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Nateglinide

Pronunciation

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

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

Compared with healthy subjects, patients with type 2 diabetes and moderate to severe renal impairment (CrCl 15-50 mL/minute) not on dialysis, displayed similar clearance, AUC, and Cmax. Patients with renal failure on dialysis exhibited reduced overall drug exposure. Hemodialysis patients experienced a reduction in plasma protein binding.

Special Populations: Hepatic Function Impairment

The peak and total exposure of nateglinide were increased 30% in patients with mild hepatic insufficiency. Use with caution in patients with chronic hepatic insufficiency.

Use: Labeled Indications

Type 2 diabetes mellitus: For the treatment of adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control.

Contraindications

Hypersensitivity to nateglinide or any component of the formulation; type 1 diabetes; diabetic ketoacidosis (this condition should be treated with insulin)

Dosing: Adult

Management of type 2 diabetes mellitus: Oral: Initial and maintenance dose: 120 mg 3 times daily, 1-30 minutes before meals; may be given alone or in combination with metformin or a thiazolidinedione. 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. Use with caution; may be more susceptible to glucose-lowering effects.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B or C): No dosage adjustment provided in manufacturers labeling. Use with caution; has not been studied.

Administration

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

Dietary Considerations

Nateglinide should be taken 1-30 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. 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. 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. Monitor therapy

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

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. 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. 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

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. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

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

Mifepristone: May increase the serum concentration of CYP2C9 Substrates. 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

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

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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; appropriate patient selection, dosage, and patient education are important to avoid hypoglycemic episodes. Ethanol may increase the risk of hypoglycemia; instruct patients to avoid ethanol.

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.

• Renal impairment: Use with caution in patients with severe renal impairment; may be more susceptible to glucose-lowering effects.

• 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:

• Insulin secretagogues: Patients not adequately controlled on oral agents which stimulate insulin release (eg, glyburide) should not be switched to nateglinide or have nateglinide added to therapy.

• 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:

• Elderly: Use with caution in the elderly; may be more susceptible to glucose-lowering effects.

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

Monitoring Parameters

Monitor weight and lipid profile. Monitor fasting blood glucose (periodically) and glycosylated hemoglobin (HbA1c) levels (every 3 months) with a goal of decreasing these levels towards the normal range. During dose adjustment, fasting glucose can be used to determine response.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in 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 2015; 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 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013).

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?)

• Have patient report immediately to prescriber signs of hypoglycemia (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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