Alvimopan

1 INDICATIONS AND USAGE Alvimopan capsules are indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. Alvimopan capsules are 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 )

2 DOSAGE AND ADMINISTRATION For hospital use only. The recommended adult dosage of alvimopan capsules 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 alvimopan capsules. Alvimopan capsules 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 alvimopan capsules. ( 2 )

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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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 alvimopan 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 alvimopan 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 alvimopan-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 (alvimopan, 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.

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 alvimopan 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 alvimopan. 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 alvimopan 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 alvimopan 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 to 80 mL/min), moderate (CrCl 31 to 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 alvimopan. 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 alvimopan with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan because alvimopan 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 alvimopan is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition or induction of CYP enzymes or inhibition of p-glycoprotein.