Pharmacy & Therapeutics - November 2008 - (Page 618)

ENTEREG® (alvimopan) Capsules BRIEF SUMMARY The following is a brief summary only; see full prescribing information for complete product information. 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)] 4 CONTRAINDICATIONS ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG. 5 WARNINGS AND PRECAUTIONS 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 m-opioid receptor antagonists. 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) of full prescribing information]. 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 6.1 ADVERSE REACTIONS 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 Bowel Resection Patients System Organ Class Blood and lymphatic system disorders Anemia Gastrointestinal disorders Constipation Dyspepsia Flatulence Metabolism and nutrition disorders Hypokalemia Musculoskeletal and connective tissue disorders Back pain Renal and urinary disorders Urinary retention 7 7.1 Placebo (n = 986) % 4.2 3.9 4.6 4.5 8.5 1.7 2.1 ENTEREG (n = 999) % 5.2 4.0 7.0 3.1 9.5 3.3 3.2 All Surgical Patients Placebo (n = 1,365) % 5.4 7.6 4.8 7.7 7.5 2.6 2.3 ENTEREG (n = 1,650) % 5.4 9.7 5.9 8.7 6.9 3.4 3.5 Coadministration of alvimopan does not appear to alter the pharmacokinetics of morphine and its metabolite, morphine-6-glucuronide, to a clinically significant degree when morphine is administered intravenously. Dosage adjustment for intravenously administered morphine is not necessary when it is coadministered with alvimopan. USE IN SPECIFIC POPULATIONS Pregnancy 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. 8.2 Nursing Mothers 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. 8.3 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.4 Geriatric Use 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 (12.3) of full prescribing information]. 8.5 Hepatic Impairment Although there is a potential for higher plasma levels of drug in patients with mild-to-moderate hepatic impairment [see Clinical Pharmacology (12.3)], 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 Warnings and Precautions (5.4) and Dosage and Administration (2.2) and Clinical Pharmacology (12.3) of full prescribing information] 8.6 Renal Impairment 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 (2.2) and Clinical Pharmacology (12.3) of full prescribing information]. 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. 9 10 DRUG ABUSE AND DEPENDENCE ENTEREG has no known potential for abuse or dependence. 8 8.1 OVERDOSAGE There is no specific antidote for overdosage with ENTEREG. Patients should be managed with appropriate supportive therapy. Single doses up to 120 mg and multiple doses up to 48 mg for 7 days have been administered to normal, healthy subjects in clinical studies and were well tolerated. 13 13.1 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Two year carcinogenicity studies have been conducted with alvimopan in CD-1 mice at oral doses up to 4000 mg/kg/day and in Sprague Dawley rats at oral doses up to 500 mg/kg/day. Oral administration of alvimopan for 104 weeks produced significant increases in the incidences of fibroma, fibrosarcoma and sarcoma in the skin/ subcutis, and osteoma/osteosarcoma in bones of female mice at 4000 mg/kg/day (about 674 times the recommended human dose based on body surface area). In rats, oral administration of alvimopan for 104 weeks did not produce any tumor up to 500 mg/kg/day (about 166 times the recommended human dose based on body surface area). Alvimopan was not genotoxic

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Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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