Nateglinide (Systemic)


VA CLASSIFICATION
Primary: HS509

Commonly used brand name(s): Starlix.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidiabetic agent —

Indications

Accepted

Diabetes, type 2 (treatment)—Nateglinide is indicated as monotherapy to lower blood glucose concentrations in patients with type 2 diabetes (previously referred to as non–insulin-dependent diabetes mellitus [NIDDM]) whose hyperglycemia cannot be controlled by diet and exercise.{01} It also is indicated in combination with metformin in patients whose hyperglycemia cannot be controlled by metformin alone.{01} In such patients, nateglinide should be added to, but not substitued for, a regimen that includes metformin.{01}
—Nateglinide is not recommended for use as monotherapy in patients who have been chronically treated with other antidiabetic agents.{02} Patients whose hyperglycemia cannot be controlled with glyburide or other insulin secretagogues should not be switched to nateglinide.{02} Nateglinide also should not be added to the regimen that includes an insulin secretagogue.{01}{02}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    317.43{01}

Solubility
    Freely soluble in methanol, ethanol, and chloroform; soluble in ether; sparingly soluble in acetonitrile and octanol; practically insoluble in water.{01}

Mechanism of action/Effect:

Nateglinide lowers blood glucose concentrations by stimulating the release of insulin from functioning beta cells of pancreatic islet tissue.{01} Nateglinide interacts with the adenosine triphosphate (ATP)-sensitive potassium channel on pancreatic beta cells.{01} The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion.{01}

Absorption:

Rapidly absorbed following oral administration prior to a meal.{01} Administration with or after a meal results in a decrease in the peak plasma concentration (C max), and a delay in the time to reach the C max (Tmax).{01} However, there is no change in the area under the plasma concentration–time curve (AUC).{01}

Distribution:

Absolute bioavailability is approximately 73%.{01} Following intravenous administration to healthy volunteers, the steady-state volume of distribution (VolD) was approximately 10 L.{01}

Nataglinide has a low affinity for heart and skeletal muscle tissue.{01}

Protein binding:

Very high (98%);{01} primarily to serum albumin and to a lesser extent to alpha 1–acid glycoprotein.{01}

Biotransformation:

Metabolism is via hydroxylation followed by glucuronidation.{01} The major metabolites have less antidiabetic activity than nateglinide, but the isoprene minor metabolite has antidiabetic activity comparable to that of nateglinide.{01}

Cytochrome P450 isoenzymes CYP2C9 and CYP3A4 have been shown in vitro to be involved in the metabolism of nateglinide.{01}

Half-life:

Elimination— 1.5 hours.{01}

Onset of action:

20 minutes.{01}

Time to peak concentration:

1 hour.{01}

Duration of action:

4 hours.{01}
{01}
Elimination:
    Renal, 83% (75% within 6 hours after dosing).{01} Approximately 16% excreted as parent compound.{01}
    Fecal, approximately 10%.{01}


Precautions to Consider

Carcinogenicity/Tumorigenicity

No evidence of carcinogenicity or tumorigenicity was found in a 2-year study in which Sprague-Dawley rats were administered nateglinide orally at doses up to 900 mg per kg of body weight (mg/kg) per day (equivalent to 30 to 40 times the human therapeutic exposure following doses of 120 mg 3 times a day before meals) or in a 2-year study in which B6C3F1 mice were administered nateglinide orally at doses up to 400 mg/kg per day (equivalent to 10 to 30 times the human therapeutic exposure following doses of 120 mg 3 times a day before meals).{01}

Mutagenicity

No evidence of mutagenicity was found following the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay in Chinese hamster lung cells, or in the in vivo mouse micronucleus test.{01}

Pregnancy/Reproduction
Fertility—
Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure following doses of 120 mg 3 times a day before meals).{01}

Pregnancy—
Adequate and well-controlled studies have not been done in humans.{01} Use of nateglinide during pregnancy is not recommended.{01}

No evidence of teratogenicity was found in rats administered doses up to 1000 mg/kg (approximately 60 times the human therapeutic exposure following doses of 120 mg 3 times a day before meals).{01} However, adverse embryonic development and an increased incidence of gallbladder agenesis or small gallbladder were observed in rabbits administered doses of 500 mg/kg (approximately 40 times the human therapeutic exposure following doses of 120 mg 3 times a day before meals).{01}

