Alvimopan

Class: GI Drugs, Miscellaneous
Chemical Name: [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R), 4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate
Molecular Formula: C25H32N2O4 • 2H2O
CAS Number: 170098-38-1
Brands: Entereg

Warning(s)

  • Only for short-term (15 doses) use in hospitalized patients. (See MI under Cautions.)1 2

  • For use only by hospitals enrolled in the Entereg Access Support and Education (EASE) program. (See Restricted Distribution Program under Dosage and Administration.)1 2

REMS:

FDA approved a REMS for alvimopan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of alvimopan and consists of the following: elements to assure safe use, communication plan, and implementation system. (See Restricted Distribution Program under Dosage and Administration.) See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Peripherally acting μ-opiate receptor antagonist.1 5 7 9 10 11 12 15 16

Uses for Alvimopan

Postoperative Ileus

Acceleration of upper and lower GI recovery following partial large or small bowel resection with primary anastomosis.1 2 3 9 10 11 12 19

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Efficacy for management of postoperative ileus in women undergoing total abdominal hysterectomy under general anesthesia not established to date.1 8

Alvimopan Dosage and Administration

General

Restricted Distribution Program

  • Available only to hospitals for short-term inpatient use through a restricted distribution program (Entereg Access Support and Education [EASE] program) because of an increased risk of ischemic cardiovascular events associated with long-term therapy.1 2 4 (See REMS and also see MI under Cautions.)

  • To enroll in the EASE program, hospitals must perform bowel resection surgeries and confirm that staff who prescribe, dispense, or administer alvimopan are provided with the EASE program enrollment kit.1 2 Hospitals must have systems, order sets, protocols, or other measures in place to limit use to short-term (≤15 doses) therapy in inpatients.2 3 Hospitals must ensure alvimopan is not dispensed for outpatient use and the drug is not transferred to a nonregistered hospital.1 2

  • Information about the EASE program is available at 866-423-6567 (866-4ADOLOR) or at .1 2 A database of registered hospitals is available on the website.2

Administration

Oral Administration

Preoperative dose administered in fasting patients in clinical studies; postoperative doses administered without regard to meals in studies.1

Dosage

Available as alvimopan dihydrate; dosage expressed in terms of anhydrous alvimopan.1

Adults

Postoperative Ileus
Oral

12 mg administered 0.5–5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery for a maximum of 7 days or until discharge.1

Administer no more than 15 doses.1 2 3

Prescribing Limits

Adults

Postoperative Ileus
Oral

Maximum of 15 doses over 7 days postoperatively in hospitalized patients.1

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 15 Not recommended in severe hepatic impairment.1 15 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required in patients with mild to severe renal impairment.1 15 Not recommended in patients with end-stage renal disease.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment based on age not needed.1

Crohn’s Disease

No dosage adjustment required.1 8 (See Special Populations under Pharmacokinetics.)

Cautions for Alvimopan

Contraindications

  • Therapeutic doses of opiates for >7 consecutive days immediately prior to alvimopan administration.1 2

Warnings/Precautions

Restricted Distribution Program

Only for short-term (15 doses) use in hospitalized patients.1 2 For use only by hospitals enrolled in the EASE program.1 2 (See Restricted Distribution Program under Dosage and Administration.)

MI

May be associated with increased incidence of MI when used long term;1 2 3 4 7 not found with short-term (i.e., ≤7 days) use following bowel resection.1 3 4 Causal relationship not established.1 (See Boxed Warning and see Restricted Distribution Program under Dosage and Administration.)

Recent Opiate Use

Increased sensitivity to alvimopan possible with recent exposure to opiates; manifests principally as GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea).1 Use caution in patients who have received >3 doses of an opiate within 1 week prior to surgery.1 (See Contraindications under Cautions.)

