Entereg

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Potential Risk of Myocardial Infarction with Long-Term Use [see Warnings and Precautions (5.1) ] Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients [see Warnings and Precautions (5.3) ] Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment [see Warnings and Precautions (5.4) ] Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction [see Warnings and Precautions (5.6) ] Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses [see Warnings and Precautions (5.7) ] Most common adverse reaction (≥1.5%): dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 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 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.

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 [see Warnings and Precautions (5.3) ]. Patients who have taken therapeutic doses of opioids for more than 7 consecutive days prior to taking ENTEREG. ( 4 )

11 DESCRIPTION ENTEREG capsules contain alvimopan, an opioid antagonist. Chemically, alvimopan is the single stereoisomer [[2(S)-[[4( R )-(3-hydroxyphenyl)-3( R ),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate. It has the following structural formula: Alvimopan is a white to light beige powder with a molecular weight of 460.6, and the empirical formula is C 25 H 32 N 2 O 4 ∙2H 2 O. It has a solubility of <0.1 mg/mL in water or buffered solutions between pH 3.0 and 9.0, 1 to 5 mg/mL in buffered solutions at pH 1.2, and 10 to 25 mg/mL in aqueous 0.1 N sodium hydroxide. At physiological pH, alvimopan is zwitterionic, a property that contributes to its low solubility. ENTEREG capsules for oral administration contain 12 mg of alvimopan on an anhydrous basis suspended in the inactive ingredient polyethylene glycol. Chemical Structure

2 DOSAGE AND ADMINISTRATION For hospital use only. The recommended adult dosage of ENTEREG is 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery until discharge for a maximum of 7 days. Patients should not receive more than 15 doses of ENTEREG. ENTEREG can be taken with or without food [see Clinical Pharmacology (12.3) ]. For hospital use only. ( 2 ) The recommended dosage is 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery until discharge for a maximum of 7 days. Patients should not receive more than 15 doses of ENTEREG. ( 2 )

1 INDICATIONS AND USAGE ENTEREG is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. ENTEREG is an opioid antagonist indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. ( 1 )

