Starlix® (nateglinide) is an oral antidiabetic agent used in the management of Type 2 diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Starlix, (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues.

The structural formula is as shown

Nateglinide is a white powder with a molecular weight of 317.43. It is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Starlix biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration.

Inactive Ingredients:colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, iron oxides (red or yellow), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.

Starlix® (nateglinide) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Starlix® (nateglinide) should be taken 1 to 30 minutes prior to meals.

Monotherapy and Combination with Metformin or a Thiazolidinedione

The recommended starting and maintenance dose of Starlix, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.

The 60-mg dose of Starlix, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.

Dosage in Geriatric Patients

No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to Starlix therapy cannot be ruled out.

Dosage in Renal and Hepatic Impairment

No dosage adjustment is necessary in patients with mild-to-severe renal insufficiency or in patients with mild hepatic insufficiency. Dosing of patients with moderate-to-severe hepatic dysfunction has not been studied. Therefore, Starlix should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS, Hepatic Impairment).

Starlix® (nateglinide) tablets

60 mg

Pink, round, beveled edge tablet with “STARLIX” debossed on one side and “60” on the other.

Bottles of 100...............................NDC 0078-0351-05

120 mg

Yellow, ovaloid tablet with “STARLIX” debossed on one side and “120” on the other.

Bottles of 100...............................NDC 0078-0352-05

Storage

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).

Dispense in a tight container, USP

REV: July 2008. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. FDA revision date: 07/15/08

In clinical trials, approximately 2,600 patients with Type 2 diabetes were treated with Starlix® (nateglinide). Of these, approximately 1,335 patients were treated for 6 months or longer and approximately 190 patients for one year or longer.

Hypoglycemia was relatively uncommon in all treatment arms of the clinical trials. Only 0.3% of Starlix patients discontinued due to hypoglycemia. Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of Starlix and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of Starlix and rosiglitazone than in patients receiving rosiglitazone alone. The following table lists events that occurred more frequently in Starlix patients than placebo patients in controlled clinical trials.

Common Adverse Events ( 2% in Starlix® patients) in Starlix® Monotherapy Trials (% of patients)

During post-marketing experience, rare cases of hypersensitivity reactions such as rash, itching and urticaria have been reported. Similarly, cases of jaundice, cholestatic hepatitis and elevated liver enzymes have been reported.

Laboratory Abnormalities

Uric Acid: There were increases in mean uric acid levels for patients treated with Starlix alone, Starlix in combination with metformin, metformin alone, and glyburide alone. The respective differences from placebo were 0.29 mg/dL, 0.45 mg/dL, 0.28 mg/dL, and 0.19 mg/dL. The clinical significance of these findings is unknown.

Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In-vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting.

Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, and non-selective beta-adrenergic-blocking agents may potentiate the hypoglycemic action of Starlix and other oral antidiabetic drugs.

Certain drugs including thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce the hypoglycemic action of Starlix and other oral antidiabetic drugs.

When these drugs are administered to or withdrawn from patients receiving Starlix, the patient should be observed closely for changes in glycemic control.

Drug/Food Interactions

The pharmacokinetics of nateglinide were not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels were significantly reduced when Starlix was administered 10 minutes prior to a liquid meal. Starlix did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.

No information provided.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Starlix or any other antidiabetic drug.

Hypoglycemia: All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Starlix® (nateglinide) should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of Starlix to reduce the risk of hypoglycemia.

Hepatic Impairment: Starlix should be used with caution in patients with moderate-to­severe liver disease because such patients have not been studied.

Loss of Glycemic Control

Transient loss of glycemic control may occur with fever, infection, trauma, or surgery. Insulin therapy may be needed instead of Starlix therapy at such times. Secondary failure, or reduced effectiveness of Starlix over a period of time, may occur.

Laboratory Tests

Response to therapies should be periodically assessed with glucose values and HbA_1C levels.

