Brand Name: Entereg¹         

Generic Name: Alvimopan¹

Manufacturer: GlaxoSmithKline¹

Drug Class: Gastrointestinal-specific opioid receptor antagonist²

Uses:

Labeled:          To accelerate time to upper and lower GI recovery following bowel resection¹

            Unlabeled:       Constipation³, Ileus³, Opiate agonist-induced constipation³

Mechanism of Action: 

Alvimopan acts as a selective antagonist of the µ-opioid receptor with no measurable opioid-agonist effects.  The drug antagonizes the gastrointestinal effect of opioids on motility and secretion by competitively binding to GI µ-opioid receptors. Alvimopan antagonizes the gastrointestinal receptors without antagonizing the central analgesic effects of µ-opioid agonists.^1,2,4

Pharmacokinetics: ^1,2,3

Metabolism:    Primarily metabolized in the intestinal wall.  Two metabolites exist, an active amide hydrolysis compound and an inactive glucuronide conjugate.

            Elimination:     Primarily eliminated through biliary excretion

35% of the active metabolite is excreted unchanged in the urine, secondarily eliminated unchanged in the feces

Efficacy:^5,6,7

Taguchi A, Sharma N, Saleem RM, Sessler DI, Carpenter RL, Seyedsadr M, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001; 345(13): 935-940.

            Study Design:  Randomized, double-blind, placebo-controlled, parallel-group study

Description:  A total of 79 patients undergoing partial colectomy (n=15) or total abdominal hysterectomy (n=63) were randomly assigned to receive alvimopan 1mg, 6mg, or placebo.  Patients received treatment 2 hours before surgery and then twice daily until the first bowel movement, until discharge from the hospital, or for a maximum of seven days.  Primary efficacy outcomes were the time to first passage of flatus, time to first bowel movement, and the time until the patient was ready for discharge.  Secondary outcome measures were the time to the first ingestion of liquids, the time to the first ingestion of solids, the time until discharge, and the visual-analogue scores for nausea, abdominal cramping, itching, and pain.  All analyses were performed with an intention-to-treat method.  Time to recovery of gastrointestinal function was significantly shorter in the patients given the 6-mg dose of alvimopan than in patients given placebo (49h vs 70 h; p=0.03).  Time to first bowel movement decreased from 111 to 70 hours (P=0.01), and the time to discharge decreased from 91 to 68 hours (P=0.03).  Alvimopan 6mg was significantly superior to alvimopan 1mg for all endpoints. 

            Limitations:  This was only a preliminary study of the drug.  The most efficacious dose of the drug was not yet known at the time of the study.  Also, many more participants received hysterectomy rather than bowel resection.

            Conclusion:  While this study does not use the most efficacious dose, it does demonstrate the dose-dependent nature of the drug.  More studies are needed to further evaluate the safety and efficacy of alvimopan.

Wolff BG, Michelassi F, Gerkin TM, Techner L, Gabriel K, Du W, et al.  Alvimopan, a novel, peripherally acting µ 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): 728-34.

            Study Design:  Randomized, double-blind, placebo-controlled, parallel-group study involving 34 centers in North America.          

Description:  The purpose of this trial was to demonstrate that alvimopan (6 or 12mg) accelerates recovery of GI function in patients undergoing laparotomy for bowel resection or radical hysterectomy.  A total of 510 patients were randomized to receive alvimopan 6mg, alvimopan 12mg, or placebo >2 hours before surgery, then twice a day until hospital discharge or for up to 7 days after having a bowel resection or radical hysterectomy.  The primary endpoint was a composite of time to recovery of GI function characterized by the time that the patient first tolerates solid food and the time the patient fist passes either flatus or a bowel movement.  A secondary outcome measure was time to hospital discharge order written.  Time to recovery of GI function was accelerated for the alvimopan 6mg (HR= 1.28; p<.05) and 12 mg (HR= 1.54; p<0.001) groups with a mean difference compared to placebo of 15 and 22 hours, respectively.  Time to hospital discharge order written was accelerated in the 12 mg group (HR= 1.42; p =0.003) with a mean difference of 20 hours compared to placebo.  Time to hospital discharge order written in the 6mg group was not significantly different compared to placebo. 

            Limitations:  The study needs to expand on the patient population parameters.  Inclusion/exclusion criteria were not mentioned to determine what type of sample was being used.  Also, variability was not reported.  The study was supported entirely by Adolor Corporation and GlaxoSmithKline, the makers of alvimopan.

Conclusion:  Alvimopan 12mg increases recovery time of patients after a bowel resection or radical hysterectomy.  Alvimopan 12mg also accelerated time to hospital discharge order written compared to placebo.  Larger and more long-term studies of alvimopan may lead to a great cost benefit in the future.

Viscusi ER, Goldstein S, Witkowski T, Andonakakis A, Jan R, Gabriel K, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery. Surg Endosc. 2006; 20: 64-70.

            Study Design:  Randomized, double-blind, placebo-controlled, parallel-group, phase III trial.