7 DRUG INTERACTIONS 7.1 Effects of Alvimopan on Intravenous Morphine 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. 7.2 Effects of Concomitant Acid Blockers or Antibiotics 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 (H 2 ) receptor antagonists) or antibiotics. No dosage adjustments are necessary in patients taking acid blockers or antibiotics with ENTEREG.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alvimopan is a selective antagonist of the cloned human μ-opioid receptor with a Ki of 0.4 nM (0.2 ng/mL) and no measurable opioid-agonist effects in standard pharmacologic assays. The dissociation of [ 3 H]-alvimopan from the human μ-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 µM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels. Postoperative ileus is the impairment of gastrointestinal motility after intra-abdominal surgery or other, non-abdominal surgeries. Postoperative ileus affects all segments of the gastrointestinal tract and may last from 5 to 6 days, or even longer. This may potentially delay gastrointestinal recovery and hospital discharge until its resolution. It is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluids in the bowel, and delayed passage of flatus and defecation. Postoperative ileus is the result of a multifactorial process that includes inhibitory sympathetic input and release of hormones, neurotransmitters, and other mediators (e.g., endogenous opioids). A component of postoperative ileus also results from an inflammatory reaction and the effects of opioid analgesics. Morphine and other μ-opioid receptor agonists are universally used for the treatment of acute postsurgical pain; however, they are known to have an inhibitory effect on gastrointestinal motility and may prolong the duration of postoperative ileus. Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract μ-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations in which alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of μ-opioid agonists. 12.2 Pharmacodynamics In an exploratory study in healthy subjects, alvimopan 12 mg administered twice a day reduced the delay in small and large bowel transit induced by codeine 30 mg administered 4 times a day, as measured by gastrointestinal scintigraphy. In the same study, concomitant alvimopan did not reduce the delay in gastric emptying induced by codeine. Cardiac Electrophysiology At a dosage of 24 mg twice daily (two times the approved recommended dosage) for 7 days, ENTEREG does not prolong the QT interval to any clinically relevant extent. The potential for QTc effects at higher doses has not been studied. 12.3 Pharmacokinetics Following oral administration of alvimopan, an amide hydrolysis compound is present in the systemic circulation, which is considered a product exclusively of intestinal flora metabolism. This compound is referred to as the 'metabolite'. It is also a mu-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL). Absorption Following oral administration of ENTEREG capsules in healthy plasma subjects, the alvimopan concentration peaked at approximately 2 hours post-dose. No significant accumulation in the concentration of alvimopan was observed following twice daily dosing. The mean peak plasma concentration was 10.98 (±6.43) ng/mL and mean AUC 0–12h was 40.2 (±22.5) ng∙h/mL after dosing of alvimopan at 12 mg twice daily for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). There was a delay in the appearance of the 'metabolite', which had a median T max of 36 hours following administration of a single dose of alvimopan. Concentrations of the 'metabolite' were highly variable between subjects and within a subject. The 'metabolite' accumulated after multiple doses of ENTEREG. The mean C max for the 'metabolite' after alvimopan 12 mg twice daily for 5 days was 35.73 ± 35.29 ng/mL. Concentrations of alvimopan and its 'metabolite' are higher (approximately 1.9-fold and 1.4-fold, respectively) in postoperative ileus patients than in healthy subjects. Effect of Food : A high-fat meal decreased the extent and rate of alvimopan absorption. The C max and AUC were decreased by approximately 38% and 21%, respectively, and the T max was prolonged by approximately 1 hour. The clinical significance of this decreased bioavailability is unknown. In postoperative ileus clinical trials, the preoperative dose of ENTEREG was administered in a fasting state. Subsequent doses were given without regard to meals. Distribution: The steady-state volume of distribution of alvimopan was estimated to be 30±10 L. Plasma protein binding of alvimopan and its 'metabolite' was independent of concentration over ranges observed clinically and averaged 80% and 94%, respectively. Both alvimopan and the 'metabolite' were bound to albumin and not to alpha-1 acid glycoprotein. Elimination Metabolism and Excretion : In vitro data suggest that alvimopan is not a substrate of CYP enzymes. The average plasma clearance for alvimopan was 402 (±89) mL/min. Renal excretion accounted for approximately 35% of total clearance. There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its 'metabolite' by gut microflora. The 'metabolite' was eliminated in the feces and in the urine as unchanged 'metabolite', the glucuronide conjugate of the 'metabolite', and other minor metabolites. The mean terminal phase half-life of alvimopan after multiple oral doses of ENTEREG ranged from 10 to 17 hours. The terminal half-life of the 'metabolite' ranged from 10 to 18 hours. Specific Populations: Geriatric Patients: The pharmacokinetics of alvimopan, but