Carcinogenesis/Mutagenesis/Impairment of Fertility

Carcinogenicity: A two-year carcinogenicity study in Sprague-Dawley rats was performed with oral doses of nateglinide up to 900 mg/kg/day, which produced AUC exposures in male and female rats approximately 30 and 40 times the human therapeutic exposure respectively with a recommended Starlix dose of 120 mg, three times daily before meals. A two-year carcinogenicity study in B6C3F1 mice was performed with oral doses of nateglinide up to 400 mg/kg/day, which produced AUC exposures in male and female mice approximately 10 and 30 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals. No evidence of a tumorigenic response was found in either rats or mice.

Mutagenesis : Nateglinide was not genotoxic in the in-vitro Ames test, mouse lymphoma assay, chromosome aberration assay in Chinese hamster lung cells, or in the in-vivo mouse micronucleus test.

Impairment of Fertility : Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure with a recommended Starlix dose of 120 mg three times daily before meals).

Pregnancy

Pregnancy Category C

Nateglinide was not teratogenic in rats at doses up to 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). In the rabbit, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at a dose of 500 mg/kg (approximately 40 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). There are no adequate and well-controlled studies in pregnant women. Starlix should not be used during pregnancy.

Labor and Delivery

The effect of Starlix on labor and delivery in humans is not known.

Nursing Mothers

Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC_0-48h ratio in milk to plasma was approximately 1:4. During the peri- and postnatal period body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). It is not known whether Starlix is excreted in human milk. Because many drugs are excreted in human milk, Starlix should not be administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Starlix in pediatric patients have not been established.

Geriatric Use

No differences were observed in safety or efficacy of Starlix between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to Starlix therapy cannot be ruled out.

In a clinical study in patients with Type 2 diabetes, Starlix® (nateglinide) was administered in increasing doses up to 720 mg a day for 7 days and there were no clinically significant adverse events reported. There have been no instances of overdose with Starlix in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. Hypoglycemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycemic reactions with coma, seizure, or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein bound, dialysis is not an efficient means of removing it from the blood.

Starlix® (nateglinide) is contraindicated in patients with:

1. Known hypersensitivity to the drug or its inactive ingredients.
2. Type 1 diabetes.
3. Diabetic ketoacidosis. This condition should be treated with insulin.

Mechanism of Action

Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+_ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.

Pharmacokinetics

Absorption

Following oral administration immediately prior to a meal, nateglinide is rapidly absorbed

with mean peak plasma drug concentrations (Cmax) generally occurring within 1 hour (Tmax) after dosing. When administered to patients with Type 2 diabetes over the dosage range 60 mg to 240 mg three times a day for one week, nateglinide demonstrated linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and Cmax. Tmax was also found to be independent of dose in this patient population. Absolute bioavailability is estimated to be approximately 73%. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in Cmax and a delay in time to peak plasma concentration (Tmax). Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal.

Distribution

Based on data following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 liters in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α₁ acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1-10 μg/mL.

Metabolism

Nateglinide is metabolized by the mixed-function oxidase system prior to elimination. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide.

In-vitro data demonstrate that nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%).

Excretion

Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within 6 hours after dosing, approximately 75% of the administered ¹⁴C-nateglinide was recovered in the urine. Eighty-three percent of the ¹⁴C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the ¹⁴C-nateglinide was excreted in the urine as parent compound. In all studies of healthy volunteers and patients with Type 2 diabetes, nateglinide plasma concentrations declined rapidly with an average elimination half-life of approximately 1.5 hours. Consistent with this short elimination half-life, there was no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.

Drug Interactions

In-vitro drug metabolism studies indicate that Starlix is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Starlix is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in-vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in-vitro experiments.

Glyburide: In a randomized, multiple-dose crossover study, patients with Type 2 diabetes were administered 120 mg Starlix three times a day before meals for 1 day in combination with glyburide 10 mg daily. There were no clinically relevant alterations in the pharmacokinetics of either agent.

Metformin : When Starlix 120 mg three times daily before meals was administered in combination with metformin 500 mg three times daily to patients with Type 2 diabetes, there were no clinically relevant changes in the pharmacokinetics of either agent.

Digoxin : When Starlix 120 mg before meals was administered in combination with a single 1-mg dose of digoxin to healthy volunteers, there were no clinically relevant changes in the pharmacokinetics of either agent.

