Entereg Capsules

CLINICAL PHARMACOLOGY

Mechanism of Action

Alvimopan is a selective antagonist of the cloned human µ-opioid receptor with a Ki of 0.4 nM (0.2 ng/mL) and no measurable opioid-agonist effects in standard pharmacologic assays. The dissociation of [3H]-alvimopan from the human µ-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 µM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels.

Postoperative ileus is the impairment of gastrointestinal motility after intra-abdominal surgery or other non-abdominal surgeries. Postoperative ileus affects all segments of the gastrointestinal tract and may last from 5 to 6 days, or even longer. This may potentially delay gastrointestinal recovery and hospital discharge until its resolution. It is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluids in the bowel, and delayed passage of flatus and defecation. Postoperative ileus is the result of a multifactorial process that includes inhibitory sympathetic input, release of hormones, neurotransmitters, and other mediators (e.g., endogenous opioids). A component of postoperative ileus also results from an inflammatory reaction and the effects of opioid analgesics. Morphine and other µ-opioid receptor agonists are universally used for the treatment of acute postsurgical pain; however, they are known to have an inhibitory effect on gastrointestinal motility and may prolong the duration of postoperative ileus.

Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract µ-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations where alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of µ-opioid agonists.

Pharmacodynamics

In exploratory studies in healthy volunteers, alvimopan 3 mg three times daily appeared to reduce the delay in gastrointestinal transit produced by morphine 30 mg twice daily as measured by radio-opaque markers.

In a study designed to evaluate potential effects on cardiac conduction, alvimopan did not cause clinically significant QTc prolongation at doses up to 24 mg twice daily for 7 days. The potential for QTc effects at higher doses has not been studied.

Pharmacokinetics

Following oral administration of alvimopan, an amide hydrolysis compound is present in the systemic circulation, which is considered a product exclusively of intestinal flora metabolism. This compound is referred to as the ‘metabolite'. It is also a µ-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL).

Absorption: Following oral administration of ENTEREG capsules in healthy volunteers, plasma alvimopan concentration peaked at approximately 2 hours postdose. No significant accumulation in alvimopan concentration was observed following twice daily (BID) dosing. The mean peak plasma concentration was 10.98 (±6.43) ng/mL and mean AUC0-12h was 40.2 (±22.5) ng•h/mL after dosing of alvimopan at 12 mg BID for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). Plasma concentrations of alvimopan increased approximately proportionally with increasing doses between 6 and 18 mg, but less than proportionally from 18 to 24 mg.

There was a delay in the appearance of the ‘metabolite', which had a median Tmax of 36 hours following administration of a single dose of alvimopan. Concentrations of the ‘metabolite' were highly variable between subjects and within a subject. The ‘metabolite' accumulated after multiple doses of ENTEREG. The mean Cmax for the ‘metabolite' after alvimopan 12 mg twice daily for 5 days was 35.73±35.29 ng/mL.

Concentrations of alvimopan and its metabolite are higher (~1.9-fold and ~1.4-fold, respectively) in POI patients than in healthy volunteers.

Food Effects: A high-fat meal decreased the extent and rate of alvimopan absorption.

The Cmax and AUC were decreased by approximately 38% and 21%, respectively, and the Tmax was prolonged by approximately 1 hour. The clinical significance of this decreased bioavailability is unknown. In POI clinical trials, the preoperative dose of ENTEREG was administered in a fasting state. Subsequent doses were given without regard to meals.

Distribution: The steady state volume of distribution of alvimopan was estimated to be 30±10 L. Plasma protein binding of alvimopan and its ‘metabolite' was independent of concentration over ranges observed clinically and averaged 80% and 94%, respectively. Both alvimopan and the ‘metabolite' were bound to albumin and not to alpha-1 acid glycoprotein.

Metabolism and Elimination: The average plasma clearance for alvimopan was 402 (±89) mL/min. Renal excretion accounted for approximately 35% of total clearance. There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its ‘metabolite' by gut microflora. The ‘metabolite' was eliminated in the feces and in the urine as unchanged ‘metabolite', the glucuronide conjugate of the ‘metabolite', and other minor metabolites. The mean terminal phase half-life of alvimopan after multiple oral doses of ENTEREG ranged from 10 to17 hours. The terminal half-life of the ‘metabolite' ranged 10 to 18 hours.

Special Populations

Age: The pharmacokinetics of alvimopan, but not its ‘metabolite', were related to age, but this effect was not clinically significant and does not warrant dosage adjustment based on increased age.

Race: The pharmacokinetic characteristics of alvimopan were not affected by Hispanic or black race. Plasma ‘metabolite' concentrations were lower in black and in Hispanic patients (by 43% and 82%, respectively) than in Caucasian patients following alvimopan administration. These changes are not considered to be clinically significant in surgical patients. Japanese male healthy volunteers had an approximately 2-fold increase in plasma alvimopan concentrations, but no change in metabolite pharmacokinetics. The pharmacokinetics of alvimopan have not been studied in subjects of other East Asian ancestry. Dosage adjustment in Japanese patients is not required [see Use in Specific Populations]

Gender: There was no effect of gender on the pharmacokinetics of alvimopan or the ‘metabolite'.

