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Criteria for Outpatient Use Guidelines

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Pramlintide (Symlin®)

[Developed, February 2006; Revised, May 2006; January 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

Pramlintide, a synthetic analog of human amylin, is FDA-approved for use as adjunct therapy in type 1 diabetics using mealtime insulin who are not adequately controlled with optimal insulin therapy, as well as type 2 diabetics not adequately controlled with optimal insulin therapy, including mealtime insulin, with or without concomitant sulfonylurea and/or metformin therapy.  Amylin is a neuroendocrine hormone secreted concurrently with insulin in response to food intake to decrease hepatic glucose output and slow gastric emptying, which results in reduced carbohydrate absorption and lower postprandial glucose levels. Similarly, pramlintide works by delaying gastric emptying, decreasing postprandial increases in glucagon levels, and causing satiety which promotes decreased caloric intake and potential weight loss.  Recommended pramlintide dosages are summarized in Table 1.

Table 1
Recommended Pramlintide Dosages
Diabetes Type Initial Dose Dosage Titration Maximum Dose
Type 1 Diabetes Mellitus 15 mcg subcutaneously immediately prior to each major meal 15 mcg increments 60 mcg subcutaneously immediately prior to each major meal
Type 2 Diabetes Mellitus 60 mcg subcutaneously immediately prior to each major meal 60 mcg increments 120 mcg subcutaneously immediately prior to each major meal

In type 1 diabetics, dosage titrations should be initiated when clinically significant nausea has been absent for at least 3 days. If nausea persists with the 45 mcg or 60 mcg dose, the dosage may be reduced to 30 mcg. If patients do not tolerate the 30 mcg dose, discontinuing therapy may be necessary. In type 2 diabetics, dosage titrations may be initiated when significant nausea is absent for 3 to 7 days. If the 120 mcg dose is not tolerated, the dosage may be decreased to 60 mcg. In both type 1 and type 2 diabetics, pre-prandial rapid or short-acting insulin dosages, including fixed-mixed insulin, should be decreased by 50% when adjunctive pramlintide therapy is instigated to minimize hypoglycemic episodes. Insulin doses may be titrated upward as needed when a maintenance pramlintide dose is established.

Patient profiles containing pramlintide prescription quantities of greater than 2 vials per month for type 1 diabetics or 4 vials per month for type 2 diabetics will be reviewed.

Pramlintide should not be administered to patients who:

  • have been diagnosed with gastroparesis within the last 2 years
  • have recurrent episodes of hypoglycemia requiring intervention in the last 6 months and/or hypoglycemia unawareness
  • have an HbA1c > 9%
  • require therapy with medications that stimulate gastrointestinal motility
  • are poorly compliant with insulin regimens and/or self-monitoring of blood glucose serum concentrations

Pediatrics
Safety and efficacy of pramlintide injections in pediatric patients have not been established.  However, a few small, short-term crossover studies have evaluated pramlintide use in adolescents with type 1 diabetes and demonstrated significant reductions in postprandial hyperglycemia.  Further long-term studies are necessary to solidify results.

2. Duration of Therapy

Pramlintide is indicated for the management of diabetes mellitus and may be continued indefinitely based on patient need to achieve desired glucose control.

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 pramlintide. 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:

a. Drugs that Slow Gastrointestinal Motility (e.g., alosetron, antimuscarinics, diphenoxylate, loperamide, octreotide, opiate agonists, tricyclic antidepressants)  [clinical significance level: 2-major (Clinical Pharmacology)]

Adjunctive administration of pramlintide with agents that slow gastrointestinal motility may produce additive pramlintide pharmacologic effects and the potential for additional blood glucose reductions and increased risk of hypoglycemia.  Patient profiles containing concurrent prescriptions for pramlintide and drugs that slow gastrointestinal motility will be reviewed as this treatment combination is not recommended by the manufacturer due to the absence of safety/efficacy clinical trial data.

b. Gastric Stimulants (e.g., metoclopramide, tegaserod, erythromycin) [clinical significance level: 2- major (Clinical Pharmacology)]

Concurrent administration of pramlintide with gastric stimulants such as metoclopramide may result in attenuated clinical effects of both agents.  The manufacturer recommends that the pramlintide/gastric stimulant drug combination be avoided due to the absence of safety/efficacy clinical trial data.  Patient profiles containing concurrent prescriptions for pramlintide and gastric stimulants will be reviewed.

c. Alpha-Glucosidase Inhibitors [e.g., acarbose (Precose®), miglitol (Glyset®)]   [clinical significance level: 3-moderate (Clinical Pharmacology)]

Alpha-glucosidase inhibitors are known to slow nutritive absorption.  Pramlintide administered concurrently with alpha-glucosidase inhibitors may potentially produce enhanced pharmacologic effects leading to additional reductions in blood glucose and increased risk of hypoglycemia.  Concomitant administration of pramlintide and alpha-glucosidase inhibitors is not recommended by the manufacturer.    Patient profiles containing concurrent prescriptions for pramlintide and alpha-glucosidase inhibitors will be reviewed.

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

Pramlintide 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 oral analgesics, antibiotics, and oral contraceptives.  If concurrent therapy with pramlintide and oral therapy requiring rapid absorption is necessary, the oral agent should be administered either one hour before or two hours after the pramlintide injection to maintain optimal therapeutic effects. 

e.   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 pramlintide 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 insulin dosages adjusted as necessary if this drug combination is required to minimize excessive hypoglycemia and associated adverse events.

References

  1. Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.  Accessed January 21st, 2010.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2010. Available at: http://www.clinicalpharmacology.com. Accessed January 21st, 2010.
  3. Pramlintide (Symlin®) Package Insert.  Amylin Pharmaceuticals, Inc., July 2008.
  4. Drug Facts and Comparisons.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2010.  Available at:  http://clineguide.com.  Accessed January 21st, 2010.
  5. 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.
  6. Singh-Franco D, Robles G, Gazze D.  Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus.  Clin Ther. 2007;29(4):535-62.
  7. Hoogwerf BJ, Doshi KB, Diab D.  Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk. Vasc Health Risk Manag. 2008;4(2):355-62.
  8. Anonymous.  Pramlintide (Symlin) for diabetes.  Med Lett Drugs Ther. 2005;47:43-4.
  9. Ratner RE, Dickey R, Fineman M, et al.  Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus:  a 1-year, randomized controlled trial.  Diabet Med. 2004;21:1204-12.
  10. Hollander PA, Levy P, Fineman MS, et al.  Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes:  a 1-year randomized controlled trial.  Diabetes Care. 2003;26:784-90.
  11. Whitehouse F, Kruger DF, Fineman M, et al.  A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes.  Diabetes Care. 2002;25:724-30.
  12. Kruger DF, Gloster MA.  Pramlintide for the treatment of insulin-requiring diabetes mellitus.  Drugs. 2004;64:1419-32.
  13. Kishiyama CM, Burdick PL, Cobry EC, et al.  A pilot trial of pramlintide home usage in adolescents with type 1 diabetes. Pediatrics. 2009;124(5):1344-7.
  14. Chase HP, Lutz K, Pencek R, Zhang B, Porter L. Pramlintide lowered glucose excursions and was well-tolerated in adolescents with type 1 diabetes: results from a randomized, single-blind, placebo-controlled, crossover study.  J Pediatr. 2009;155(3):369-73.
  15. Hassan K, Heptulla RA.  Reducing postprandial hyperglycemia with adjuvant premeal pramlintide and postmeal insulin in children with type 1 diabetes mellitus. Pediatr Diabetes. 2009;10(4):264-8.

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.