Warfarin : When healthy subjects were administered Starlix 120 mg three times daily before meals for four days in combination with a single dose of warfarin 30 mg on day 2, there were no alterations in the pharmacokinetics of either agent. Prothrombin time was not affected.

Diclofenac : Administration of morning and lunch doses of Starlix 120 mg in combination with a single 75-mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent.

Special Populations

Geriatric: Age did not influence the pharmacokinetic properties of nateglinide. Therefore, no dose adjustments are necessary for elderly patients.

Gender: No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Therefore, no dose adjustment based on gender is necessary.

Race: Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide.

Renal Impairment: Compared to healthy matched subjects, patients with Type 2 diabetes and moderate-to-severe renal insufficiency (CrCl 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and Cmax. Patients with Type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure. However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.

Hepatic Impairment: The peak and total exposure of nateglinide in non-diabetic subjects with mild hepatic insufficiency were increased by 30% compared to matched healthy subjects. Starlix® (nateglinide) should be used with caution in patients with chronic liver disease. (See PRECAUTIONS, Hepatic Impairment.)

Pharmacodynamics

Starlix is rapidly absorbed and stimulates pancreatic insulin secretion within 20 minutes of oral administration. When Starlix is dosed three times daily before meals there is a rapid rise in plasma insulin, with peak levels approximately 1 hour after dosing and a fall to baseline by 4 hours after dosing.

In a double-blind, controlled clinical trial in which Starlix was administered before each of three meals, plasma glucose levels were determined over a 12-hour, daytime period after 7 weeks of treatment. Starlix was administered 10 minutes before meals. The meals were based on standard diabetic weight maintenance menus with the total caloric content based on each subject's cally significant decreases in fasting andheight. Starlix postprandial glycemia compared to placebo.

Clinical Studies

A total of 3,566 patients were randomized in nine double-blind, placebo- or active-controlled studies 8 to 24 weeks in duration to evaluate the safety and efficacy of Starlix® (nateglinide). 3,513 patients had efficacy values beyond baseline. In these studies Starlix was administered up to 30 minutes before each of three main meals daily.

Starlix® Monotherapy Compared to Placebo

In a randomized, double-blind, placebo-controlled, 24-week study, patients with Type 2 diabetes with HbA_1C ≥ 6.8% on diet alone were randomized to receive either Starlix (60 mg or 120 mg three times daily before meals) or placebo. Baseline HbA_1C ranged from 7.9% to 8.1% and 77.8% of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization. The addition of Starlix before meals resulted in statistically significant reductions in mean HbA_1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 1). The reductions in HbA_1C and FPG were similar for patients naïve to, and those previously exposed to, antidiabetic medications.

In this study, one episode of severe hypoglycemia (plasma glucose < 36 mg/dL) was reported in a patient treated with Starlix 120 mg three times daily before meals. No patients experienced hypoglycemia that required third party assistance. Patients treated with Starlix had statistically significant mean increases in weight compared to placebo (see Table 1).

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA_1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Starlix monotherapy resulted in significant reductions in mean HbA_1C and mean FPG compared to placebo that were similar to the results of the study reported above (see Table 2).

Table 1: Endpoint results for a 24-week, fixed dose study of Starlix® monotherapy

Starlix® Monotherapy Compared to Other Oral Antidiabetic Agents

Glyburide

In a 24-week, double-blind, active-controlled trial, patients with Type 2 diabetes who had been on a sulfonylurea for ≥ 3 months and who had a baseline HbA_1C ≥ 6.5% were randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to Starlix had significant increases in mean HbA_1C and mean FPG at endpoint compared to patients randomized to glyburide.

Metformin

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA_1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. The reductions in mean HbA_1C and mean FPG at endpoint with metformin monotherapy were significantly greater than the reductions in these variables with Starlix monotherapy (see Table 2). Relative to placebo, Starlix monotherapy was associated with significant increases in mean weight whereas metformin monotherapy was associated with significant decreases in mean weight. Among the subset of patients naïve to antidiabetic therapy, the reductions in mean HbA_1C and mean FPG for Starlix monotherapy were similar to those for metformin monotherapy (see Table 2). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA_1C in the Starlix monotherapy group increased slightly from baseline, whereas HbA_1C was reduced in the metformin monotherapy group (see Table 2).