not its 'metabolite', were related to age, but this effect was not clinically significant and does not warrant dosage adjustment based on increased age. Racial or Ethnic Groups: The pharmacokinetic characteristics of alvimopan were not affected by Hispanic or Black race. Plasma 'metabolite' concentrations were lower in Black and Hispanic patients (by 43% and 82%, respectively) than in Caucasian patients following alvimopan administration. These changes are not considered to be clinically significant in surgical patients. Japanese healthy male subjects had an approximately 2-fold increase in plasma alvimopan concentrations, but no change in 'metabolite' pharmacokinetics. The pharmacokinetics of alvimopan have not been studied in subjects of other East Asian ancestry. Dosage adjustment in Japanese patients is not required [see Use in Specific Populations (8.8) ]. Male and Female Patients: There was no effect of sex on the pharmacokinetics of alvimopan or the 'metabolite'. Patients with Hepatic Impairment: Exposure to alvimopan following a single 12 mg dose tended to be higher (1.5- to 2-fold, on average) in patients with mild or moderate hepatic impairment (as defined by Child-Pugh Class A and B, n = 8 each) compared with healthy controls (n = 4). There were no consistent effects on the C max or half-life of alvimopan in patients with hepatic impairment. However, 2 of 16 patients with mild-to-moderate hepatic impairment had longer than expected half-lives of alvimopan, indicating that some accumulation may occur upon multiple dosing. The C max of the 'metabolite' tended to be more variable in patients with mild or moderate hepatic impairment than in matched normal subjects. A study of 3 patients with severe hepatic impairment (Child-Pugh Class C), indicated similar alvimopan exposure in 2 patients and an approximately 10-fold increase in C max and exposure in 1 patient with severe hepatic impairment when compared with healthy controls [see Warnings and Precautions (5.4) , Use in Specific Populations (8.6) ]. Patients with Renal Impairment: There was no relationship between renal function (i.e., creatinine clearance [CrCl]) and plasma alvimopan pharmacokinetics (C max , AUC, or half-life) in patients with mild (CrCl 51–80 mL/min), moderate (CrCl 31–50 mL/min), or severe (CrCl less than 30 mL/min) renal impairment (n = 6 each). Renal clearance of alvimopan was related to renal function; however, because renal clearance was only a small fraction (35%) of the total clearance, renal impairment had a small effect on the apparent oral clearance of alvimopan. The half-lives of alvimopan were comparable in the mild, moderate, and control renal impairment groups but longer in the severe renal impairment group. Exposure to the 'metabolite' tended to be 2- to 5-fold higher in patients with moderate or severe renal impairment compared with patients with mild renal impairment or control subjects. Thus, there may be accumulation of alvimopan and 'metabolite' in patients with severe renal impairment receiving multiple doses of ENTEREG. Patients with end-stage renal disease were not studied [see Warnings and Precautions (5.5) , Use in Specific Populations (8.7) ]. Patients with Crohn's Disease: There was no relationship between disease activity in patients with Crohn's disease (measured as Crohn's Disease Activity Index or bowel movement frequency) and alvimopan pharmacokinetics (AUC or C max ). Patients with active or quiescent Crohn's disease had increased variability in alvimopan pharmacokinetics, and exposure tended to be 2-fold higher in patients with quiescent disease than in those with active disease or in normal subjects. Concentrations of the 'metabolite' were lower in patients with Crohn's disease. Drug Interaction Studies Potential for Drugs to Affect Alvimopan Pharmacokinetics: Concomitant administration of ENTEREG with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan because ENTEREG is metabolized mainly by non-CYP enzyme pathway. No clinical studies have been performed to assess the effect of concomitant administration of inducers or inhibitors of cytochrome P450 enzymes on alvimopan pharmacokinetics. In vitro studies suggest that alvimopan and its 'metabolite' are substrates for p-glycoprotein. A population pharmacokinetic analysis did not reveal any evidence that alvimopan or 'metabolite' pharmacokinetics were influenced by concomitant medications that are mild-to-moderate p-glycoprotein inhibitors. No clinical studies of concomitant administration of alvimopan and strong inhibitors of p-glycoprotein (e.g., verapamil, cyclosporine, amiodarone, itraconazole, quinine, spironolactone, quinidine, diltiazem, bepridil) have been conducted. A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. However, plasma concentrations of the 'metabolite' were lower in patients receiving acid blockers or preoperative oral antibiotics (49% and 81%, respectively). No dosage adjustments are necessary in these patients. Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs: Alvimopan and its 'metabolite' are not inhibitors of CYP 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 in vitro at concentrations far in excess of those observed clinically. Alvimopan and its 'metabolite' are not inducers of CYP 1A2, 2B6, 2C9, 2C19, and 3A4. In vitro studies also suggest that alvimopan and its 'metabolite' are not inhibitors of p-glycoprotein. These in vitro findings suggest that ENTEREG is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition or induction of CYP enzymes or inhibition of p-glycoprotein.

