Alvimopan

424.53

424.53

1312995-182-4

Q153V49P3Z

DTXSID60166035

A - Alimentary tract and metabolism

2933399090

89.9

1.7

Solid

1.166±0.06 g/cm3(Predicted)

210-213ºC

684.1±55.0 °C(Predicted)

367.5±31.5 °C

1.572

H2O: <0.1 mg/mL

Store at 25 deg C (77 deg F); excursions permitted to 15-30 deg C (59-86 deg F)

4.15X10-17 mm Hg at 25 deg C (est)

pKa1 = 3.71 (phenol); pKa2 = 10.66 (tertiary amine); pKa3 = -2.03

Zwitterion at physiological pH /Alvimpoan dihydrate/|Crystals; mp: 210-213 °C. Specific optical rotation = +51.8 deg at 25 °C/D (c = 1.0 in DMSO) /Alvimopan dihydrate/

Ⅲ

3077

9

P273-P280-P305 + P351 + P338-P337 + P313-P391

H315-H319-H400

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl alvimopan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Drug Name: Entereg; FDA Application No.: (NDA) 021775; Active Ingredient: Alvimopan; Company: Cubist Pharms; Original Approval or Tentative Approval Date: May 20, 2008; Chemical Type: 1 New molecular entity (NME); Review Classification: Standard review drug.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 35 companies from 1 notifications to the ECHA C&L Inventory.

Exposure to alvimopan may be substantially increased (tenfold) in patients with severe hepatic impairment (Child-Pugh class C). Use in such patients is not recommended.

80% to 90% bound in after entering systemic circulation.

EXPERIMENTAL: Alvimopan and its metabolite are distributed into milk in rats; it is unknown whether the drug or its metabolite is distributed into human milk.

Used to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis. Also investigated for use in the treatment of pain (acute or chronic).|FDA Label

Gastrointestinal Agents|Entereg is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis. /Included in US product label/|Although alvimopan has been studied for the management of postoperative ileus in women undergoing total abdominal hysterectomy under general anesthesia, efficacy of the drug for this indication has not been established to date. /NOT included in US product label/|/EXPL/ Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or= 25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or= 30 mg oral morphine/day were randomized to alvimopan 0.5 mg twice daily (BID), 1mg once daily (QD), 1 mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5 mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1 mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5 mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

/BOXED WARNING/ 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. 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 Entereg Access Support and Education (E.A.S.E.) Program [see|A numerically higher incidence of myocardial infarction was reported in patients receiving alvimopan 0.5 mg twice daily compared with placebo in a 12-month clinical study evaluating long-term use of the drug for management of opiate-induced bowel dysfunction in patients with chronic pain; a majority of events occurred 1 - 4 months after initiation of therapy. Similar results have not been observed in patients receiving short-term alvimopan therapy (12 mg twice daily for 7 days or less) following bowel resection. A causal relationship between myocardial infarction and alvimopan has not been established. Because of an increased risk of ischemic cardiac events with long-term therapy, alvimopan is available only to hospitals through a restricted distribution program (EASE program).|Use of alvimopan in patients undergoing surgical correction of complete bowel obstruction is not recommended.|Increased variability in alvimopan pharmacokinetics has been observed in patients with active or quiescent Crohn's disease; exposure to the drug generally was twofold higher in patients with quiescent disease compared with healthy individuals or patients with active disease. Concentrations of alvimopan's metabolite were lower in patients with Crohn's disease. However, the manufacturer states that dosage adjustments are not necessary.|For more Drug Warnings (Complete) data for ALVIMOPAN (12 total), please visit the HSDB record page.

Drugs used for their effects on the gastrointestinal system, as to control gastric acidity, regulate gastrointestinal motility and water flow, and improve digestion. (See all compounds classified as Gastrointestinal Agents.)