Starlix® Combination Therapy

Metformin

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA_1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization. The combination of Starlix and metformin resulted in statistically significantly greater reductions in HbA_1C and FPG compared to either Starlix or metformin monotherapy (see Table 2). Starlix, alone or in combination with metformin, significantly reduced the prandial glucose elevation from pre-meal to 2-hours post-meal compared to placebo and metformin alone.

In this study, one episode of severe hypoglycemia (plasma glucose ≤ 36 mg/dL) was reported in a patient receiving the combination of Starlix and metformin and four episodes of severe hypoglycemia were reported in a single patient in the metformin treatment arm. No patient experienced an episode of hypoglycemia that required third party assistance. Compared to placebo, Starlix monotherapy was associated with a statistically significant increase in weight, while no significant change in weight was observed with combined Starlix and metformin therapy (see Table 2).

In another 24-week, double-blind, placebo-controlled trial, patients with Type 2 diabetes with HbA_{1C ≥} 6.8% after treatment with metformin ( ≥ 1500 mg daily for ≥ 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or placebo in addition to metformin. Combination therapy with Starlix and metformin was associated with statistically significantly greater reductions in HbA_1C compared to metformin monotherapy (-0.4% and -0.6% for Starlix 60 mg and Starlix 120 mg plus metformin, respectively).

Table 2: Endpoint results for a 24-week study of Starlix® monotherapy and combination with metformin

Rosiglitazone

A 24-week, double blind multicenter, placebo-controlled trial was performed in patients with Type 2 diabetes not adequately controlled after a therapeutic response to rosiglitazone monotherapy 8 mg daily. The addition of Starlix (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA_1C compared to rosiglitazone monotherapy. The difference was -0.77% at 24 weeks. The mean change in weight from baseline was about +3 kg for patients treated with Starlix plus rosiglitazone vs. about +1 kg for patients treated with placebo plus rosiglitazone.

Glyburide

In a 12-week study of patients with Type 2 diabetes inadequately controlled on glyburide 10 mg once daily, the addition of Starlix (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

Patients should be informed of the potential risks and benefits of Starlix and of alternative modes of therapy. The risks and management of hypoglycemia should be explained. Patients should be instructed to take Starlix 1 to 30 minutes before ingesting a meal, but to skip their scheduled dose if they skip the meal so that the risk of hypoglycemia will be reduced. Drug interactions should be discussed with patients. Patients should be informed of potential drug-drug interactions with Starlix.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

NATEGLINIDE - ORAL

(nah-TEGG-lin-ide)

COMMON BRAND NAME(S): Starlix

USES: Nateglinide is used alone or with other medications to control high blood sugar along with a proper diet and exercise program. It is used in people with type 2 (non-insulin-dependent) diabetes. Effectively controlling high blood sugar helps prevent heart disease, strokes, kidney disease, blindness, circulation problems, and decreased sexual ability. It works by stimulating the body to produce more insulin. Insulin is a natural substance that allows the body to properly use sugar from the diet.

HOW TO USE: Take this medication by mouth before each meal, usually 2-4 times daily 1-30 minutes before meals or as directed by your doctor. Take this drug no earlier than 30 minutes before the meal. You may also take it just before the meal if necessary. If you are having liquid meals, a higher dose of this medication may be necessary to control your blood sugar. Consult your doctor for more details.

The dosage is based on your medical condition, number of meals per day, and response to therapy.

Use this medication regularly as directed by your doctor in order to get the most benefit from it. Carefully follow the medication treatment plan, meal plan, and exercise program your doctor has recommended. Monitor your blood sugar on a regular basis. Keep track of the results, and share them with your doctor. This is very important in order to determine the correct nateglinide dose. Inform your doctor if your blood sugar measurements are too high or too low. Your dosage may need to be changed.