12.1 Mechanism of Action Alvimopan is a selective antagonist of the cloned human μ-opioid receptor with a Ki of 0.4 nM (0.2 ng/mL) and no measurable opioid-agonist effects in standard pharmacologic assays. The dissociation of [ 3 H]-alvimopan from the human μ-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 µM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels. Postoperative ileus is the impairment of gastrointestinal motility after intra-abdominal surgery or other, non-abdominal surgeries. Postoperative ileus affects all segments of the gastrointestinal tract and may last from 5 to 6 days, or even longer. This may potentially delay gastrointestinal recovery and hospital discharge until its resolution. It is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluids in the bowel, and delayed passage of flatus and defecation. Postoperative ileus is the result of a multifactorial process that includes inhibitory sympathetic input and release of hormones, neurotransmitters, and other mediators (e.g., endogenous opioids). A component of postoperative ileus also results from an inflammatory reaction and the effects of opioid analgesics. Morphine and other μ-opioid receptor agonists are universally used for the treatment of acute postsurgical pain; however, they are known to have an inhibitory effect on gastrointestinal motility and may prolong the duration of postoperative ileus. Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract μ-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations in which alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of μ-opioid agonists.

12.2 Pharmacodynamics In an exploratory study in healthy subjects, alvimopan 12 mg administered twice a day reduced the delay in small and large bowel transit induced by codeine 30 mg administered 4 times a day, as measured by gastrointestinal scintigraphy. In the same study, concomitant alvimopan did not reduce the delay in gastric emptying induced by codeine. Cardiac Electrophysiology At a dosage of 24 mg twice daily (two times the approved recommended dosage) for 7 days, ENTEREG does not prolong the QT interval to any clinically relevant extent. The potential for QTc effects at higher doses has not been studied.

