Hepatic Failure/GI/Endocrine Emergencies
| (b) | Alvimopan was studied in four North American phase III randomized controlled trials for |
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POI. Each trial included adult surgical patients (generally bowel resection and abdominal
hysterectomy) who received standard postoperative care for prevention of POI. In all four
trials, patients were randomized to receive placebo, alvimopan 6 mg orally twice daily, or
alvimopan 12 mg orally twice daily beginning immediately before surgery and continuing
for 7 days (total of 15 doses).
| (1) | Three of the four trials showed significant reductions in time to return of normal |
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bowel function (i.e., tolerating solid food and passing bowel movements). The 12-mg
dose was especially beneficial in females and patients older than 65.
| (2) | A pooled analysis from the four phase III trials comparing outcomes in patients who |
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received the 12-mg dose versus placebo showed a 20-hour reduction in time to return
of normal bowel function (102 hours vs. 121.8 hours, p<0.05) and a reduction in
hospital length of stay (6.6 days vs. 7.6 days, p<0.001).
| (c) | Alvimopan was also associated with significantly less POI-related morbidity, including |
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NG tube insertion (6.6% vs. 11.5%, p<0.001), and fewer POI complications, including
paralytic ileus, as well as adverse events of nausea, vomiting, and abdominal distension
(2.9% vs. 8.8%, p<0.001).
| (d) | In a 12-month study of alvimopan for opioid-induced bowel dysfunction in patients with |
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chronic non-cancer pain, myocardial infarction rates were higher in patients treated with
alvimopan than in placebo (7 [1.3%] vs. 0 [0%]).
| (1) | This higher risk did not appear to be related to the therapy duration (12 months). In |
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addition, increased risk of cardiovascular events has not occurred in other alvimopan
studies, including POI studies, and no causal relationship has been established.
| (2) | However, given the concern of added risk, the FDA has since developed REMS (Risk |
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Evaluation and Mitigation Strategies) for the use of alvimopan. Hospitals that intend
to use alvimopan should be enrolled in the EASE (ENTEREG Access Support &
Education) program. The EASE program limits the use of alvimopan to short-term
inpatient use, and patients cannot receive more than 15 doses.
ii.
Methylnaltrexone
| (a) | Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist approved for |
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treatment of chronic opioid-induced constipation. Methylnaltrexone is not FDA approved
for the treatment of POI.
| (b) | Methylnaltrexone is typically given subcutaneously daily or every other day for opioid- |
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induced constipation in a weight-based dose of 0.15 mg/kg rounded to the nearest 2 mg
(usually 8 or 12 mg)
| (c) | Results from phase III trials showed no reduction in duration of POI compared with |
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placebo, but methylnaltrexone may be an alternative to alvimopan if oral therapy is not
an option.
iii.
Naloxegol
| (a) | Naloxegol is another oral peripherally acting mu-opioid receptor antagonist, which is |
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approved for opioid-induced constipation. Dosing for opioid-induced constipation is 25 mg
orally once daily, with dosing reductions required for renal dysfunction and concomitant
CYP3A4 inhibitors.
| (b) | Like methylnaltrexone, naloxegol is not FDA approved for the treatment of POI. |
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