Nateglinide

Pronunciation

Class: Meglitinides
VA Class: HS502
Chemical Name: (–)-N-[(trans-4-Isopropyl-cyclohexyl)carbonyl]-d-phenylalanine
Molecular Formula: C19H27NO3
CAS Number: 105816-04-4
Brands: Starlix

Introduction

Nateglinide, a meglitinide derivative, is a short-acting, insulinotropic antidiabetic agent.

Uses for Nateglinide

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone and who have not been treated chronically with other oral antidiabetic agents.1 5

Slideshow: Prediabetes - Am I at Risk?

May be used in combination with metformin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with metformin monotherapy.1 Should be added to, not substituted for, metformin therapy in such patients.1

Should not be added to or substituted for other insulin secretagogues (e.g., sulfonylureas) in patients not controlled adequately with such drugs.1 5

Not indicated for type 1 diabetes mellitus or ketoacidosis.1

Nateglinide Dosage and Administration

Administration

Oral Administration

Administer 3 times daily 1–30 minutes before meals to reduce the risk of hypoglycemia.1

If a meal is skipped, the dose of nateglinide should be omitted.1

Dosage

Adults

Diabetes Mellitus
Oral

120 mg 3 times daily before meals.1 For patients who are near their goal glycosylated hemoglobin (HbA1c) when nateglinide therapy is initiated, 60 mg 3 times daily before meals.1 5

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild impairment.1 Use with caution in patients with moderate or severe impairment.1

Renal Impairment

No dosage adjustment necessary.1

Geriatric Patients

No dosage adjustment necessary.1

Cautions for Nateglinide

Contraindications

  • Known hypersensitivity to nateglinide or any ingredient in the formulation.1

  • Type 1 (insulin-dependent) diabetes mellitus or diabetic ketoacidosis.1

Warnings/Precautions

General Precautions

Hypoglycemia

Potential for hypoglycemia.1 3 4 Malnourished or geriatric patients and patients with adrenal or pituitary insufficiency may be particularly susceptible.1 Strenuous exercise, alcohol ingestion, insufficient caloric intake acutely or chronically, or use in combination with other antidiabetic agents may increase risk.1 Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy or in those receiving β-adrenergic blocking agents.1

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).1 Temporary discontinuance of nateglinide and administration of insulin may be required.1

Efficacy of nateglinide may decrease over time.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; use not recommended.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

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

Hepatic Impairment

Use with caution in patients with moderate to severe hepatic impairment.1

Common Adverse Effects

Upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, diarrhea, accidental trauma, bronchitis, cough, hypoglycemia.1

Interactions for Nateglinide

Extensively metabolized by CYP2C9 and, to a lesser extent, CYP3A4.1 3 Based on in vitro data, the drug is a potential inhibitor of CYP2C9 in vivo.1 (See Specific Drugs under Interactions.)

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered metabolism of nateglinide) when administered concomitantly with inhibitors or inducers of CYP2C9 or CYP3A4.1

Drugs That May Increase Hypoglycemic Effects

Pharmacodynamic interaction with such drugs as MAO inhibitors, nonselective β-adrenergic-blocking agents, and NSAIAs (e.g., salicylates).1 Observe patient closely for altered glycemic control when these drugs are initiated or withdrawn in patients receiving nateglinide.1

Drugs That May Antagonize Hypoglycemic Effects

Pharmacodynamic interaction with such drugs as corticosteroids, sympathomimetic agents, thiazide diuretics, and thyroid hormones.1 Observe patient closely for altered glycemic control when these drugs are initiated or withdrawn in patients receiving nateglinide.1

Protein-bound Drugs

Potential pharmacokinetic interaction, but no important effects on nateglinide protein binding observed in vitro with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, aspirin, tolbutamide, and metformin.1 In addition, nateglinide had no influence in vitro on protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, aspirin, or tolbutamide.1

Specific Drugs

Drug

Interaction

Diclofenac

No clinically important pharmacokinetic interaction observed with single dose of diclofenac1

Digoxin

No clinically important pharmacokinetic interaction observed with single dose of digoxin1

Glyburide

No clinically important pharmacokinetic interaction observed with single dose of glyburide1

Metformin

No clinically important pharmacokinetic interaction observed1

Tolbutamide

In vitro inhibition of tolbutamide metabolisma

Warfarin

No clinically important pharmacokinetic interaction observed with single dose of warfarin1