12.3 Pharmacokinetics Following oral administration of alvimopan, an amide hydrolysis compound is present in the systemic circulation, which is considered a product exclusively of intestinal flora metabolism. This compound is referred to as the 'metabolite'. It is also a mu-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL). Absorption Following oral administration of ENTEREG capsules in healthy plasma subjects, the alvimopan concentration peaked at approximately 2 hours post-dose. No significant accumulation in the concentration of alvimopan was observed following twice daily dosing. The mean peak plasma concentration was 10.98 (±6.43) ng/mL and mean AUC 0–12h was 40.2 (±22.5) ng∙h/mL after dosing of alvimopan at 12 mg twice daily for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). There was a delay in the appearance of the 'metabolite', which had a median T max of 36 hours following administration of a single dose of alvimopan. Concentrations of the 'metabolite' were highly variable between subjects and within a subject. The 'metabolite' accumulated after multiple doses of ENTEREG. The mean C max for the 'metabolite' after alvimopan 12 mg twice daily for 5 days was 35.73 ± 35.29 ng/mL. Concentrations of alvimopan and its 'metabolite' are higher (approximately 1.9-fold and 1.4-fold, respectively) in postoperative ileus patients than in healthy subjects. Effect of Food : A high-fat meal decreased the extent and rate of alvimopan absorption. The C max and AUC were decreased by approximately 38% and 21%, respectively, and the T max was prolonged by approximately 1 hour. The clinical significance of this decreased bioavailability is unknown. In postoperative ileus clinical trials, the preoperative dose of ENTEREG was administered in a fasting state. Subsequent doses were given without regard to meals. Distribution: The steady-state volume of distribution of alvimopan was estimated to be 30±10 L. Plasma protein binding of alvimopan and its 'metabolite' was independent of concentration over ranges observed clinically and averaged 80% and 94%, respectively. Both alvimopan and the 'metabolite' were bound to albumin and not to alpha-1 acid glycoprotein. Elimination Metabolism and Excretion : In vitro data suggest that alvimopan is not a substrate of CYP enzymes. The average plasma clearance for alvimopan was 402 (±89) mL/min. Renal excretion accounted for approximately 35% of total clearance. There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its 'metabolite' by gut microflora. The 'metabolite' was eliminated in the feces and in the urine as unchanged 'metabolite', the glucuronide conjugate of the 'metabolite', and other minor metabolites. The mean terminal phase half-life of alvimopan after multiple oral doses of ENTEREG ranged from 10 to 17 hours. The terminal half-life of the 'metabolite' ranged from 10 to 18 hours. Specific Populations: Geriatric Patients: The pharmacokinetics of alvimopan, but not its 'metabolite', were related to age, but this effect was not clinically significant and does not warrant dosage adjustment based on increased age. Racial or Ethnic Groups: The pharmacokinetic characteristics of alvimopan were not affected by Hispanic or Black race. Plasma 'metabolite' concentrations were lower in Black and Hispanic patients (by 43% and 82%, respectively) than in Caucasian patients following alvimopan administration. These changes are not considered to be clinically significant in surgical patients. Japanese healthy male subjects had an approximately 2-fold increase in plasma alvimopan concentrations, but no change in 'metabolite' pharmacokinetics. The pharmacokinetics of alvimopan have not been studied in subjects of other East Asian ancestry. Dosage adjustment in Japanese patients is not required [see Use in Specific Populations (8.8) ]. Male and Female Patients: There was no effect of sex on the pharmacokinetics of alvimopan or the 'metabolite'. Patients with Hepatic Impairment: Exposure to alvimopan following a single 12 mg dose tended to be higher (1.5- to 2-fold, on average) in patients with mild or moderate hepatic impairment (as defined by Child-Pugh Class A and B, n = 8 each) compared with healthy controls (n = 4). There were no consistent effects on the C max or half-life of alvimopan in patients with hepatic impairment. However, 2 of 16 patients with mild-to-moderate hepatic impairment had longer than expected half-lives of alvimopan, indicating that some accumulation may occur upon multiple dosing. The C max of the 'metabolite' tended to be more variable in patients with mild or moderate hepatic impairment than in matched normal subjects. A study of 3 patients with severe hepatic impairment (Child-Pugh Class C), indicated similar alvimopan exposure in 2 patients and an approximately 10-fold increase in C max and exposure in 1 patient with severe hepatic impairment when compared with healthy controls [see Warnings and Precautions (5.4) , Use in Specific Populations (8.6) ]. Patients with Renal Impairment: There was no relationship between renal function (i.e., creatinine clearance [CrCl]) and plasma alvimopan pharmacokinetics (C max , AUC, or half-life) in patients with mild (CrCl 51–80 mL/min), moderate (CrCl 31–50 mL/min), or severe (CrCl less than 30 mL/min) renal impairment (n = 6 each). Renal clearance of alvimopan was related to renal function; however, because renal clearance was only a small fraction (35%) of the total clearance, renal impairment had a small effect on the apparent oral clearance of alvimopan. The half-lives of alvimopan were comparable in the mild, moderate, and control renal impairment groups but longer in the severe renal impairment group. Exposure to the 'metabolite' tended to be 2- to 5-fold higher in patients with moderate or severe renal impairment compared with patients with mild renal impairment or control subjects. Thus, there may be accumulation of alvimopan and 'metabolite' in patients with severe renal impairment receiving multiple doses of ENTEREG. Patients with end-stage renal disease were not studied [see Warnings and Precautions (5.5) , Use in Specific Populations (8.7) ]. Patients with Crohn's Disease: There was no relationship between disease activity in patients with Crohn's disease (measured as Crohn's Disease Activity Index or bowel movement frequency) and alvimopan pharmacokinetics (AUC or C max ). Patients with active or quiescent Crohn's disease had increased variability in alvimopan pharmacokinetics, and exposure tended to be 2-fold higher in patients with quiescent disease than in those with active disease or in normal subjects. Concentrations of the 'metabolite' were lower in patients with Crohn's disease. Drug Interaction Studies Potential for Drugs to Affect Alvimopan Pharmacokinetics: Concomitant administration of ENTEREG with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan because ENTEREG is metabolized mainly by non-CYP enzyme pathway. No clinical studies have been performed to assess the effect of concomitant administration of inducers or inhibitors of cytochrome P450 enzymes on alvimopan pharmacokinetics. In vitro studies suggest that alvimopan and its 'metabolite' are substrates for p-glycoprotein. A population pharmacokinetic analysis did not reveal any evidence that alvimopan or 'metabolite' pharmacokinetics were influenced by concomitant medications that are mild-to-moderate p-glycoprotein inhibitors. No clinical studies of concomitant administration of alvimopan and strong inhibitors of p-glycoprotein (e.g., verapamil, cyclosporine, amiodarone, itraconazole, quinine, spironolactone, quinidine, diltiazem, bepridil) have been conducted. A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. However, plasma concentrations of the 'metabolite' were lower in patients receiving acid blockers or preoperative oral antibiotics (49% and 81%, respectively). No dosage adjustments are necessary in these patients. Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs: Alvimopan and its 'metabolite' are not inhibitors of CYP 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 in vitro at concentrations far in excess of those observed clinically. Alvimopan and its 'metabolite' are not inducers of CYP 1A2, 2B6, 2C9, 2C19, and 3A4. In vitro studies also suggest that alvimopan and its 'metabolite' are not inhibitors of p-glycoprotein. These in vitro findings suggest that ENTEREG is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition or induction of CYP enzymes or inhibition of p-glycoprotein.

