General Information

Entereg is an oral, peripherally-acting, mu-opioid receptor (PAMOR) antagonist. Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract mu-opioid receptors.

Entereg is specifically indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.

Entereg is supplied as a tablet designed for oral administration. The recommended initial dose of the drug is 12 mg administered 30 minutes to 5 hours prior to 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 of Entereg.

Side Effects

Adverse events associated with the use of Enetereg may include, but are not limited to, the following:

Constipation

Flatulence

Hypokalemia

Dyspepsia

Anemia

Urinary retention

Back pain

The Entereg drug label comes with the following Black Box Warning: Increased incidence of myocardial infarction was seen in a clinical trial of patients taking alvimopan for long-term use. Entereg is available only through a restricted program for short-term use (15 doses) called the Alvimopan REMS Program

Clinical Trial Results

FDA approval of Entereg is based on the results of five multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: four in the US and one ex-US. The trials enrolled over 2,000 adult subjects undergoing partial large or small bowel resection surgery with primary anastomosis or total abdominal hysterectomy under general anesthesia. The subjects were randomly assigned to receive oral doses of Entereg 12 mg or matching placebo. The initial dose was administered at least 30 minutes and up to 5 hours prior to the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first postoperative day and continued until hospital discharge or a maximum of 7 days. There were no limitations on the type of general anesthesia used, but intrathecal or epidural opioids or anesthetics were prohibited. All patients in the US studies were scheduled to receive intravenous patient-controlled opioid analgesia, while in the non-US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration. There were no restrictions on the type or duration of opioid use. Subjects who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery were excluded. The primary endpoint was time to achieve resolution of postoperative ileus, defined as a composite measure of both upper and lower gastrointestinal recovery. This was based on two components: GI2-toleration of solid food and first bowel movement.

Study One- In the Entereg arm the mean number of hours to GI2 was 92.0 hours versus 111.8 hours in the placebo arm.

Study Two- Mean number of hours to GI2 was 105.9 in the Entereg arm and 132.0 in the placebo arm.

Study Three- In the Entereg arm the mean number of hours to GI2 was 116.4 verses 130.3 hours in the placebo arm.

Study Four- The mean number of hours to GI2 in the Entereg arm was 106.7 versus 119.9 hours in the placebo arm.

Study Five- In the Entereg arm the mean number of hours to GI2 was 98.8 versus 109.5 hours in the placebo arm. In addition, across studies 1-4, subjects receiving Entereg had their discharge order written approximately 13 to 21 hours sooner compared to subjects receiving placebo. The incidence of anastomotic leak was low and comparable in subjects receiving either Entereg or placebo (0.8% and 1.1%, respectively). Entereg did not reverse opioid analgesia as measured by visual analog scale pain intensity scores and/or amount of postoperative opioids administered across all 5 studies.

Bowel Resection
The efficacy of Entereg following total abdominal hysterectomy has not been established. Therefore, the following data are for the bowel resection population only. A total of 1,877 subjects underwent bowel resection. In the non-US study (Study 5), average daily postoperative opioid consumption was approximately 50% lower and the use of non-opioid analgesics substantially higher, as compared with the US studies (Studies 1-4) for both treatment groups. During the first 48 hours postoperatively, the use of non-opioid analgesics was 69% compared with 4% for the non-US and US studies, respectively. In each of the 5 studies, Entereg accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written as compared with placebo.