            Description:  Patients (666) were stratified by surgery type and treatment center and were randomized to receive 6mg alvimopan (220), 12mg alvimopan (222), or placebo (224) by mouth with water at least 2 hours before surgery and then twice daily beginning on postoperative day 1 until hospital discharge or for a maximum of 7 days.  The primary endpoint measure was time to recovery of GI function as characterized by flatus, bowel movement, and toleration of solid food. The secondary endpoint measures included time to readiness for hospital discharge based on recovery of GI function alone, discharge order written, first flatus, first bowel movement, and first tolerance of solid food.  Patients were questioned twice daily regarding the occurrence of flatus, BM, and the tolerability of liquid and solid food.  The patients’ answers were then verified against patient progress notes.  Analyses were performed on the modified intent-to-treat population, which included all randomized patients who had a protocol-specified surgery, took at least one dose of study drug, and had an efficacy assessment (BM, flatus, or solid food).  Initially, researchers found no differences between the groups.  After adjustment for significant covariates (sex/surgical duration) benefits were significant for both doses compared to placebo (6mg: HR= 1.24, p = 0.037; 12mg: HR = 1.26, p=0.028) in regard to the primary endpoint.  Both drugs significantly accelerated the secondary outcome measure (toleration of solid food and first BM) (6mg: HR = 1.37, p = 0.008; 12mg: HR= 1.33, p = 0.018).  Both doses of alvimopan significantly accelerated time to readiness for hospital discharge based on recovery of GI function alone (6mg: HR = 1.26, p = 0.023; 12mg: HR= 1.28, p= 0.017), time to first BM (6mg: HR = 1.52, p<0.001; 12mg: HR = 1.48, p<0.001) and time to discharge order written (6mg: HR = 1.31, p = 0.008; 12mg: HR = 1.28, p = 0.015) compared with placebo. 

            Limitations:  The primary endpoints of occurrence of flatus, BM, and solid food were not statistically significant until adjustment for significant covariates.  Also, it is difficult to determine clinical significance when most outcomes were reported with only odds ratios and not actual data.  Measures of variability were not reported for most results.  Furthermore, the trial was supported by the Adolor Corporation and GlaxoSmithKline, the manufacturers of the drug.

            Conclusion:  Alvimopan showed significantly accelerated results in regard to secondary outcome measures.  Both 6mg and 12mg accelerated the combination of time to toleration of solid food and first bowel movement.  Both doses also accelerated time to readiness for hospital discharge based on recovery of GI function alone, time to first BM, and time to discharge order written.  However, the clinical significance of these results cannot be determined.

Contraindications:

            Alvimopan currently carries a black-box warning and is only available for short-term (15 doses) hospital use.  Hospitals that have registered and met all requirements for the ENTEREG Access Support and Education (EASE) program may use alvimopan.²

            Use of opioids at therapeutic doses for more than 7 consecutive days immediately prior to taking alvimopan is contraindicated.^1,2

Precautions:^1,2,3

• Complete bowel obstruction surgery
• Mild-to-moderate hepatic impairment; increased risk for adverse effects; discontinue use if adverse events occur
• Severe hepatic impairment; largely increased plasma levels of alvimopan
• Not recommended in end-stage renal disease
• Severe renal impairment (CrCl <30ml/min); increased risk for adverse effects; discontinue use if adverse events occur
• Use of 3 or more doses of opioids in the week prior to surgery 

Adverse effects:^1,2

            Most common:            Anemia 5.2-5.4%

                                                Dyspepsia 5.9-7%

                                                Hypokalemia >1%

                                                Back pain 3.3%

                                                Urinary retention 3.2-3.5%

Drug Interactions:

            No interactions are known at this time.

Dosing/Administration:^1,2,3,4,5,6

Usual Dose: 12mg administered 30 minutes to 5 hours prior to surgery followed by 12mg twice daily beginning the day after surgery for a maximum of 7 days.   

Geriatric Dose: No adjustment needed.

Pediatric Dose: Safety and efficacy has not been established in this population.

Renal impairment Dose: No adjustment necessary in patients with mild-to-severe renal impairment; monitor for adverse effects.  Alvimopan is not recommended for use in patients with end-stage renal disease.

Hepatic impairment Dose: No adjustment necessary in patients with mild-to-severe hepatic impairment; monitor for adverse effects.  Alvimopan is not recommended for use in patients with severe hepatic impairment.

Use in special circumstances:^1,2

Pregnancy: Pregnancy Category B; Drug should be used during pregnancy only if clearly needed.

Lactation: It is not known whether alvimopan is excreted in milk.  Caution should be exercised when being administered to nursing women.

Conclusion:

            Alvimopan is a unique compound that may be useful in treating post-bowel surgery patients.  It is the only drug of its kind available in the US.  Further studies should be conducted to determine alvimopan’s efficacy in regard to other types of abdominal surgery.  The studies mentioned above have revealed the possibility of saving thousands of dollars in the health-care field related to recovery from major bowel surgeries.   

Recommended References:

1. Entereg® [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
2. Alvimopan. In: DrugDex® System [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically. Accessed June 11, 2008.
3. Alvimopan. Clinical Pharmacology [Internet database]. Gold Standard, Inc., 2008. Available at: http://www.clinicalpharmacology.com. Accessed: June, 11, 2008.
4. Paulson DM, Kennedy DT, Donovick RA, Carpenter RL, Cherubini M, Techner L, et al. Alvimopan: an oral, peripherally acting mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction—a 21-day treatment- randomized clinical trial. J Pain. 2005; 6(3):184-92.
5. Wolff BG, Michelassi F, Gerkin TM, Techner L, Gabriel K, Du W, et al.  Alvimpan, a novel, peripherally acting µ 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): 728-34. 
6. Viscusi ER, Goldstein S, Witkowski T, Andonakakis A, Jan R, Gabriel K, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery. Surg Endosc. 2006; 20: 64-70.
7. Taguchi A, Sharma N, Saleem RM, Sessler DI, Carpenter RL, Seyedsadr M, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001; 345(13): 935-940.

Prepared by:  Dana Stone, Doctor of Pharmacy Candidate.