Hepatic Impairment: Exposure to alvimopan following a single 12-mg dose tended to be higher (1.5 to 2 fold, on average) in patients with mild or moderate hepatic impairment (as defined by Child-Pugh Class A and B, n = 8 each) compared with healthy controls (n = 4). There were no consistent effects on the Cmax or half-life of alvimopan in patients with hepatic impairment. However, two of 16 patients with mild to moderate impairment had longer than expected half-lives of alvimopan indicating that some accumulation may occur upon multiple dosing. The Cmax of the ‘metabolite' tended to be more variable in patients with mild or moderate hepatic impairment than in matched normal subjects. A study of 3 patients with severe hepatic impairment (Child-Pugh Class C), indicated similar alvimopan exposure in 2 patients and

an approximately 10-fold increase in Cmax and exposure in 1 patient with severe hepatic impairment when compared with healthy control volunteers [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Renal Impairment: There was no relationship between renal function (i.e., creatinine clearance [CrCl]) and plasma alvimopan pharmacokinetics (Cmax, AUC, or half-life) in patients with mild (CrCl 51-80 mL/min), moderate (CrCl 31-50 mL/min), or severe (CrCl < 30 mL/min) renal impairment (n = 6 each). Renal clearance of alvimopan was related to renal function; however, because renal clearance was only a small fraction (35%) of the total clearance, renal impairment had a small effect on the apparent oral clearance of alvimopan. The half-lives of alvimopan were comparable in the mild, moderate and control renal impairment groups but longer in the severe renal impairment group. Exposure to the ‘metabolite' tended to be 2- to 5fold higher in patients with moderate or severe renal impairment compared to patients with mild renal impairment or control subjects. Thus, there may be accumulation of alvimopan and ‘metabolite' in patients with severe renal impairment receiving multiple doses of ENTEREG. Patients with end-stage renal disease were not studied [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Crohn's Disease: There was no relationship between disease activity in patients with Crohn's disease (measured as Crohn's Disease Activity Index or bowel movement frequency) and alvimopan pharmacokinetics (AUC or Cmax). Patients with active or quiescent Crohn's disease had increased variability in alvimopan pharmacokinetics and exposure tended to be 2fold higher in patients with quiescent disease than in those with active disease or normal subjects. Concentrations of the ‘metabolite' were lower in patients with Crohn's disease.

Animal Toxicology and/or Pharmacology

A single oral dose of 500 mg/kg of alvimopan was not lethal to mice and rats.

Reproduction studies have been performed in pregnant rats at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on the body surface area) and intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on the body surface area) and in pregnant rabbits at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on the body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to alvimopan.

Clinical Studies

Postoperative Ileus

The efficacy of ENTEREG in the management of postoperative ileus was evaluated in 5 multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: 4 US studies (Studies 1-4) and 1 non-US study (Study 5). Patients 18 years of age or older undergoing partial large or small bowel resection surgery with primary anastomosis or total abdominal hysterectomy under general anesthesia 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. In the non-US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration (intravenous or intramuscular). In all studies, there was no restriction on the type of opioid used or the duration of intravenous patient-controlled opioid analgesia. A standardized accelerated postoperative care pathway was implemented: early nasogastric tube removal (end of surgery); early ambulation (day following surgery); early diet advancement (liquids offered the day following surgery) and solids by the second day following surgery, as tolerated.

Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded.

The primary endpoint for all studies was time to achieve resolution of postoperative ileus, a clinically defined composite measure of both upper and lower gastrointestinal recovery. Although both 2-component (GI2: toleration of solid food and first bowel movement) and 3-component (GI3: toleration of solid food and either first flatus or bowel movement) endpoints were used in all studies, GI2 is presented as it represents the most objective and clinically relevant measure of treatment response in the bowel resection population. The time from the end of surgery to when the discharge order was written represented the length of hospital stay. In the 5 studies, 1,081 patients received placebo (157 for total abdominal hysterectomy) and 1,096 patients received ENTEREG (143 for total abdominal hysterectomy).

The efficacy of ENTEREG following total abdominal hysterectomy has not been established. Therefore, the following data are presented for the bowel resection population only.

Bowel Resection: A total of 1,877 patients underwent bowel resection. The average age was 61 years with equal proportions of males and females, and 88% were Caucasian. The most common indications for surgery were colon or rectal cancer and diverticular disease. 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. Hazard ratios greater than 1 indicate a higher probability of achieving the event during the study period with treatment with ENTEREG than with placebo. Table 2 provides the Hazard Ratios, Kaplan Meier means and the mean treatment differences (hours) in gastrointestinal recovery between ENTEREG and placebo.

Table 2. GI2 Recovery (Hours) in Bowel Resection Patients

Study No. ENTEREG
12 mg
Mean
Placebo Mean Treatment Difference Mean Hazard Ratio
(95% CI)
1 92.0 111.8 19.8 1.533
(1.293, 1.816)
2 105.9 132.0 26.1 1.625
(1.256, 2.102)
3 116.4 130.3 14.0 1.365
(1.057, 1.764)
4 106.7 119.9 13.2 1.400
(1.035, 1.894)
5 98.8 109.5 10.7 1.299
(1.070, 1.575)

Gastrointestinal recovery began after approximately 48 hours post surgery. The proportion of patients receiving ENTEREG who achieved GI2 was higher at all times throughout the study observation period compared with those receiving placebo (Figure 1).

Figure 1: Time to GI2 Based on the Combined Data from Five Studies

Time to GI2 - Illustration

Across studies 1-4, patients receiving ENTEREG had their discharge order written approximately 13 to 21 hours sooner compared to patients receiving placebo.

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.

There were no gender-, age-, or race-related differences in treatment effect.

The incidence of anastomotic leak was low and comparable in patients receiving either ENTEREG or placebo (0.8% and 1.1%, respectively).

Last reviewed on RxList: 12/3/2009
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.