20231210

15

3 DOSAGE FORMS AND STRENGTHS 12 mg blue, hard-gelatin capsules with "ADL2698" printed on both the body and the cap of the capsule. Capsules: 12 mg ( 3 )

Entereg alvimopan alvimopan alvimopan anhydrous POLYETHYLENE GLYCOL, UNSPECIFIED GELATIN, UNSPECIFIED ADL2698

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were 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 of 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). Mutagenesis: Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK +/− ) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test, or the mouse micronucleus test. The pharmacologically active 'metabolite' was negative in the Ames test, chromosome aberration test in CHO cells, and mouse micronucleus test. Impairment of Fertility: Alvimopan 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) was found to have no adverse effect on fertility and reproductive performance of male or female rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were 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 of 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). Mutagenesis: Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK +/− ) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test, or the mouse micronucleus test. The pharmacologically active 'metabolite' was negative in the Ames test, chromosome aberration test in CHO cells, and mouse micronucleus test. Impairment of Fertility: Alvimopan 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) was found to have no adverse effect on fertility and reproductive performance of male or female rats.

NDA021775

Entereg

alvimopan

67919-020

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 12 mg Capsule Blister Pack Carton NDC 67919-020-10 ENTEREG ® (alvimopan) capsules 12 mg Rx only HOSPITAL USE ONLY 30 capsules 12 mg unit dose pack PRINCIPAL DISPLAY PANEL - 12 mg Capsule Blister Pack Carton

Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA Manufactured by: Pharmaceutical Manufacturing Research Services, Inc., Horsham, PA 19044, USA For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2015-2022 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk3753-c-2205r005

17 PATIENT COUNSELING INFORMATION Recent Use of Opioids Inform patients that they must disclose long-term or intermittent opioid pain therapy to their healthcare provider, including any use of opioids in the week prior to receiving ENTEREG. Inform patients that recent use of opioids may make them more susceptible to adverse reactions to ENTEREG, primarily those limited to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Hospital Use Only Inform patients that ENTEREG is available only through a program called the Alvimopan REMS Program under a REMS that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG. ENTEREG is for hospital use only for no more than 7 days after their bowel resection surgery. Most Common Adverse Reaction Inform patients that the most common adverse reaction with ENTEREG in patients undergoing surgeries that include bowel resection is dyspepsia.