FDA Pregnancy Category C.{01}


Labor and delivery—

The effect of nateglinide on labor and delivery in humans is not known.{01}

Breast-feeding

It is not known whether nateglinide is distributed into human breast milk.{01} However, studies have shown that nateglinide is distributed into the milk of lactating rats.{01} Nateglinide should not be administered to nursing mothers.{01}

Pediatrics

No information is available on the relationship of age to the effects of nateglinide in pediatric patients. Safety and efficacy have not been established.{01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of nateglinide in the elderly.{01} However, elderly patients may be more susceptible to hypoglycemia.{02}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anti-inflammatory drugs, nonsteroidal (NSAIDs) or
Beta-adrenergic blocking agents, nonselective or
Monoamine oxidase (MAO) inhibitors or
Salicylates    (these medications may potentiate the hypoglycemic action of nateglinide or other oral antidiabetic agents;{01} glycemic control should be monitored closely when these medications are either administered to or withdrawn from patients taking nateglinide{01})


» Beta-adrenergic blocking agents    (these medications may blunt some of the symptoms of hypoglycemia, making detection of this condition more difficult{01})


Corticosteroids or
Diuretics, thiazide or
Sympathomimetic agents or
Thyroid hormones    (these medications may reduce the hypoglycemic action of nateglinide or other oral antidiabetic agents;{01} glycemic control should be monitored closely when these medications are either administered to or withdrawn from patients taking nateglinide{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Uric acid    (in clinical trials, concentrations were slightly increased in patients who received nateglinide alone, nateglinide in combination with metformin, metformin alone, and glyburide alone;{01}{02} the clinical significance of this finding is unknown{01}{02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Diabetic ketoacidosis or
» Type 1 diabetes    ( these conditions should be treated with insulin{01})


» Hypersensitivity to nateglinide or any components of the formulation{01}
Risk-benefit should be considered when the following medical problems exist
Fever or
Infection or
Surgery or
Trauma    (transient loss of glycemic control may accompany these conditions; insulin therapy may be needed{01} )


Hepatic function impairment    (area under the plasma concentration–time curve [AUC] and peak plasma concentration [Cmax] were increased by 30% in nondiabetic volunteers who had mild hepatic function impairment compared with healthy volunteers;{01} however, studies have not been done in patients with moderate to severe hepatic disease;{01} caution is recommended in patients with chronic hepatic disease{01})


» Neuropathy, autonomic    (some of the symptoms of hypoglycemia may be blunted, making detection more difficult{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Glucose concentrations, blood{02} and
» Glycosylated hemoglobin (HbA1C ) values    (recommended periodically to assess the response to therapy{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Hypoglycemia {01}(anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; coma; confusion; cool, pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat ; headache; nausea; nervousness ; nightmares; restless sleep; seizures; shakiness; slurred speech; unusual tiredness or weakness)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Upper respiratory infection {01}(cough; runny or stuffy nose; sore throat)

Incidence less frequent
    
Arthropathy (joint pain ; swelling in joints){01}
    
back pain {01}
    
dizziness {01}
    
flu symptoms {01}(abdominal pain; chills; cough; headache; pain in joints or muscles; runny nose; sneezing; sore throat)
{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

There have been no instances of overdose with nateglinide in clinical trials. {01}

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Hypoglycemia {01}(anxiety; behavior change similar to drunkenness ; blurred vision; cold sweats; coma; confusion; cool, pale skin ; difficulty in concentrating; drowsiness ; excessive hunger; fast heartbeat; headache; nausea; nervousness; nightmares; restless sleep; seizures ; shakiness; slurred speech; unusual tiredness or weakness){01}


Treatment of overdose


To enhance elimination:
Dialysis is not expected to be effective since nateglinide is highly protein-bound.{01}



Specific treatment:
Mild hypoglycemic symptoms without loss of consciousness or other neurological symptoms may require only oral glucose, dose adjustment, or adjusted timing of meals.{01}

More severe hypoglycemic reactions involving neurological symptoms should be treated with intravenous glucose.{01}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nateglinide (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy— Not recommended for use during pregnancy





Breast-feeding—Not recommended while breast-feeding





Use in the elderly— Elderly patients may be more susceptible to hypoglycemia
Other medications, especially beta-adrenergic blocking agents
Other medical problems, especially autonomic neuropathy, diabetic ketoacidosis, or type 1 diabetes

