ENTEREG®

(alvimopan) capsules 12 mg, for oral use

Mechanism of Action 

Background information

Bowel resection and postoperative ileus (POI)

Burden of POI

Postoperative ileus is the transient cessation of coordinated bowel function after surgery.1 The reduction of gastrointestinal (GI) motility may result in POI and prolonged hospital stay.

POI impacts all parts of the GI tract and may last for 5 to 6 days.

POI is expected to some extent in all patients after they undergo bowel resection surgery.2

  • The duration and severity of POI cannot be reliably predicted before bowel resection surgery.2
  • Identifying which patients will experience POI after bowel resection surgery remains challenging.1
  • A fully developed risk equation has not been evaluated in clinical studies.1

The characteristics of POI include3,4:

  • Abdominal distention and bloating
  • Pain
  • Nausea and vomiting
  • Accumulation of gas and fluids in the bowel
  • Delayed passage of flatus and defecation
The pathogenesis of POI is multifactorial, stemming from many risk factors, including1,5–7:
  • Surgeon-assessed bowel handling
  • Duration of the operation
  • Patient health status
  • Amount of opioids administered
  • Older age and male gender

Opioids may delay GI recovery

Morphine and other opioid analgesics are commonly used for the treatment of acute postsurgical pain.8 In the central nervous system, opioid analgesics bind to μ-opioid receptors, inhibiting neural transmission and producing analgesia.

In the gastrointestinal (GI) system, normal patterns of neuronal firing within the enteric nervous system are inhibited by opioid analgesics.9 These agents bind to μ-opioid receptors on enteric neurons, which inhibit neural transmission and GI motility.

GI Motility Icon

Naturally occurring endogenous opioids AND opioids exogenously administered for surgical pain management may have a negative effect on GI motility.10

Indication

ENTEREG is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis.

Selected Safety Information

WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY

  • Increased incidence of myocardial infarction was seen in a clinical trial of patients taking alvimopan for long-term use. No increased risk was observed in short-term trials.
  • Because of the potential risk of myocardial infarction, ENTEREG is available only through a restricted program for short-term use (15 doses) called the ENTEREG Access Support and Education (E.A.S.E.) Program.

Contraindications

ENTEREG Capsules are contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG.

Warnings and Precautions

There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic pain. In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan, including studies of patients undergoing bowel resection surgery who received alvimopan 12 mg twice daily for up to 7 days. A causal relationship with alvimopan has not been established.

E.A.S.E. Program for ENTEREG: ENTEREG is available only to hospitals that enroll in the E.A.S.E. ENTEREG REMS Program. To enroll in the E.A.S.E. Program, the hospital must acknowledge that:

  • Hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use
  • Patients will not receive more than 15 doses of ENTEREG
  • ENTEREG will not be dispensed to patients after they have been discharged from the hospital

ENTEREG should be administered with caution to patients receiving more than 3 doses of an opioid within the week prior to surgery. These patients may be more sensitive to ENTEREG and may experience GI side effects (eg, abdominal pain, nausea and vomiting, diarrhea).

ENTEREG is not recommended for use in patients with severe hepatic impairment, end-stage renal disease, complete gastrointestinal obstruction, or pancreatic or gastric anastomosis, or in patients who have had surgery for correction of complete bowel obstruction.

Adverse Reactions

The most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo among ENTEREG-treated patients undergoing surgeries that included a bowel resection was dyspepsia (ENTEREG, 1.5%; placebo, 0.8%).

Before prescribing ENTEREG, please read the accompanying Prescribing Information, including the Boxed Warning about potential risk of myocardial infarction with long-term use.

References

1. Delaney C, Kehlet H, Senagore AJ, et al. Postoperative ileus: profiles, risk factors, and definitions—a framework for optimizing surgical outcomes in patients undergoing major abdominal and colorectal surgery. http://www.clinicalwebcasts.com/pdfs/GenSurg_WEB.pdf. Published May 1, 2006. Accessed March 25, 2018. 

2. Woods MS. Postoperative ileus: dogma versus data from bench to bedside. Perspect Colon Rectal Surg. 2000;12:57-76. 

3. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000;87(11):1480-1493. 

4. Livingston EH, Passaro EP. Postoperative ileus. Dig Dis Sci. 1990;35(1):121-132. 

5. Vather R, Josephson R, Jaung R, Robertson J, Bissett I. Development of a risk stratification system for the occurrence of prolonged postoperative ileus after colorectal surgery: a prospective risk factor analysis. Surgery. 2015;157(4):764-773. 

6. Moghadamyeghaneh Z, Hwang GS, Hanna MH, et al. Risk factors for prolonged ileus following colon surgery. Surg Endosc. 2016;30(2):603-609. 

7. Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut. 2009;58(9):1300-1311.

8. Gutstein HB, Akil H. Opioid analgesics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006:547-590. 

9. Galligan JJ, Akbarali HI. Molecular physiology of enteric opioid receptors. Am J Gastroenterol Suppl. 2014;2(1):17-21. 

10. Beard TL, Leslie JB, Nemeth J. The opioid component of delayed gastrointestinal recovery after bowel resection. J Gastrointest Surg. 2011;15(7):1259-1268.

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