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    Peripheral Mu Opioid Receptor Antagonists for Constipation
    Peripheral Opioid Receptor Antagonists

    BOXED WARNING

    Myocardial infarction, requires a specialized care setting

    Due to a potential risk for myocardial infarction (MI) with long-term use, alvimopan is for short-term use only. Administration of alvimopan requires a specialized care setting; it must be given in a hospital only. In a 12-month study of patients treated with opioids for chronic pain, MI occurred more frequently in patients taking alvimopan 0.5 mg twice daily compared to placebo. Most cases occurred between 1 and 4 months after treatment initiation. This increase in the risk of MI was not duplicated in any other study of alvimopan, including studies in patients receiving alvimopan 12 mg twice daily for 7 days following bowel resection. Causality has not been established. Patients should not receive more than 15 doses of alvimopan. Hospitals administering alvimopan must be registered in and meet all the requirements for the Alvimopan Shared System REMS program. More information is available at alvimopanREMS.com or 1-800-278-0340.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, gastrointestinal-specific opioid receptor antagonist
    Used to accelerate time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis (i.e., prevention of postoperative ileus)
    Only available to hospitals that enroll in Alvimopan REMS Program; information available at alvimopanREMS.com or 1-800-278-0340

    COMMON BRAND NAMES

    Entereg

    HOW SUPPLIED

    Alvimopan/Entereg Oral Cap: 12mg

    DOSAGE & INDICATIONS

    For the acceleration of time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis (i.e., postoperative ileus prophylaxis).
    Oral dosage
    Adults

    A single 12 mg PO dose is given 30 minutes to 5 hours before surgery. Start subsequent doses of 12 mg PO twice daily the day after surgery (i.e., post-op day 1) until discharge for a maximum of 7 days. Max: 15 doses/patient. All doses are given in-hospital only. Only for use in hospitalized patients in hospitals that have registered and met all requirements for the Alvimopan REMS program. More information is available at alvimopanREMS.com or 1-800-278-0340. CLINICAL DATA: One study evaluated doses of 6 mg and 12 mg in patients undergoing bowel surgery. The mean time to GI function recovery (defined as time to tolerating food and first bowel movement) was significantly accelerated for alvimopan-treated patients. The mean difference compared to placebo was 15 hours for alvimopan 6 mg (hazard ratio = 1.28; p is less than 0.05) and 22 hours for alvimopan 12 mg (hazard ratio = 1.54; p is less than 0.001). The time until the hospital discharge order was written was also accelerated in the alvimopan 12 mg group (hazard ratio = 1.42; p is less than 0.003), with a mean difference of 20 hours compared with placebo. Similar results were found with a subsequent study in patients undergoing partial bowel resection with primary anastomosis. A significantly accelerated GI tract function recovery and a reduced time to hospital discharge were noted compared to placebo. Alvimopan was also associated with reduced postoperative ileus-related morbidity (e.g., postoperative nasogastric tube placement, small intestinal obstruction) compared with placebo.

    For the treatment of opiate agonist-induced constipation†.
    Oral dosage
    Adults

    Limited data suggest that 0.5 mg or 1 mg PO once daily may be effective. Alvimopan was evaluated in a phase III trial involving patients who had received chronic opioid therapy for nonmalignant pain for at least 1 month, with a minimum oral morphine dose of 10 mg/day (or equivalent), and who had < 3 bowel movements per week (without aid of laxatives or enemas). The proportion of patients having at least 1 bowel movement within 8 hours after each dose of alvimopan during a 21-day period was 43% and 54% for the 0.5 mg and 1 mg doses, respectively, and 29% for placebo (p < 0.001 for both active doses compared to placebo).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    24 mg/day PO (administered as 12 mg PO twice daily) with a maximum of 15 doses.

    Elderly

    24 mg/day PO (administered as 12 mg PO twice daily) with a maximum of 15 doses.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    It appears that no dosage adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B); however, in patients with severe hepatic impairment (Child-Pugh Class C), use is not recommended.