14 CLINICAL STUDIES The efficacy of ENTEREG in the management of postoperative ileus was evaluated in 6 multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: 5 US studies (Studies 1-4 and 6) and 1 non–US study (Study 5). Patients 18 years of age or older undergoing partial large or small bowel resection surgery with primary anastomosis for colorectal or small bowel disease, total abdominal hysterectomy, or radical cystectomy for bladder cancer (in this procedure, resected segments of bowel are used for reconstruction of the urinary tract) under general anesthesia were randomly assigned to receive oral doses of ENTEREG 12 mg or matching placebo. The initial dose was administered at least 30 minutes and up to 5 hours prior to the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first postoperative day and continued until hospital discharge or a maximum of 7 days. There were no limitations on the type of general anesthesia used, but intrathecal or epidural opioids or anesthetics were prohibited. All patients in the US studies were scheduled to receive intravenous patient-controlled opioid analgesia. In the non–US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration (intravenous or intramuscular). In all studies, there was no restriction on the type of opioid used or the duration of intravenous patient-controlled opioid analgesia. A standardized accelerated postoperative care pathway was implemented: early nasogastric tube removal (before the first postoperative dose); early ambulation (day following surgery); early diet advancement (liquids offered the day following surgery for patients undergoing bowel resection and by the third day following surgery for patients undergoing radical cystectomy; solids by the second day following surgery for patients undergoing bowel resection and by the fourth day following surgery for patients undergoing radical cystectomy), as tolerated. Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded. The primary endpoint for all studies was time to achieve resolution of postoperative ileus, a clinically defined composite measure of both upper and lower gastrointestinal recovery. Although both 2-component (GI2: toleration of solid food and first bowel movement) and 3-component (GI3: toleration of solid food and either first flatus or bowel movement) endpoints were used in all studies, GI2 is presented as it represents the most objective and clinically relevant measure of treatment response in patients undergoing surgeries that include a bowel resection. The time from the end of surgery to when the discharge order was written represented the length of hospital stay. In the 6 studies, 1,058 patients who underwent a surgery that included a bowel resection received placebo (not including 157 for total abdominal hysterectomy) and 1,096 patients received ENTEREG 12 mg (not including 143 for total abdominal hysterectomy). The efficacy of ENTEREG following total abdominal hysterectomy has not been established. Therefore, the following data are presented only for surgeries that included a bowel resection (i.e., bowel resection or radical cystectomy). Bowel Resection or Radical Cystectomy: A total of 2,154 patients underwent a surgery that included a bowel resection. The average age was 62 years, 54% were males, and 89% were Caucasian. The most common indications for surgery were colon or rectal cancer/malignancy, bladder cancer, and diverticular disease. In the non–US bowel resection study (Study 5), average daily postoperative opioid consumption was approximately 50% lower and the use of non-opioid analgesics substantially higher, as compared with the US bowel resection studies (Studies 1-4) for both treatment groups. During the first 48 hours postoperatively, the use of non-opioid analgesics was 69% compared with 4% for the non–US and US bowel resection studies, respectively. In each of the 6 studies, ENTEREG accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written as compared with placebo. Hazard ratios greater than 1 indicate a higher probability of achieving the event during the study period with treatment with ENTEREG than with placebo. Table 1 provides the Hazard Ratios, Kaplan Meier means, medians, and mean and median treatment differences (hours) in gastrointestinal recovery between ENTEREG and placebo. Table 1: GI2 Recovery (Hours) in Bowel Resection Patients Study No. Study 1 = 14CL314; Study 2 = 14CL313; Study 3 = 14CL308; Study 4 = 14CL302; Study 5 = SB-767905/001; Study 6 = 14CL403 ENTEREG 12 mg Placebo Treatment Difference Hazard Ratio (95% CI) Mean The estimates of the means and differences of treatment means are biased because of the censoring of events not achieved prior to the end of the observation period (10 days). The estimates of the differences of treatment means are likely to be underestimates. Median Mean Median Means Medians 1 92.0 80.0 111.8 96.6 19.8 16.6 1.533 (1.293, 1.816) 2 105.9 98.0 132.0 115.2 26.1 17.2 1.625 (1.256, 2.102) 3 116.4 101.8 130.3 116.8 14.0 15.0 1.365 (1.057, 1.764) 4 106.7 101.4 119.9 113.3 13.2 11.9 1.400 (1.035, 1.894) 5 98.2 92.8 108.8 95.9 10.6 3.1 1.299 (1.070, 1.575) 6 132.7 117.0 164.2 145.6 31.5 28.5 1.773 (1.359, 2.311) The Kaplan Meier estimate probabilities of patients receiving ENTEREG who achieved GI2 were numerically higher at all times throughout the study observation period compared with those of patients receiving placebo (see Figures 1 and 2 ). Figure 1: Time to GI2 Based on Results from Studies 1 through 5 Figure 2: Time to GI2 Based on Results from Study 6 In Studies 1–4, the differences between ENTEREG and placebo patient groups in median time to 'discharge order written' ranged from 6 to 22 hours, in favor of ENTEREG patients. The group differences in mean time to 'discharge order written' ranged from 13 to 21 hours. In Study 6, the median time difference was 19 hours in favor of ENTEREG patients (mean time difference 22 hours). ENTEREG did not reverse opioid analgesia as measured by visual analog scale pain intensity scores and/or amount of postoperative opioids administered across all 6 studies. There were no sex-, age-, or race-related differences in treatment effect. The incidence of anastomotic leak was low and comparable in patients receiving either ENTEREG or placebo (0.7% and 1.0%, respectively). Figure 1 Figure 2