Alvimopan's high affinity for the peripheral mu-receptor leads to slower absorption dependent on dissociation from the receptor and subsequently low oral bioavailability of less than 7%.|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. Feces (via biliary excretion) & urine (35%)|30±10 L|402 ± 89 mL/min|Following oral administration of Entereg capsules in healthy volunteers, plasma alvimopan concentration peaked at approximately 2 hours postdose. No significant accumulation in alvimopan concentration was observed following twice daily (BID) dosing. The mean peak plasma concentration was 10.98 (+ or - 6.43) ng/mL and mean AUC0-12hr was 40.2 (+ or - 22.5) ng hr/mL after dosing of alvimopan at 12 mg BID for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). Plasma concentrations of alvimopan increased approximately proportionally with increasing doses between 6 and 18 mg, but less than proportionally from 18 to 24 mg.|Alvimopan and its metabolite are distributed into milk in rats; it is unknown whether the drug or its metabolite is distributed into human milk.|The steady state volume of distribution of alvimopan was estimated to be 30 + or - 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.|The average plasma clearance for alvimopan was 402 (+ or - 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 population pharmacokinetics of orally administered alvimopan and its primary metabolite in healthy subjects/special populations, and surgical patients at risk for ileus /was characterized/. Models were consistent with known physiology/pharmacology. Alvimopan's model had two compartments with first-order elimination. Metabolite was modeled with a catenary chain and lag for alvimopan's metabolism within the gut followed by absorption, one systemic compartment with first-order elimination. Weight, gender, and renal function did not affect alvimopan or metabolite. Steady-state alvimopan and metabolite concentrations were 87 and 40% higher, respectively, in patients. Alvimopan concentrations were 35% higher in the elderly, but were not affected by race, acid blockers, or antibiotics. Metabolite concentrations were 43 and 82% lower in African Americans and Hispanics, respectively, compared to Caucasians, 49% lower with acid blockers and 81% lower with preoperative antibiotics. Although alvimopan's pharmacokinetics was described with a traditional model, its metabolite required a novel model accommodating gut metabolism.

Alvimopan is primarily metabolized by intestinal flora to an active metabolite although it has no clinically significant contribution to the effects of the drug.|... There was no evidence that hepatic metabolism was a significant route 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.|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). ... There was a delay in the appearance of the metabolite, which had a median Tmax 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 Cmax for the metabolite after alvimopan 12 mg twice daily for 5 days was 35.73 + or - 35.29 ng/mL.

10 to 17 hours (gut metabolite: 10 to 18 hours)|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 10 to 18 hours.

Alvimopan competitively binds to mu-opioid receptor in the gastrointestinal tract but, unlike methylnaltrexone which relies upon it ionic charge, alvimopan owes its selectivity for peripheral receptors to its pharmacokinetics. Alvimopan binds to peripheral mu-receptors with a Ki of 0.2 ng/mL.|Alvimopan is a selective antagonist of the cloned human mu-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 mu-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 uM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels.|Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract mu-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations where alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of mu-opioid agonists.|This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human delta and guinea pig kappa opioid receptors. ADL 08-0011 had the highest mu receptor selectivity. With respect to their mu opioid receptor functional activity ([(35)S]GTPgammaS incorporation), methylnaltrexone had a positive intrinsic activity, consistent with partial agonism, unlike alvimopan and ADL 08-0011, which had negative intrinsic activities. Alvimopan, ADL 08-0011, and methylnaltrexone antagonized inhibitory responses mediated by the mu opioid agonist, endomorphin-1 (pA (2) values of 9.6, 9.4, and 7.6, respectively) and by U69593, a kappa opioid agonist (pA (2) values of 8.4, 7.2, and 6.7, respectively). In morphine-naive guinea pig ileum, methylnaltrexone reduced, while alvimopan and ADL 08-0011 increased, the amplitude of electrically evoked contractions and spontaneous mechanical activity. In tissue from morphine-dependent animals, alvimopan and ADL 08-0011 increased spontaneous activity to a greater degree than methylnaltrexone. The data suggested that alvimopan-induced contractions resulted predominantly from an interaction with kappa opioid receptors. It is concluded that alvimopan, ADL 08-0011, and methylnaltrexone differ in their in vitro pharmacological properties, particularly with respect to opioid receptor subtype selectivity and intrinsic activity.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

ADL 8-2698

Oral: Capsules: 12 mg (of anhydrous alvimopan), Entereg (Adolor, comarketed by GlaxoSmithKline).

Adolor Corporation, the manufacturer of Entereg, is based in Exton, PA. Adolor and GlaxoSmithKline, London, England.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients