B. 5 C. 15 D. There is no maximum for alvimopan. 14. Alvimopan is available in: A. multiple-dose vials. B. single-use vials. C. capsules for oral administration. D. prefilled syringes. 15. LC experiences abdominal discomfort, nausea, and vomi ting 4 days after surgery. The nurse requests that the pharmacy provide a month s supply of alvimopan for LC on discharge. Assuming the hospital is enrolled in the EASE program, can the pharmacy provide the alvimopan prescription for LC? A. No, because the EASE program only allows for outpatient use in the therapy of chronic, opioidinduced constipation. B. No, because alvimopan is only approved for use in hospitalized patients. C. No, because alvimopan is given intravenously only and must be administered by a nurse. D. Yes, because alvimopan is indicated for use until resumption of normal gastrointestinal function. 828 Volume 43, October 2008

11 Drug Evaluation: Alvimopan ACPE # H01-P 0.15 CEU Program Expires: October 1, 2011 To receive continuing education credit, complete this form and mail with your $7 processing fee (made payable to WSU College of Pharmacy) to: College of Pharmacy, Continuing Education Dept. Washington State University Spokane PO Box 1495 Spokane, WA Print clearly or type. Allow 4 weeks for processing. Name Address City State Zip Note: Your answer sheet will be graded confidentially, and you will receive prompt notification of your score. To receive continuing education credit for this program, you need a minimum correct response rate of 70%. PROGRAM EVALUATION Please rate our continuing education offering by responding to the following questions. 1. This program described the pharmacology and pharmacokinetics of alvimopan: completely fairly well not at all 2. I was able to apply the knowledge from this educational program and other resources to answer questions associated with the case study: completely fairly well not at all 3. The program discussed the risks associated with the use of alvimopan: completely fairly well not at all 4. After this program, I was able to discuss the potential benefit of alvimopan for an individual patient: completely fairly well not at all 5. The overall quality of the program was: excellent good fair poor 6. Was the content of this article relevant to the practice of pharmacy? excellent good fair poor 7. How long did it take you to complete this continuing education program? hours 8. What other continuing education programs or topics would you like to see? Answer Form 1. A B C D 2. A B C D 3. A B C D 4. A B C D 5. A B C D 6. A B C D 7. A B C D 8. A B C D 9. A B C D 10. A B C D 11. A B C D 12. A B C D 13. A B C D 14. A B C D 15. A B C D The Washington State Uni - versity College of Phar macy is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a pro - vider of continuing phar - macy education. Hospital Pharmacy 829