8.5 Geriatric Use 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) ].

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary 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. Data Animal Data 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).

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment : Monitor patients with mild-to-moderate impairment for gastrointestinal adverse reactions. ( 8.6 ) Renal Impairment : Monitor patients with mild-to-severe impairment for gastrointestinal adverse reactions. ( 8.7 ) Race/Ethnicity : Monitor Japanese patients for gastrointestinal adverse reactions. ( 8.8 ) 8.1 Pregnancy Risk Summary 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. Data Animal Data 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). 8.2 Lactation Risk Summary 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. Data 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use 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) ]. 8.6 Hepatic Impairment 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) ]. 8.7 Renal Impairment 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) ]. 8.8 Race/Ethnicity 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) ].

16 HOW SUPPLIED/STORAGE AND HANDLING ENTEREG capsules, 12 mg, are blue, hard-gelatin capsules printed with "ADL2698" on both the body and the cap of the capsule. ENTEREG capsules are available in unit-dose packs of 30 capsules (30 doses) (NDC 67919-020-10) for hospital use only. Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY There was a greater incidence of myocardial infarction in alvimopan-treated patients compared to placebo-treated patients in a 12-month clinical trial, although a causal relationship has not been established. In short-term trials with ENTEREG ® , no increased risk of myocardial infarction was observed [see Warnings and Precautions (5.1) ]. Because of the potential risk of myocardial infarction with long-term use, ENTEREG is available only through a restricted program for short-term use (15 doses) under a Risk Evaluation and Mitigation Strategy (REMS) called the Alvimopan REMS Program [see Warnings and Precautions (5.1 , 5.2) ]. WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY See full prescribing information for complete boxed warning. Increased incidence of myocardial infarction was seen in a clinical trial of patients taking alvimopan for long-term use. ( 5.1 ) ENTEREG is available only through a restricted program for short-term use (15 doses) called the Alvimopan REMS Program. ( 5.1 , 5.2 )