Bowel Obstruction

Not recommended for use in patients undergoing surgical correction of complete bowel obstruction.1

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 15

Hepatic Impairment

Slight increase in plasma alvimopan concentrations possible in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 Monitor for adverse effects (e.g., diarrhea, abdominal pain or cramping) that may indicate alvimopan or metabolite accumulation; discontinue if such effects occur.1 15 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 8 15 Substantially increased plasma concentrations possible.1

Renal Impairment

Monitor for possible adverse effects in patients with renal impairment.1 15 Closely monitor those with severe renal impairment for adverse effects (e.g., diarrhea, abdominal pain or cramping) that may indicate elevated alvimopan or metabolite concentrations; discontinue if such effects occur.1 15 (See Renal Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Not studied in patients with end-stage renal disease.1 Use not recommended.1

Common Adverse Effects

Constipation,1 hypokalemia,1 11 flatulence,1 dyspepsia,1 anemia,1 back pain,1 urinary retention.1

Interactions for Alvimopan

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 3A4, 2D6, or 2E1 or induce isoenzymes 1A2, 2B6, 2C9, 2C19, or 3A4.1 15

Alvimopan does not inhibit P-glycoprotein; alvimopan and its metabolite are substrates for P-glycoprotein.1 15

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1 15

Drugs Affecting or Affected by P-glycoprotein Transport

Pharmacokinetic interactions unlikely with mild-to-moderate P-glycoprotein inhibitors.1 15 The effect of potent P-glycoprotein inhibitors is unknown.1 15

Pharmacokinetic interactions with P-glycoprotein substrates are unlikely.1 15

Specific Drugs

Drug

Interaction

Comments

Antibiotics (preoperative oral antibiotics)

Decreased plasma concentrations of alvimopan metabolite; no alteration in alvimopan pharmacokinetics1

No dosage adjustment necessary1

Histamine H2-receptor antagonists

Decreased plasma concentrations of alvimopan metabolite; no alteration in alvimopan pharmacokinetics1 8

No dosage adjustment necessary1

Morphine

Pharmacokinetic interaction unlikely (no change in morphine pharmacokinetics);1 8 15 alvimopan does not reverse analgesic effects1

No dosage adjustment necessary1 8 15

Proton-pump inhibitors

Decreased plasma concentrations of alvimopan metabolite; no alteration in alvimopan pharmacokinetics1 8

No dosage adjustment necessary1

Alvimopan Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability averages 6% (range 1–19%).1 7 11

Food

High-fat meal decreases rate and extent of absorption.1

Distribution

Extent

Does not readily cross blood-brain barrier.1 6 7 14 15 16

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Alvimopan: 80%.1 Metabolite: 94%.1 Bound to albumin.1

Elimination

Metabolism

Metabolized by intestinal flora to active metabolite;1 metabolite not required for pharmacologic activity.8 16

No substantial hepatic metabolism.1

Elimination Route

Excreted principally via biliary secretion (65%) and in the urine (35%).1 16

Half-life

10–17 hours.1

Special Populations

Exposure to alvimopan is 1.5-fold to twofold higher in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); accumulation possible after multiple doses.1 Exposure may be increased approximately tenfold in patients with severe hepatic impairment (Child-Pugh class C).1

Exposure to metabolite is twofold to fivefold higher in patients with moderate or severe renal impairment.1 Alvimopan half-life is prolonged in patients with severe renal impairment.1 Accumulation of alvimopan and metabolite is possible after multiple doses in patients with severe renal impairment.1 Not studied in patients with end-stage renal disease.1

Exposure to alvimopan is twofold higher in patients with quiescent Crohn’s disease relative to healthy individuals or those with active Crohn’s disease; metabolite concentrations are lower in patients with Crohn’s disease.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Actions

  • Peripherally acting μ-opiate receptor antagonist.1 5 7 9 10 11 12 15 16

  • Blocks μ-opiate receptors in GI tract, thereby antagonizing peripheral inhibitory effects of opiates on GI motility and improving GI function.1 7 14 16

  • Does not readily cross the blood-brain barrier; therefore, does not affect opiate analgesic activity or precipitate opiate withdrawal, unlike centrally active opiate antagonists (e.g., naltrexone, naloxone).1 6 7 14 15 16

  • Exhibits greater affinity for μ-opiate receptors than for δ- and κ-opiate receptors;7 14 15 16 a more potent μ-opiate receptor antagonist than naloxone.14 15

