Alvimopan

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 )

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 )

WARNINGS AND PRECAUTIONS • Myocardial Infarction : A higher number of myocardial infarctions was reported in patients treated with alvimopan 0.5 mg twice daily compared with placebo in a 12-month study in patients treated with opioids for chronic non-cancer pain, although a causal relationship with long-term use has not been established. ( 5.1 ) • Gastrointestinal Adverse Reactions in Opioid Tolerant Patients : Patients recently exposed to opioids may be more sensitive to the effects of alvimopan and experience gastrointestinal adverse reactions (e.g., abdominal pain, nausea and vomiting, and diarrhea). ( 5.3 ) • Patients with Severe Hepatic Impairment : Increased risk of serious adverse reactions due to higher plasma concentrations; use is not recommended. ( 5.4 , 8.6 ) • Patients with End-Stage Renal Disease : No studies have been conducted; use is not recommended. ( 5.5 , 8.7 ) • Patients with Complete Gastrointestinal Obstruction : No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction; use is not recommended. ( 5.6 ) • Patients with Pancreatic and Gastric Anastomoses : No studies have been conducted; use is not recommended. ( 5.7 ) 5.1 Potential Risk of Myocardial Infarction with Long-Term Use There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic non-cancer pain (alvimopan 0.5 mg, n = 538; placebo, n = 267). In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan in patients treated with opioids for chronic pain, nor in patients treated within the surgical setting, including patients undergoing surgeries that included bowel resection who received alvimopan 12 mg twice daily for up to 7 days (the indicated dose and patient population; alvimopan 12 mg, n = 1,142; placebo, n = 1,120). A causal relationship with alvimopan with long-term use has not been established. Alvimopan capsules are available only through a program under a REMS that restricts use to enrolled hospitals [see Warnings and Precautions ( 5.2 )] . 5.2 Alvimopan REMS Program Alvimopan capsules are available only through a program called the Alvimopan REMS Program that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of alvimopan capsules [see Warnings and Precautions ( 5.1 )] . Notable requirements of the Alvimopan REMS Program include the following: Alvimopan capsules are available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the Alvimopan REMS Program may use alvimopan capsules. To enroll in the Alvimopan REMS Program, an authorized hospital representative must acknowledge that: • hospital staff who prescribe, dispense, or administer alvimopan capsules have been provided the educational materials on the need to limit use of alvimopan capsules to short-term, inpatient use; • patients will not receive more than 15 doses of alvimopan capsules; and • alvimopan capsules will not be dispensed to patients after they have been discharged from the hospital. Further information is available at www.alvimopanREMS.com or 1-800-278-0340. 5.3 Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists, such as alvimopan. Since alvimopan acts peripherally, clinical signs and symptoms of increased sensitivity would be related to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Patients receiving more than 3 doses of an opioid within the week prior to surgery were not studied in the postoperative ileus clinical trials. Therefore, if alvimopan is administered to these patients, they should be monitored for gastrointestinal adverse reactions. Alvimopan is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking alvimopan [see Contraindications ( 4 )] . 5.4 Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment Patients with severe hepatic impairment may be at higher risk of serious adverse reactions (including dose-related serious adverse reactions) because up to 10-fold higher plasma concentrations of alvimopan have been observed in such patients compared with patients with normal hepatic function. Therefore, the use of alvimopan is not recommended in this population [see Use in Specific Populations ( 8.6 )] . 5.5 End-Stage Renal Disease No studies have been conducted in patients with end-stage renal disease. Alvimopan is not recommended for use in these patients [see Use in Specific Populations ( 8.7 )] . 5.6 Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. Alvimopan is not recommended for use in these patients. 5.7 Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses Alvimopan has not been studied in patients having pancreatic or gastric anastomosis. Therefore, alvimopan is not recommended for use in these patients.

CONTRAINDICATIONS Alvimopan capsules are contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking alvimopan capsules [see Warnings and Precautions ( 5.3 )] . Patients who have taken therapeutic doses of opioids for more than 7 consecutive days prior to taking alvimopan capsules. ( 4 )

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 alvimopan. 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 alvimopan.

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.

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.