| Initial U.S. Approval: 2008
ENTEREG Capsules contain alvimopan, a peripherally-acting µ-opioid receptor (PAM-OR) antagonist. Chemically, alvimopan is the single stereoisomer [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate.
Alvimopan is a white to light beige powder with a molecular weight of 460.6, and the empirical formula is C25H32N2O4•2H2O. It has a solubility of <0.1 mg/mL in water or buffered solutions between pH 3.0 and 9.0, 1 to 5 mg/mL in buffered solutions at pH 1.2, and 10 to 25 mg/mL in aqueous 0.1 N sodium hydroxide. At physiological pH, alvimopan is zwitterionic, a property that contributes to its low solubility.
ENTEREG Capsules for oral administration contain 12 mg of alvimopan on an anhydrous basis suspended in the inactive ingredient polyethylene glycol.
| 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.
| INDICATIONS AND USAGE
ENTEREG is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.
USE IN SPECIFIC POPULATIONS
Renal impairment: Alvimopan has not been studied in patients with end stage renal disease. ENTEREG is not recommended for use in these patients. Dosage adjustment is not required in patients with mild to severe renal impairment but they should be monitored for adverse effects.
ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG.
| WARNINGS AND PRECAUTIONS
| ADVERSE REACTIONS
Most common adverse reactions (incidence >/=3% and >/=1% placebo) in patients undergoing bowel resection were anemia, dyspepsia, hypokalemia, back pain, and urinary retention.
To report SUSPECTED ADVERSE REACTIONS, contact Adolor Corporation at 1-866-4ADOLOR (1-866-423-6567) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
| DOSAGE AND ADMINISTRATION
Usual Dosage in Adults
Hepatic Impairment: No dosage adjustment is necessary in patients with mild-to-moderate hepatic impairment (Child-Pugh Class A and B). ENTEREG is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations and Clinical Pharmacology - package insert].
Renal Impairment: No dosage adjustment is necessary in patients with mild-to-severe renal impairment, but they should be monitored for adverse effects. ENTEREG is not recommended for use in patients with end-stage renal disease [see Use in Specific Populations and Clinical Pharmacology - package insert].
Race: No dosage adjustment is necessary in Black, Hispanic and Japanese patients,
| DOSAGE FORMS AND STRENGTHS
12 mg blue, hard gelatin capsules with “ADL2698” printed on both the body and the cap of the capsule.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature.]
| Package Insert data:
Manufactured for Adolor Corporation
Exton, PA 19341-1127
Distributed by GlaxoSmithKline
US Patent Nos. 5,250,542; 5,434,171; 6,469,030
18 PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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