WARNING: FOR SHORT-TERM HOSPITAL USE ONLY ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have registered in and met all of the requirements for the ENTEREG Access Support and Education (E.A.S.E.) program may use ENTEREG. [see Warnings and Precautions (5.1 and 5.2) ] WARNING: FOR SHORT-TERM HOSPITAL USE ONLY ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have registered in and met all of the requirements for the ENTEREG Access Support and Education (E.A.S.E.™) program may use ENTEREG.
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warnings and cautions
5 WARNINGS AND PRECAUTIONS A higher number of myocardial infarctions was reported in patients treated with alvimopan 0.5 mg twice daily compared with placebo in a 12-month study in patients treated with opioids for chronic pain, although a causal relationship has not been established. ( 5.1 ) Patients recently exposed to opioids are expected to be more sensitive to the effects of ENTEREG and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. ( 5.3 ) Not recommended in patients with severe hepatic impairment. ( 5.4 ) Not recommended in patients with end stage renal disease. ( 5.5 ) 5.1 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. 5.2 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). 5.3 Opioid Tolerance and Gastrointestinal-Related Adverse Effects Patients recently exposed to opioids are expected to be more sensitive to the effects of µ-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. 5.4 Severe Hepatic Impairment In patients with severe hepatic impairment, there is a potential for 10-fold higher plasma levels of drug [see Clinical Pharmacology (12.3) ] . 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. 5.5 End-Stage Renal Disease No studies have been conducted with end-stage renal disease. ENTEREG is not recommended for use in these patients. 5.6 Bowel Obstruction Use of ENTEREG in patients undergoing surgery for correction of complete bowel obstruction is not recommended.
6 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. ( 6.1 ) 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. The data described below reflect exposure to ENTEREG in 1,650 patients in 9 placebo-controlled studies worldwide. The population was 19 to 97 years old, 68% were female, and 83% were Caucasian; 61% were undergoing bowel resection surgery. The first dose of ENTEREG was administered 30 minutes to 5 hours before the scheduled start of surgery and then twice daily until hospital discharge (or for a maximum of 7 days of postoperative treatment). Table 1 presents treatment-emergent adverse reactions reported in ≥3% patients treated with ENTEREG and for which the rate for ENTEREG was ≥1% than placebo. Treatment-emergent adverse reactions are those events occurring after the first dose of study medication treatment and within 7 days of the last dose of study medication or those events present at baseline that increased in severity after the start of study medication treatment. Table 1. Treatment-Emergent Adverse Reactions That Were Reported in ≥3% of Either Bowel Resection Patients Treated With ENTEREG or All Surgical Patients Treated With ENTEREG and for Which the Rate for ENTEREG Was ≥1% Than Placebo System Organ Class Bowel Resection Patients All Surgical Patients Placebo (n = 986) % ENTEREG (n = 999) % Placebo (n = 1,365) % ENTEREG (n = 1,650) % Blood and lymphatic system disorders Anemia 4.2 5.2 5.4 5.4 Gastrointestinal disorders Constipation 3.9 4.0 7.6 9.7 Dyspepsia 4.6 7.0 4.8 5.9 Flatulence 4.5 3.1 7.7 8.7 Metabolism and nutrition disorders Hypokalemia 8.5 9.5 7.5 6.9 Musculoskeletal and connective tissue disorders Back pain 1.7 3.3 2.6 3.4 Renal and urinary disorders Urinary retention 2.1 3.2 2.3 3.5