Texas Health and Human Services Commission
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Criteria for Outpatient Use Guidelines

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Exenatide (Byetta®)

[Developed, February 2006; Revised, May 2006; August 2006, January 2010; February 2010]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
Incretin hormones such as glucagon-like peptide (GLP-1) are peptides released from gastrointestinal tract cells in response to food ingestion that stimulate glucose-dependent insulin release from the pancreas, decrease glucagon production, and slow gastric emptying. The incretin mimetic, exenatide, a GLP-1 agonist, is FDA-approved as adjunct therapy to diet and exercise to improve glycemic control in adult type 2 diabetics. The initial exenatide dose is 5 mcg subcutaneously twice daily within 60 minutes prior to the morning and evening meals, or prior to the two main meals of the day spaced six hours or more apart. Doses may be increased to 10 mcg twice daily prior to the morning and evening meals (or the two main meals of the day, spaced six hours or more apart) after one month of therapy based on clinical response. Exenatide is packaged as either a 5 mcg per dose or 10 mcg per dose prefilled pen containing 60 doses. Patient profiles containing prescriptions for more than one exenatide pen per month will be reviewed.

Exenatide should not be administered to patients:

  • with type 1 diabetes
  • experiencing diabetic ketoacidosis
  • receiving insulin therapy
    • with a history of pancreatitis
    • experiencing hypersensitivity reactions to exenatide or its components
  • with severe gastrointestinal disease, including gastroparesis
  • with severe renal impairment (CrCl < 30 ml/min) and/or end-stage renal disease
  • without HgA1c measurements during the previous 6 months

Pediatrics
Exenatide is not recommended for use in children as safety and efficacy of exenatide injections in pediatric patients have not been established.

2. Duration of Therapy

Exenatide is indicated for the management of type 2 diabetes mellitus and may be continued indefinitely, as control of blood glucose is a chronic, lifelong process.

3.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

The following drug-drug interactions are considered clinically relevant for exenatide. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

Oral Drugs With Hypoglycemic Effects (e.g., oral antidiabetic agents, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), disopyramide, fibric acid derivatives, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates, sulfonamide antibiotics) [clinical significance level: 3-moderate (Clinical Pharmacology)]

Concurrent administration of exenatide with either oral antidiabetic agents or other agents that promote hypoglycemic activity may result in enhanced hypoglycemic pharmacologic and adverse effects. Blood glucose concentrations should be closely monitored and dosages adjusted as necessary if this drug combination is required to minimize excessive hypoglycemia and associated adverse events.

Orally Administered Drugs Requiring Threshold Concentrations for Effect (e.g., antibiotics, oral contraceptives) [clinical significance level: 4-minor (Clinical Pharmacology)]

Exenatide delays gastric emptying, which may alter the rate and extent of absorption of orally administered drugs. This may adversely impact the effectiveness of drugs for which threshold concentrations are necessary for effect, such as analgesics, antibiotics, and oral contraceptives. If concurrent therapy with exenatide and oral therapy requiring rapid absorption is necessary, the oral agent should be administered at least one hour before the exenatide injection to maintain optimal therapeutic effects. If these oral medications are given with food, administer the oral agent with a snack at a time when an exenatide dose is not necessary.

Drugs that Slow Gastrointestinal Motility (e.g., alosetron, antimuscarinics, diphenoxylate, loperamide, octreotide, opiate agonists, tricyclic antidepressants) [clinical significance level –unknown]

Adjunctive administration of exenatide with agents that slow gastrointestinal motility may produce additive exenatide pharmacologic effects and the potential for additional blood glucose reductions and increased risk of hypoglycemia. Concurrent prescriptions for exenatide and drugs that slow gastrointestinal motility should be avoided until further clinical data become available.

Gastric Stimulants (e.g., metoclopramide, tegaserod, erythromycin) [clinical significance level: 3-moderate (Clinical Pharmacology)]

Concurrent administration of exenatide with gastric stimulants such as metoclopramide may
result in attenuated clinical activity of both agents due to competing effects on gastric emptying. Hypoglycemic effects may be modified; therefore, blood glucose concentrations
should be closely monitored and antidiabetic agent doses, including exenatide doses, should be
adjusted as necessary.

Warfarin [clinical significance level: 3-moderate (Clinical Pharmacology)]; moderate (DrugReax)]

Concurrent administration of exenatide and warfarin may result in an elevated INR and increased bleeding risk. While a pharmacokinetic study did not demonstrate appreciable effects on INR or Cmax when exenatide and warfarin were given concomitantly in healthy volunteers, postmarketing reports have documented increased INR with accompanying bleeding in some cases when this drug combination is utilized. If concurrent exenatide-warfarin therapy is necessary, INR should be closely monitored and patients should be observed for signs and symptoms of bleeding, with warfarin dosages adjusted as necessary.

References

  1. Exenatide (Byetta®) Package Insert. Amylin Pharmaceuticals, Inc., October 2009.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2010. Available at: http://www.clinicalpharmacology.com. Accessed January 22nd, 2010.
  3. AHFS Drug Information 2009 [book online]. Jackson, WY: Teton Data Systems, Version 6.6.0, 2009. Based on: McEvoy GK, editor. AHFS drug information 2009. Bethesda (MD): American Society of Health-System Pharmacists; 2009. Stat!Ref Electronic Medical Library.
  4. Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu. Accessed January 22nd, 2010.
  5. U.S. Department of Health and Human Services. U.S. Food and Drug Administration. Exenatide (marketed as Byetta) information. (11/2/2009). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/uc m113705.htm. Accessed January 22nd, 2010.
  6. Joy SV, Rodgers PT, Scates AC. Incretin mimetics as emerging treatments for type 2 diabetes. Ann Pharmacother. 2005;39:110-8.
  7. Nauck MA, Meier JJ. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul Pept. 2005;128:135-48.
  8. Anonymous. Exenatide (Byetta) for type 2 diabetes. Med Lett Drugs Ther. 2005;47:45-6.
  9. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
  10. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-35.
  11. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-91.
  12. Bray GM. Exenatide. Am J Health Syst Pharm. 2006;63:411-8.
  13. Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo- controlled, parallel-group study. Clin Ther. 2008;30(8):1448-60.
  14. Zarowitz BJ, Conner C. The intersection of safety and adherence: new incretin-based therapies in patients with type 2 diabetes mellitus. Pharmacotherapy. 2009;29(12 Pt 2):55S-67S.
  15. Davies MJ, Donnelly R, Barnett AH, et al. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab. 2009;11(12):1153-62.
  16. Bunck MC, Diamant M, Corner A, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care. 2009;32(5):762-8.

 

Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.