Source: FDA, National Drug Code (US) Revision Year: 2020
ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG [see Warnings and Precautions (5.3)].
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 non-cancer pain (alvimopan 0.5 mg, n = 538; placebo, n = 267). 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 ENTEREG in patients treated with opioids for chronic pain, nor in patients treated within the surgical setting, including patients undergoing surgeries that included bowel resection who received ENTEREG 12 mg twice daily for up to 7 days (the indicated dose and patient population; ENTEREG 12 mg, n = 1,142; placebo, n = 1,120). A causal relationship with alvimopan with long-term use has not been established.
ENTEREG is available only through a program under a REMS that restricts use to enrolled hospitals [see Warnings and Precautions (5.2)].
ENTEREG is available only through a program called the Alvimopan REMS Program that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG [see Warnings and Precautions (5.1)].
Notable requirements of the Alvimopan REMS Program include the following:
ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the Alvimopan REMS program may use ENTEREG.
To enroll in the Alvimopan REMS Program, an authorized hospital representative must acknowledge that:
Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists, such as ENTEREG. Since ENTEREG acts peripherally, clinical signs and symptoms of increased sensitivity would be related 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, if ENTEREG is administered to these patients, they should be monitored for gastrointestinal adverse reactions. ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG [see Contraindications (4)].
Patients with severe hepatic impairment may be at higher risk of serious adverse reactions (including dose-related serious adverse reactions) because up to 10-fold higher plasma concentrations of alvimopan have been observed in such patients compared with patients with normal hepatic function. Therefore, the use of ENTEREG is not recommended in this population [see Use in Specific Populations (8.6)].
No studies have been conducted in patients with end-stage renal disease. ENTEREG is not recommended for use in these patients [see Use in Specific Populations (8.7)].
No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. ENTEREG is not recommended for use in these patients.
ENTEREG has not been studied in patients having pancreatic or gastric anastomosis. Therefore, ENTEREG is not recommended for use in these patients.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly with 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 12 mg in 1,793 patients in 10 placebo-controlled studies. The population was 19 to 97 years old, 64% were female, and 84% were Caucasian; 64% were undergoing a surgery that included bowel resection. 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).
Among ENTEREG-treated patients undergoing surgeries that included a bowel resection, the most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo was dyspepsia (ENTEREG, 1.5%; placebo, 0.8%). Adverse reactions are events that occurred after the first dose of study medication treatment and within 7 days of the last dose of study medication or events present at baseline that increased in severity after the start of study medication treatment.
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 ENTEREG.
A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers (proton pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists) or antibiotics. No dosage adjustments are necessary in patients taking acid blockers or antibiotics with ENTEREG.
Available data regarding use of ENTEREG in pregnant women are limited, and are insufficient to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
No fetal harm was observed in animal reproduction studies with oral administration of alvimopan during organogenesis to pregnant rats at doses 68 to 136 times the recommended human oral dose, or with intravenous administration during organogenesis to pregnant rats and pregnant rabbits at doses 3.4 to 6.8 times, and 5 to 10 times, respectively, the recommended human oral dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Embryo-fetal studies were performed in pregnant rats during organogenesis (gestation days 7 through 19, or 20) at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on body surface area) and at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area). A study in pregnant rabbits during organogenesis (gestation days 6 through 18) at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on body surface area) revealed no evidence of harm to the fetus due to alvimopan.
In an intravenous pre- and postnatal development study (gestation day 7 through lactation day 20) in rats, alvimopan did not cause any adverse effect on pre- and postnatal development at doses up to 10 mg/kg/day (about 6.8 times the recommended human oral dose based on body surface area).
There are no data on the presence of alvimopan in human milk, the effects on the breastfed infant, or the effects on milk production. Alvimopan and its ‘metabolite’ are detected in the milk of lactating rats following intravenous administration (see Data). It is unknown if alvimopan is present in rat milk following oral administration.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENTEREG and any potential adverse effects on the breastfed child from ENTEREG or from the underlying maternal condition.
Following intravenous administration of alvimopan to lactating rats at 10 mg/kg/day, concentrations of alvimopan and its ‘metabolite’ in the milk were approximately 15- and 0.11-fold, respectively, the concentration of alvimopan in maternal plasma at 1-hour post-dose.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients in 6 clinical efficacy studies treated with ENTEREG 12 mg or placebo, 46% 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)].
ENTEREG is not recommended for use in patients with end-stage renal disease. Dosage adjustment is not required for patients with mild-to-severe renal impairment, but they should be monitored for adverse reactions. Patients with severe renal impairment should be closely monitored for possible adverse reactions (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high alvimopan or ‘metabolite’ concentrations, and ENTEREG should be discontinued if adverse reactions occur [see Clinical Pharmacology (12.3)].
ENTEREG is not recommended for use in patients with severe hepatic impairment.
Dosage adjustment is not required for patients with mild-to-moderate hepatic impairment. Patients with mild-to-moderate hepatic impairment should be closely monitored for possible adverse reactions (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high alvimopan or ‘metabolite’ concentrations, and ENTEREG should be discontinued if adverse reactions occur [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].
No dosage adjustment is necessary in Black, Hispanic, and Japanese patients. However, the exposure to ENTEREG in Japanese healthy male subjects was approximately 2-fold greater than in Caucasian subjects. Japanese patients should be closely monitored for possible adverse reactions (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high alvimopan or ‘metabolite’ concentrations, and ENTEREG should be discontinued if adverse reactions occur [see Clinical Pharmacology (12.3)].
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