WARNINGS AND PRECAUTIONS
Myocardial Infarction in a 12 Month Study in Patients treated with Opioids for Chronic Pain
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 in 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.
Distribution Program for ENTEREG
ENTEREG is available only to hospitals that enroll in the E.A.S.E. 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 alvimopan; and
- ENTEREG will not be dispensed to patients after they have been discharged from the hospital.
Contact the E.A.S.E. program at 1-866-4ADOLOR (1-866-423-6567).
Opioid Tolerance and Gastrointestinal-Related Adverse Effects
Patients recently exposed to opioids are expected to be more sensitive to the effects of Î¼-opioid receptor antagonists, such as ENTEREG. Since ENTEREG acts peripherally, clinical signs and symptoms of increased sensitivity would likely be limited to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Patients receiving more than 3 doses of an opioid within the week prior to surgery were not studied in the postoperative ileus clinical trials; therefore, ENTEREG 12 mg capsules should be administered with caution to these patients.
Severe Hepatic Impairment
In patients with severe hepatic impairment, there is a potential for 10-fold higher plasma levels of drug [see Clinical Pharmacology]. There are no studies of ENTEREG in patients with severe hepatic impairment undergoing bowel resection. Because of the limited data available, ENTEREG is not recommended for use in patients with severe hepatic impairment.
End-Stage Renal Disease
No studies have been conducted with end-stage renal disease. ENTEREG is not recommended for use in these patients.
Use of ENTEREG in patients undergoing surgery for correction of complete bowel obstruction is not recommended.
USE IN SPECIFIC POPULATIONS
Teratogenic Effects: Pregnancy Category B
Reproduction studies have been performed in pregnant rats at about 68 to 136 times the recommended human oral dose based on the body surface area and intravenous doses of 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 at 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. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Alvimopan and its "metabolite" are detected in the milk of lactating rats. It is not known whether alvimopan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ENTEREG is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients in 5 clinical efficacy studies treated with ENTEREG or placebo, 45% were 65 years of age and over, while 18% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment based on increased age is required [see Clinical Pharmacology].
Although there is a potential for higher plasma levels of drug in patients with mild-to-moderate hepatic impairment [see Clinical Pharmacology], dosage adjustment in these patients is not required. Patients with mild-to-moderate hepatic impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or "metabolite" levels, and ENTEREG should be discontinued if adverse events occur. ENTEREG is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology].
Alvimopan has not been studied in patients with end-stage renal disease and ENTEREG is not recommended for use in these patients. Patients with mild-to-severe renal impairment do not require dosage adjustment, but they should be monitored for adverse effects. [see Dosage and Administration and Clinical Pharmacology]. Patients with severe impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or "metabolite" levels, and ENTEREG should be discontinued if adverse events occur.
No dosage adjustment is necessary in Black, Hispanic and Japanese patients. However, the exposure of ENTEREG in Japanese male healthy volunteers was approximately 2-fold greater than in Caucasian subjects. Japanese patients should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or 'metabolite' levels, and ENTEREG should be discontinued if adverse events occur.
see Dosage and Administration