SIDE EFFECTS: Nausea, vomiting, diarrhea, upset stomach, joint pain, and flu-like symptoms may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Too much of this medication can cause low blood sugar (hypoglycemia). This effect may also occur if you do not consume enough calories. The symptoms include chills, cold sweats, blurred vision, dizziness, drowsiness, shaking, fast heartbeat, weakness, headache, fainting, tingling of the hands/feet, or hunger. It is a good habit to carry glucose (sugar) tablets or gel to treat low blood sugar. If you don't have these reliable forms of glucose, raise your blood sugar quickly by eating a quick source of sugar such as table sugar, honey, candy, or drinking a glass of fruit juice or non-diet soda. Tell your doctor immediately about the reaction. To help prevent low blood sugar, eat meals on a regular schedule, and do not skip meals.

Too little of this medication can cause high blood sugar (hyperglycemia). Symptoms of high blood sugar include thirst, increased urination, confusion, drowsiness, flushing, rapid breathing, or fruity breath odor. If these symptoms occur, tell your doctor immediately. Your medication dosage may need to be increased.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking nateglinide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: type 1 diabetes (insulin dependent), a certain blood acid complication of uncontrolled diabetes (ketoacidosis).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: adrenal or pituitary gland problems, thyroid problems, severe kidney disease, long-term liver disease, gout, high blood uric acid levels, nerve problems (e.g., diabetic neuropathy), infections, inability to eat due to loss of appetite, nausea/vomiting.

Do not change the dose of this medication unless your doctor has given you instructions on how to do so. Follow your doctor's instructions carefully. Know the symptoms of low blood sugar and high blood sugar (see Side Effects section). Tell your doctor immediately if you experience symptoms of high or low blood sugar.

Do not use this medication when you have low blood sugar.

You may experience blurred vision, dizziness, or drowsiness due to extremely low or high blood sugar levels. Use caution engaging in activities requiring alertness such as driving or using machinery.

Limit alcohol while taking this medication because it can increase the risk of developing low blood sugar.

During times of stress, such as fever, infection, injury, surgery, or quitting smoking, it may be more difficult to control your blood sugar. Consult your doctor because a change in your dose may be required.

Changes in your lifestyle or activity level may affect the amount of nateglinide your body needs to control blood sugar levels. If you notice an unusual change in your blood sugar measurements, tell your doctor.

Check your blood sugar before and after exercise. You may need a snack before exercising. During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: gatifloxacin.

If you are currently using the medication listed above, tell your doctor or pharmacist before starting nateglinide.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: warfarin, tolbutamide, phenytoin.

Some drugs may affect your blood sugar levels and make control of your blood sugar more difficult. If you start or stop these medications while taking nateglinide, you should check your blood sugar levels more frequently. Tell your doctor or pharmacist if you are taking any of these medications/herbal products: certain "water pills" (e.g., furosemide, hydrochlorothiazide), oral corticosteroids (e.g., prednisone, dexamethasone, prednisolone), phenothiazines (e.g., chlorpromazine, trifluoperazine), newer drugs for mental/mood problems (e.g., olanzapine, clozapine, risperidone, ziprasidone), birth control pills, estrogens, niacin, sympathomimetics (e.g., pseudoephedrine), isoniazid, thyroid drugs, some calcium channel blockers (e.g., nifedipine), some beta blockers (e.g., propranolol), fenugreek, ginseng, gymnema, alcohol, quinolone antibiotics (e.g., ciprofloxacin, levofloxacin), some protease inhibitors (e.g., indinavir, amprenavir), somatropin.

Check the labels on all your nonprescription medicines (e.g., cough-and-cold products) because they may contain ingredients that could affect your blood sugar. Ask your pharmacist about the safe use of those products.

Other medications can affect the results of urine tests for sugar or ketones. Consult your doctor or pharmacist for more information.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: very fast heartbeat, vision changes, unexplained heavy sweating, agitation, fainting, seizures.

NOTES: Do not share this medication with others.

It is recommended you attend a diabetes education program to understand diabetes and all the important aspects of its treatment, including meals/diet, exercise, personal hygiene, medications, and getting regular eye, foot, and medical exams.

Keep all medical appointments. Laboratory and/or medical tests (e.g., liver and kidney function tests, fasting blood glucose, hemoglobin A1C, complete blood counts) will be performed to monitor for side effects and response to therapy.

Wear or carry identification stating that you have diabetes and are using this drug.

MISSED DOSE: If you miss a dose, skip that dose and resume your regular dosage schedule with your next meal. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage at 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.