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Nateglinide

Pronunciation

(na te GLYE nide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Starlix: 60 mg, 120 mg

Generic: 60 mg, 120 mg

Brand Names: U.S.

  • Starlix

Pharmacologic Category

  • Antidiabetic Agent, Meglitinide Analog

Pharmacology

Nonsulfonylurea hypoglycemic agent which blocks ATP-dependent potassium channels, depolarizing the membrane and facilitating calcium entry through calcium channels. Increased intracellular calcium stimulates insulin release from the pancreatic beta cells. Nateglinide-induced insulin release is glucose-dependent.

Absorption

Rapid

Distribution

10 L

Metabolism

Hepatic via hydroxylation followed by glucuronide conjugation via CYP2C9 (70%) and CYP3A4 (30%) to metabolites, including M1 (a major metabolite)

Excretion

Urine (83%, 16% as unchanged drug); feces (10%)

Onset of Action

Insulin secretion: ~20 minutes; Peak effect: 1 hour

Time to Peak

≤1 hour

Duration of Action

4 hours

Half-Life Elimination

1.5 hours

Protein Binding

98%, primarily to albumin

Special Populations: Renal Function Impairment

Accumulation of M1, a major metabolite with modest hypoglycemic activity, was observed following repeated administration in patients with severe renal impairment (CrCl <17 mL/minute/1.73 m2). Hemodialysis sessions did significantly reduce M1 levels in these patients (Inoue 2003)

Special Populations: Hepatic Function Impairment

Cmax increased 37% and AUC increased 30% in patients with mild hepatic insufficiency.

Use: Labeled Indications

Diabetes mellitus, type 2: Treatment of adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control

Limitations of use: Should not be used in patients with type 1 diabetes mellitus or diabetic ketoacidosis.

Guideline recommendations: Meglitinides (eg, nateglinide) are generally not used in patients with type 2 diabetes except in specific situations, such as patients with irregular meal schedules, those who develop late postprandial hypoglycemia when taking a sulfonylurea, or instead of a sulfonylurea in patients with sulfa allergies (ADA 2017a).

Contraindications

Hypersensitivity to nateglinide or any component of the formulation

Dosing: Adult

Management of type 2 diabetes mellitus: Oral: Initial and maintenance dose: 120 mg 3 times daily before meals. Patients close to HbA1c goal at initiation of therapy may be started at 60 mg 3 times daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment: No dosage adjustment necessary; however, use with caution due to potential accumulation of a metabolite with hypoglycemic activity (Inoue 2003).

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary although pharmacokinetics are altered (peak and total exposure increases).

Moderate to severe impairment (Child-Pugh class B or C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, use with caution due to potential for hypoglycemia.

Administration

Administer 1 to 30 minutes prior to meals. Scheduled dose should not be administered if a meal is missed to avoid hypoglycemia.

Dietary Considerations

Nateglinide should be taken 1 to 30 minutes prior to meals. Scheduled dose should not be taken if meal is missed to avoid hypoglycemia. Dietary modification based on ADA recommendations is a part of therapy. Decreases blood glucose concentration. Hypoglycemia may occur. Must be able to recognize symptoms of hypoglycemia (sweating, dizziness, palpitations, increased appetite, trembling).

Storage

Store at 25°C (77°F); excursions are permitted between 15˚C and 30˚C (59˚F and 86˚F).

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Fluconazole: May increase the serum concentration of Nateglinide. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

As reported with nateglinide monotherapy:

>10%: Respiratory: Upper respiratory infection (11%)

1% to 10%:

Central nervous system: Dizziness (4%)

Endocrine & metabolic: Hypoglycemia (2%), increased uric acid, weight gain

Neuromuscular & skeletal: Arthropathy (3%)

Respiratory: Flu-like symptoms (4%)

Miscellaneous:Accidental injury (3%)

Postmarketing and/or case reports (Limited to important or life-threatening): Cholestatic hepatitis, hypersensitivity reactions (including pruritus, rash, urticaria), increased liver enzymes, jaundice

Warnings/Precautions

Concerns related to adverse effects:

• Hypoglycemia: May cause hypoglycemia; risk factors include inconsistent nutrition, physical activity changes, concomitant use with other antidiabetic therapy, ethanol use, renal impairment, and hepatic impairment. Appropriate patient selection, dosage, and patient education are important to avoid hypoglycemic episodes.

Disease-related concerns:

• Adrenal/pituitary impairment: Use with caution in patients with adrenal and/or pituitary impairment; may be more susceptible to glucose-lowering effects.

• Hepatic impairment: Use with caution in patients with moderate-to-severe hepatic impairment due to risk of hypoglycemia.

• Renal impairment: Use with caution in patients with severe renal impairment; use may result in prolonged hypoglycemia due to accumulation of a metabolite with hypoglycemic activity (Inoue 2003).

• Stress-related states: It may be necessary to discontinue nateglinide and administer insulin if the patient is exposed to stress (eg, fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Metformin: Indicated for adjunctive therapy with metformin; not to be used as a substitute for metformin monotherapy.

• Sulfonylureas: Combination treatment with sulfonylureas is not recommended (no additional benefit).

Special populations:

• Malnourished patients: Use with caution in malnourished patients; may be more susceptible to glucose-lowering effects.

Monitoring Parameters

Weight, lipid profile, fasting blood glucose (periodically), and HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2017a]). During dose adjustment, fasting glucose can be used to determine response.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Information describing the effects of nateglinide on pregnancy outcomes is limited (Twaites 2007).

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008). Agents other than nateglinide are currently recommended to treat diabetes in pregnant women (ADA 2017c).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience common cold symptoms. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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