    Renal Impairment

    It appears that no dosage adjustment is needed in patients mild to severe renal impairment; however, in patients with end stage renal disease, use is not recommended.

    ADMINISTRATION

    Oral Administration

    Administer with or without food.
    Alvimopan is only approved for administration to hospitalized patients. Hospitals must register and met all requirements of the Alvimopan REMS Program. More information is available at alvimopanREMS.com or 1-800-278-0340.

    STORAGE

    Entereg:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Alvimopan is contraindicated for use in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately before starting alvimopan. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists (e.g., abdominal pain, nausea/vomiting, diarrhea). Additionally, patients receiving > 3 doses of an opioid within the 7 days prior to starting alvimopan were not studied in clinical trials; use with caution in these patients.
     
    Alvimopan has not been studied in patients having pancreatic or gastric anastomosis. Therefore, use is not recommended in these patients.

    Myocardial infarction, requires a specialized care setting

    Due to a potential risk for myocardial infarction (MI) with long-term use, alvimopan is for short-term use only. Administration of alvimopan requires a specialized care setting; it must be given in a hospital only. In a 12-month study of patients treated with opioids for chronic pain, MI occurred more frequently in patients taking alvimopan 0.5 mg twice daily compared to placebo. Most cases occurred between 1 and 4 months after treatment initiation. This increase in the risk of MI was not duplicated in any other study of alvimopan, including studies in patients receiving alvimopan 12 mg twice daily for 7 days following bowel resection. Causality has not been established. Patients should not receive more than 15 doses of alvimopan. Hospitals administering alvimopan must be registered in and meet all the requirements for the Alvimopan Shared System REMS program. More information is available at alvimopanREMS.com or 1-800-278-0340.

    GI obstruction

    The manufacturer recommends that alvimopan not be used in patients undergoing surgery for a correction of complete GI obstruction.

    Hepatic disease

    A 10-fold higher plasma concentration of alvimopan is possible in patients with hepatic disease or severe hepatic impairment; it is recommended that alvimopan not be used in patients with severe hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for adverse events; alvimopan should be discontinued if adverse reactions occur.

    Renal disease

    Alvimopan has not been studied in patients with end-stage renal disease; it is recommended that alvimopan not be used in patients with end-stage renal disease. Patients with mild to severe renal impairment do not require dosage adjustments; however, such patients should be monitored for adverse effects. Alvimopan should be discontinued if adverse effects occur.

    Pregnancy

    There are no adequate and well-controlled studies in pregnant women. Animal studies have not indicated a potential for fetal harm. Alvimopan should be considered during pregnancy only when the benefits of therapy outweigh the risks to the fetus.

    Breast-feeding

    According to the manufacturer, it is unknown if alvimopan is excreted in human milk. Use with caution in women who are breast-feeding their infants. There are no published cases of use during lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The use of alvimopan in adolescents, children, and infants has not been established. Safety and efficacy have not been established in pediatric patients. 

    ADVERSE REACTIONS

    Severe

    myocardial infarction / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 4.0-9.7
    hypokalemia / Delayed / 6.9-9.5
    anemia / Delayed / 5.2-5.4
    urinary retention / Early / 3.2-3.5