  • Does not possess opiate agonist activity 1 or affinity for nonopiate receptors, including α1-, α2-, and β-adrenergic; dopamine types 1 and 2 (D1, D2); serotonin type 2 (5-hydroxytryptamine [5-HT2A]); histamine (H1); GABA; benzodiazepine; and muscarinic receptors.15 16

Advice to Patients

  • Importance of informing clinicians of long-term or intermittent opiate therapy, including any use of opiates in the week prior to receiving alvimopan.1 Potential for alvimopan to precipitate GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea) in patients who have recently received opiate therapy; importance of informing clinician if such adverse events occur.1

  • Importance of informing patients that alvimopan is indicated for hospital use only and for no more than 7 days following bowel resection.1

  • Advise patients that the most common adverse effects of alvimopan are constipation, dyspepsia, and flatulence.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of alvimopan is restricted.1 2 (See Restricted Distribution Program under Dosage and Administration.)

Alvimopan

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

12 mg (of anhydrous alvimopan)

Entereg

Adolor, (comarketed by GlaxoSmithKline)

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 27, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Adolor Corporation. Entereg (alvimopan) capsules prescribing information. Exton, PA; 2008 May.

2. Adolor Corporation. The EASE program. From Entereg website: (). Accessed 2008 Aug 28.

3. Food and Drug Administration. FDA News: FDA approves Entereg to help restore bowel function following surgery. Rockville, MD; 2008 May 20. From FDA website: .

4. Food and Drug Administration, Center for Drug Evaluation and Research. Application number 21-775: Risk assessment and risk mitigation review(s): Entereg (alvimopan). 2008 May 2. From FDA website: .

5. Maron DJ, Fry RD. New therapies in the treatment of postoperative ileus after gastrointestinal surgery. Am J Ther. 2008; 15:59-65. [PubMed 18223355]

6. McNicol ED, Boyce D, Schumann R et al. Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database Syst Rev. 2008; 2:CD006332. [PubMed 18425947]

7. Kraft MD. Emerging pharmacologic options for treating postoperative ileus. Am J Health-Syst Pharm. 2007; 64 (Suppl 13):S13-20. [PubMed 17909271]

8. GlaxoSmithKline, Research Triangle Park, NC: Personal communication.

9. Büchler MW, Seiler CM, Monson JRT et al. Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study. Aliment Pharmacol Ther. 2008; 28:312-25.

10. Delaney CP, Weese JL, Hyman NH et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005; 48:1114-1129. [PubMed 15906123]

11. Viscusi ER, Goldstein S, Witkowski T et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery. Surg Endosc. 2006; 20:64-70. [PubMed 16333556]

12. Wolff BG, Michelassi F, Gerkin TM et al. Alvimopan, a novel, peripherally acting opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004; 240:728-735. [PubMed 15383800]

13. Steinbrook RA. An opioid antagonist for postoperative ileus. N Engl J Med. 2001; 345:988-9. [PubMed 11575292]

14. Schmidt WK. Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg. 2001; 182 (Suppl 5A):27S-38S. [PubMed 11755894]

15. Leslie JB. Alvimopan for the management of postoperative ileus. Ann Pharmacother. 2005; 39:1502-10. [PubMed 16076918]

16. Leslie JB. Alvimopan: a peripherally acting mu-opioid receptor antagonist. Drugs Today. 2007; 43:611-625. [PubMed 17940638]

17. Reichle FM, Conzen PF. Methylnaltrexone, a new peripheral μ-receptor antagonist for the prevention and treatment of opioid-induced extracerebral side effects. Curr Opin Investig Drugs. 2008; 9:90-100. [PubMed 18183536]

18. Beattie DT, Cheruvu M, Mai N et al. The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone. Naunyn Schmiedebergs Arch Pharmacol. 2007; 375:205-20. [PubMed 17340127]

19. Ludwig K, Enker WE, Delaney CP et al. Gastrointestinal tract recovery in patients undergoing bowel resection: resluts of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway. Arch Surg. 2008; 43:1098-1105.

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