Nateglinide Pharmacokinetics

Absorption

Bioavailability

Approximately 73% (absolute),1 b c indicating a modest first-pass effect.b c

Onset

Stimulates pancreatic insulin secretion within 20 minutes following oral administration.1

Duration

Peak insulin concentrations occur approximately 1 hour after dose and return to baseline by 4 hours.1

Food

When administered with or after meals, food delays absorption, as evidenced by a decrease in peak plasma concentration and prolongation of the time to peak plasma concentration; however, extent of absorption is not affected.1 When nateglinide is administered 10 minutes prior to a liquid meal, peak plasma drug concentrations are reduced appreciably.a Pharmacokinetics are not affected by the composition of a meal (e.g., high protein, fat, carbohydrate).a

Distribution

Extent

Distributed into milk in animals; not known whether the drug distributes into milk or crosses the placenta in humans.1

Plasma Protein Binding

98%.1

Elimination

Metabolism

Predominantly metabolized by CYP2C9 (70%) and CYP3A4 (30%).1 The major metabolites are less potent than the parent drug.1 The isoprene minor metabolite is as potent as the parent compound.1

Elimination Route

In urine, principally as unchanged drug and metabolites.1 b

Half-life

Approximately 1.5 hours.1 2

Special Populations

Mild hepatic insufficiency increases the peak and total exposure of nateglinide by 30%.1

Stability

Storage

Oral

Tablets

Tight containers at 25°C; may be exposed to 15–30°C.a

Actions

  • Insulinotropic antidiabetic agent (a d-phenylalanine derivative).1 2 3 4 5 8 c

  • Requires functioning pancreatic β-cells for hypoglycemic activity.1 2 3 4 8 Lowers blood glucose concentrations principally by augmenting endogenous insulin secretion from the pancreas in response to a meal.1 2 3 4 8

Advice to Patients

  • Importance of patient managing hypoglycemia and hyperglycemia appropriately.1

  • Importance of patient taking medication 1–30 minutes before each meal and of skipping scheduled dose of nateglinide if a meal is skipped.1

  • Importance of patient adhering to diet and exercise regimen.1

  • Importance of regular monitoring of blood glucose (preferably self-monitoring) and glycosylated hemoglobin (HbA1c).1

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

  • Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

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

Preparations

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

Nateglinide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

60 mg

Starlix

Novartis

120 mg

Starlix

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nateglinide 60MG Tablets (PAR): 30/$47.99 or 90/$135.97

Starlix 120MG Tablets (NOVARTIS): 30/$70.99 or 90/$194.96

Starlix 60MG Tablets (NOVARTIS): 30/$66.99 or 90/$176.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis. Starlix (nateglinide) tablets prescribing information. East Hanover, NJ; 2001 Jan.

2. Landgraf R. Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging. 2000; 17:411-25. [PubMed 11190420]

3. Dunn CJ, Faulds D. Nateglinide. Drugs. 2000; 60:607-15. [PubMed 11030470]

4. Horton ES, Foley J, Clinkingbeard C et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000; 23:1660-65. [IDIS 455201] [PubMed 11092289]

5. Novartis, East Hanover, NJ: Personal communication.

6. Hollander PA, Schwartz SL, Gatlin MR et al. Nateglinide, but not glyburide, selectively enhances early insulin release and more effectively controls post-meal glucose excursions with less total insulin exposure. Diabetes. 2000; 49(Suppl 1):A111.

7. Marre M, Whatmough I, Pongowski M et al. Nateglinide added to metformin offers safe and effective treatment for type 2 diabetes. Diabetes. 2000; 49(Suppl 1):A361.

8. Anon. Nateglinide for type 2 diabetes. Med Lett Drugs Ther. 2001; 43:29-30. [PubMed 11283474]

a. Novartis. Starlix (nateglinide) tablets prescribing information. East Hanover, NJ; 2002 Nov.

b. Weaver ML, Orwig BA, Rodriguez LC et al. Pharmacokinetics and metabolism of nateglinide in humans. Drug Metab Dispos. 2001; 29:415-21. [PubMed 11259325]

c. Halas CJ. Nateglinide. Am J Health Syst Pharm. 2001; 58:1200-5. [PubMed 11449877]

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