Alvimopan (entereg) uses, brand name, doses and side effects

Description of Alvimopan (entereg)

Alvimopan is the first oral, gastrointestinal-specific mu-opioid receptor antagonist and is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis (i.e., prevention of postoperative ileus). The efficacy of alvimopan in the management of postoperative ileus was evaluated in 6 multicenter, randomized, double-blind, parallel-group, placebo-controlled studies. Primary approval was supported by trials in patients undergoing bowel resection for benign or malignant colorectal or small bowel disease; expanded approval was supported by a Phase IV controlled trail in patients undergoing radical cystectomy, an extensive surgical procedure that includes resecting a segment of the bowel to reconstruct the lower urinary tract. Because alvimopan is a gastrointestinal-specific mu-opioid receptor antagonist, it does not block the desired pain-relieving effects of opioid agonists which may be used concurrently. It has limited systemic bioavailability and does not cross the blood-brain barrier due to its large molecular size. Alvimopan is only available to hospitals that meet all the requirements of a restricted access program, Alvimopan Shared System REMS Program. Requirements of the program include education of all staff involved in the medication use process, limiting the duration of treatment to 15 dosesor less, and restricting alvimopan use to hospitalized patients only.

Mechanism of Action of Alvimopan (entereg)

Alvimopan is a peripherally-selective, mu-opioid receptor antagonist that is restricted in activity to the GI tract. Postoperative ileus can affect all segments of the gastrointestinal tract and is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluid in the bowel, and delayed passage of flatus and defecation, potentially prolonging gastrointestinal recover hospitalization after bowel surgery. Opioid agonists (e.g., morphine) are used universally and effectively for the treatment of postoperative pain; however, their use may result in inhibition of gastrointestinal motility and contribute to the development of postoperative ileus. Because it acts within the gastrointestinal tract, it antagonizes opioid-induced gastrointestinal dysfunction while maintaining the central analgesic effects of opioid agonists. In isolated guinea pig ileum, alvimopan competitively antagonizes the effects of morphine on contractility.

Pharmacokinetics of Entereg

Alvimopan is administered orally. After administration, it undergoes amide hydrolysis by intestinal flora to a ‘metabolite’; there is no evidence of hepatic metabolism. Biliary secretion is the primary pathway for elimination, with renal excretion accounting for 35% of total clearance. The ‘metabolite’ is eliminated in the feces and in the urine as unchanged ‘metabolite’. The mean terminal phase half-life after multiple oral doses ranges from 10—17 hours; for the ‘metabolite’, the mean terminal phase half-life is 10—18 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

Route-Specific Pharmacokinetics
Oral Route
Alvimopan undergoes amide hydrolysis by intestinal flora to a ‘metabolite’ after oral administration; both alvimopan and the ‘metabolite’ are mu-opioid receptor antagonists. The absolute bioavailability is estimated to be 6%. High fat meals decrease the extent and rate of alvimopan absorption; however, the clinical significance of this is unknown. Peak plasma concentrations of alvimopan occur in approximately 2 hours. The time to reach peak plasma concentration of the ‘metabolite’ is 36 hours. Plasma concentrations increase proportionally with increasing doses between 6 mg and 18 mg, but less than proportionally from 18 mg to 24 mg. In patients with postoperative ileus, plasma concentrations of both alvimopan and the ‘metabolite’ are higher than concentrations in healthy subjects. Alvimopan and its ‘metabolite’ are highly protein bound (80% and 94%, respectively).

Special Populations
Hepatic Impairment
On average, a 1.5—2 fold increase in alvimopan plasma concentration is seen in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). However, a 10-fold higher plasma concentration of alvimopan is possible in patients with hepatic disease or severe hepatic impairment.

• Alvimopan

• Entereg

• Gastrointestinal Agent
• Opioid Antagonist

• Postoperative ileus, Following partial large or small bowel resection surgery with primary anastomosis: Adult

• Gastrointestinal: Indigestion (1.5% )

• Cardiovascular: Myocardial infarction

• Oral: For in-hospital use only
• Oral: Can be administered with or without food
• Oral: Do not administer more than 15 doses

• Entereg: Oral Capsule: 12 MG

• Oral Capsule: 12 MG

• Important Note: Alvimopan (Entereg(R)) is approved only for short-term, in-hospital use. Due to the risk of myocardial infarction with long-term use, availability of alvimopan is restricted to hospitals who have registered in and met all the requirements for the Alvimopan Risk Evaluation and Mitigation Strategy (REMS) program. In order to enroll in the program, hospitals must acknowledge that 1) hospital staff who prescribe, dispense, or administer alvimopan have received educational materials regarding the need to limit alvimopan use to short-term, inpatient use, 2) patients will not receive more than 15 doses, and 3) alvimopan will not be dispensed to patients after hospital discharge.
  
• Postoperative ileus, Following partial large or small bowel resection surgery with primary anastomosis: 12 mg ORALLY 30 minutes to 5 hours prior to surgery, followed by 12 mg ORALLY twice daily beginning the day after surgery for up to 7 days or until hospital discharge; MAX 15 doses

• Important Note: Alvimopan (Entereg(R)) is approved only for short-term, in-hospital use. Due to the risk of myocardial infarction with long-term use, availability of alvimopan is restricted to hospitals who have registered in and met all the requirements for the Alvimopan Risk Evaluation and Mitigation Strategy (REMS) program. In order to enroll in the program, hospitals must acknowledge that 1) hospital staff who prescribe, dispense, or administer alvimopan have received educational materials regarding the need to limit alvimopan use to short-term, inpatient use, 2) patients will not receive more than 15 doses, and 3) alvimopan will not be dispensed to patients after hospital discharge.
  
• General Dosage Information: safety and effectiveness have not been established in pediatric patients

• Oral (Capsule): There was a greater incidence of myocardial infarction in alvimopan-treated patients compared to placebo-treated patients in a 12-month clinical trial, although a causal relationship has not been established. In short-term trials with Alvimopan, no increased risk of myocardial infarction was observed. Because of the potential risk of myocardial infarction with long-term use, alvimopan is available only through a restricted program for short-term use (15 doses) under a Risk Evaluation and Mitigation Strategy (REMS) called the Alvimopan REMS Program .

• Bioavailability: 6%
• Effect of food: decreased extent and rate of absorption