    Mild

    flatulence / Early / 3.1-8.7
    dyspepsia / Early / 5.9-7.0
    back pain / Delayed / 3.4-3.4
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Acetaminophen; Codeine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Acetaminophen; Hydrocodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Acetaminophen; Oxycodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Alfentanil: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Aspirin, ASA; Oxycodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Belladonna; Opium: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Benzhydrocodone; Acetaminophen: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Celecoxib; Tramadol: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Chlorpheniramine; Codeine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Chlorpheniramine; Hydrocodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Codeine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Codeine; Guaifenesin: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Codeine; Phenylephrine; Promethazine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Codeine; Promethazine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Cyclosporine: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as cyclosporine, has not been studied. Coadministration of cyclosporine and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
    Dextromethorphan; Quinidine: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as quinidine, has not been studied. Coadministration of quinidine and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
    Fentanyl: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Guaifenesin; Hydrocodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Homatropine; Hydrocodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Hydrocodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Hydrocodone; Ibuprofen: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Hydrocodone; Pseudoephedrine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Hydromorphone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Ibuprofen; Oxycodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Itraconazole: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as itraconazole has not been studied. Coadministration of itraconazole and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
    Levorphanol: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Meperidine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Meperidine; Promethazine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Methadone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Methylnaltrexone: (Major) Avoid coadministration of methylnaltrexone and other opiate antagonists, like alvimopan. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Morphine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Morphine; Naltrexone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Naldemedine: (Major) Avoid coadministration of alvimopan and other opiate antagonists, like naldemedine. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Naloxegol: (Major) Avoid coadministration of alvimopan and other opiate antagonists, like naloxegol. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Oliceridine: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Opiate Agonists: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Oxycodone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Oxymorphone: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Quinidine: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as quinidine, has not been studied. Coadministration of quinidine and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
    Quinine: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as quinine has not been studied. Coadministration of quinine and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
    Remifentanil: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Sufentanil: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Tapentadol: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Tramadol: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Tramadol; Acetaminophen: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Trandolapril; Verapamil: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as verapamil has not been studied. Coadministration of verapamil and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
    Verapamil: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as verapamil has not been studied. Coadministration of verapamil and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies in pregnant women. Animal studies have not indicated a potential for fetal harm. Alvimopan should be considered during pregnancy only when the benefits of therapy outweigh the risks to the fetus.

    According to the manufacturer, it is unknown if alvimopan is excreted in human milk. Use with caution in women who are breast-feeding their infants. There are no published cases of use during lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Alvimopan is a peripherally-selective, mu-opioid receptor antagonist that is restricted in activity to the GI tract. Postoperative ileus can affect all segments of the gastrointestinal tract and is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluid in the bowel, and delayed passage of flatus and defecation, potentially prolonging gastrointestinal recover hospitalization after bowel surgery. Opioid agonists (e.g., morphine) are used universally and effectively for the treatment of postoperative pain; however, their use may result in inhibition of gastrointestinal motility and contribute to the development of postoperative ileus. Because alvimopan acts within the gastrointestinal tract, it antagonizes opioid-induced gastrointestinal dysfunction while maintaining the central analgesic effects of opioid agonists. In isolated guinea pig ileum, alvimopan competitively antagonizes the effects of morphine on contractility.

    PHARMACOKINETICS

    Alvimopan is administered orally. After administration, it undergoes amide hydrolysis by intestinal flora to a 'metabolite'; there is no evidence of hepatic metabolism. Biliary secretion is the primary pathway for elimination, with renal excretion accounting for 35% of total clearance. The 'metabolite' is eliminated in the feces and in the urine as unchanged 'metabolite'. The mean terminal phase half-life after multiple oral doses ranges from 10—17 hours; for the 'metabolite', the mean terminal phase half-life is 10—18 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Oral Route

    Alvimopan undergoes amide hydrolysis by intestinal flora to a 'metabolite' after oral administration; both alvimopan and the 'metabolite' are mu-opioid receptor antagonists. The absolute bioavailability is estimated to be 6%. High fat meals decrease the extent and rate of alvimopan absorption; however, the clinical significance of this is unknown. Peak plasma concentrations of alvimopan occur in approximately 2 hours. The time to reach peak plasma concentration of the 'metabolite' is 36 hours. Plasma concentrations increase proportionally with increasing doses between 6 mg and 18 mg, but less than proportionally from 18 mg to 24 mg. In patients with postoperative ileus, plasma concentrations of both alvimopan and the 'metabolite' are higher than concentrations in healthy subjects. Alvimopan and its 'metabolite' are highly protein bound (80% and 94%, respectively).