Proper use of this medication
» Importance of adherence to recommended regimens for diet, exercise, and glucose monitoring

» Taking medication 1 to 30 minutes before each meal; skipping dose if meal is skipped

» Taking medication even when not feeling ill; possibility of having to take antidiabetic medication for the rest of life to prevent or delay complications of diabetes

» Proper dosing
Taking before next main meal;{02} not doubling doses; not taking if corresponding meal was skipped

Proper storage

Precautions while using this medication
» Regular visits to physician
»
Carefully following special instructions of health care team
Discussing use of alcohol

Not taking other medications unless discussed with physician

Getting counseling for family members to help the patient with diabetes; also, special counseling for pregnancy planning and contraception

Making travel plans that include readiness for diabetic emergencies and eating meals at the usual times, even with changing time zones
» Preparing for and understanding what to do in case of diabetic emergency; carrying medical history and current medication list and wearing medical identification

» Recognizing what brings on symptoms of hypoglycemia, such as using other antidiabetic medication; delaying or missing a meal; exercising more than usual; drinking significant amounts of alcohol; or illness, including vomiting or diarrhea

» Recognizing symptoms of hypoglycemia: anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; confusion; cool, pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat; headache; nausea; nervousness; nightmares; restless sleep; shakiness; slurred speech; and unusual tiredness or weakness

» Knowing what to do if symptoms of hypoglycemia occur, such as eating glucose tablets or gel, corn syrup, honey, or sugar cubes; drinking fruit juice, nondiet soft drink, or sugar dissolved in water; or getting emergency medical assistance if symptoms are severe

» Recognizing what brings on symptoms of hyperglycemia, such as not taking enough antidiabetic medication, skipping a dose of antidiabetic medication, overeating or not following meal plan, having a fever or infection, or exercising less than usual

» Recognizing symptoms of hyperglycemia and ketoacidosis: blurred vision; drowsiness; dry mouth; flushed, dry skin; fruit-like breath odor; increased urination (frequency and volume); ketones in urine; loss of appetite; stomachache, nausea, or vomiting; tiredness; troubled breathing (rapid and deep); unconsciousness; and unusual thirst

» Knowing what to do if symptoms of hyperglycemia occur, such as checking blood glucose and contacting a member of the health care team


Side/adverse effects
Sign of potential side effects, especially hypoglycemia


General Dosing Information
Secondary failure of nateglinide may occur over time.{01}

Diet/Nutrition
Nateglinide should be taken 1 to 30 minutes before a meal.{01} Taking nateglinide before a meal reduces the risk of hypoglycemia.{01}

Taking nateglinide with or after a meal results in a decrease in the peak plasma concentration (Cmax) and a delay in the time to reach Cmax (T max).{01}

When a meal is skipped, the scheduled dose of nateglinide also should be skipped to reduce the risk of hypoglycemia.{01}


Oral Dosage Forms

NATEGLINIDE TABLETS

Usual Adult Dose
Antidiabetic agent
As monotherapy or in combination with metformin: Oral, 120 mg three times a day before meals.{01} A dose of 60 mg three times a day before meals may be used in patients who are close to their target glycosylated hemoglobin (HbA1c) values at the time of initiation of nateglinide.{01}{02}


Usual Pediatric Dose
Antidiabetic agent
Safety and efficacy have not been established.{01}


Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


60 mg (Rx) [Starlix (colloidal silicon dioxide) (croscarmellose sodium) (hydroxypropyl methylcellulose) (iron oxides [red or yellow]) (lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) ( povidone) (talc) (titanium dioxide)]{01}


120 mg [Starlix (colloidal silicon dioxide) (croscarmellose sodium) (hydroxypropyl methylcellulose) (iron oxides [red or yellow]) (lactose monohydrate) (magnesium stearate ) (microcrystalline cellulose) ( polyethylene glycol) (povidone) ( talc) (titanium dioxide)]{01}

Packaging and storage:
Store at 25°C (77° F); excursions permitted between 15 and 30 °C (59 and 86 °F). Dispense in a tight container.{01}



Developed: 05/29/2001



References
  1. Product Information: Starlix, nateglinide. Novartis®, East Hanover, New Jersey, (PI revised 12/2000) reviewed 4/2001.
  1. Manufacturer's comment, 06/11/2001.
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