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Nateglinide

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

Medically reviewed by Drugs.com on Jun 21, 2021. Written by ASHP.

Introduction

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

Uses for Nateglinide

Type 2 Diabetes Mellitus

Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.

Not for the treatment of type 1 diabetes mellitus or ketoacidosis.

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A1c; HbA1c], weight, and cardiovascular mortality).

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA1c (>7.5% or ≥1.5% above target). In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy. Glinides (e.g., nateglinide, repaglinide) generally not preferred as second-line therapy by some experts after failure of metformin monotherapy because of their lower effectiveness and comparatively limited clinical data; however, may be appropriate choices in selected patients.

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose ≥300 mg/dL or HbA1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.

Nateglinide Dosage and Administration

Administration

Oral Administration

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

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

Dosage

Adults

Type 2 Diabetes Mellitus
Oral

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

Special Populations

Hepatic Impairment

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

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

No dosage adjustment necessary.

Cautions for Nateglinide

Contraindications

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

Warnings/Precautions

Hypoglycemia

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

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk in rats; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

Hepatic Impairment

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

Common Adverse Effects

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

Interactions for Nateglinide

Extensively metabolized by CYP2C9 and, to a lesser extent, CYP3A4. Based on in vitro data, the drug is a potential inhibitor of CYP2C9 in vivo. (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.

Drugs That May Increase Hypoglycemic Effects

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

Drugs That May Antagonize Hypoglycemic Effects

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

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. In addition, nateglinide had no influence in vitro on protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, aspirin, or tolbutamide.

Specific Drugs

Drug

Interaction

Diclofenac

No clinically important pharmacokinetic interaction observed with single dose of diclofenac

Digoxin

No clinically important pharmacokinetic interaction observed with single dose of digoxin

Glyburide

No clinically important pharmacokinetic interaction observed with single dose of glyburide

Metformin

No clinically important pharmacokinetic interaction observed

Tolbutamide

In vitro inhibition of tolbutamide metabolism

Warfarin

No clinically important pharmacokinetic interaction observed with single dose of warfarin

Nateglinide Pharmacokinetics

Absorption

Bioavailability

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

Onset

Stimulates pancreatic insulin secretion within 20 minutes following oral administration.

Duration

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

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. When nateglinide is administered 10 minutes prior to a liquid meal, peak plasma drug concentrations are reduced appreciably. Pharmacokinetics are not affected by the composition of a meal (e.g., high protein, fat, carbohydrate).

Distribution

Extent

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

Plasma Protein Binding

98%.

Elimination

Metabolism

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

Elimination Route

In urine, principally as unchanged drug and metabolites.

Half-life

Approximately 1.5 hours.

Special Populations

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

Stability

Storage

Oral

Tablets

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

Actions

  • Insulinotropic antidiabetic agent (a d-phenylalanine derivative).

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

Advice to Patients

  • Importance of patient managing hypoglycemia and hyperglycemia appropriately.

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

  • Importance of patient adhering to diet and exercise regimen.

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

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

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

  • 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nateglinide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

60 mg*

Nateglinide Tablets

120 mg*

Nateglinide Tablets

AHFS DI Essentials™. © Copyright 2022, Selected Revisions June 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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