Starlix

Nateglinide
(nateglinide) Tablets USP

DESCRIPTION

Nateglinide tablets USP are 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]. Nateglinide, (-)-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 methan

Nateglinide
(nateglinide) Tablets USP

DESCRIPTION

Nateglinide tablets USP are 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]. Nateglinide, (-)-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. Nateglinide biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration.

Inactive ingredients : carnauba wax, copovidone, croscarmellose sodium, mannitol, silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, corn starch and talc.

ol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Nateglinide biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration.

Inactive ingredients : carnauba wax, copovidone, croscarmellose sodium, mannitol, silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, corn starch and talc.

What is Starlix and how is it used?

Starlix is a prescription medicine used to treat the symptoms of Type 2 Diabetes Mellitus (non-insulin dependent diabetes mellitus). Starlix may be used alone or with other medications.

Starlix belongs to a class of drugs called Antidiabetics, Meglitinides Derivatives.

It is not known if Starlix is safe and effective in children.

What are the possible side effects of Starlix?

Starlix may cause serious side effects including:

• hives,
• difficulty breathing,
• swelling of your face, lips, tongue, or throat,
• seizure, and
• yellowing of the skin or eyes (jaundice)

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Starlix include:

• runny or stuffy nose,
• sneezing,
• cough,
• cold or flu symptoms,
• diarrhea,
• back pain,
• dizziness, and
• joint pain or stiffness

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Starlix. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

STARLIX^® (nateglinide) is an oral blood glucose-lowering drug of the glinide class. 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.

INDICATIONS

Nateglinide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

DOSAGE AND ADMINISTRATION

Nateglinide tablets 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 nateglinide tablets, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.

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

Dos Age In Geriatric Patients

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

Dos Age 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, nateglinide tablets should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS, Hepatic Impairment).

HOW SUPPLIED

Nateglinide tablets USP are available as 60 mg white to off-white, round, biconvex tablets embossed with ‘RDY’ on one side and ‘328’ on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 x 10).

Bottles of 30 NDC 55111-328-30
Bottles of 90 NDC 55111-328-90
Bottles of 100 NDC 55111-328-01
Bottles of 500 NDC 55111-328-05
Unit dose package of 100 (10 x 10) NDC 55111-328-78

Nateglinide tablets USP are available as 120 mg white to off-white, round, biconvex tablets embossed with ‘RDY’ on one side and ‘329’ on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 x 10).

Bottles of 30 NDC 55111-329-30
Bottles of 90 NDC 55111-329-90
Bottles of 100 NDC 55111-329-01
Bottles of 500 NDC 55111-329-05
Unit dose package of 100 (10 x 10) NDC 55111-329-78

Storage

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].

Dispense in a tight container, USP.

Manufactured by: Dr. Reddy’s Laboratories Limited, Bachupally – 500 090 INDIA. Revised: Apr 2015

INDICATIONS

STARLIX is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations Of Use

STARLIX should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

DOSAGE AND ADMINISTRATION

The recommended dose of STARLIX is 120 mg orally three times daily before meals.

The recommended dose of STARLIX is 60 mg orally three times daily before meals in patients who are near glycemic goal when treatment is initiated.

Instruct patients to take STARLIX 1 to 30 minutes before meals.

In patients who skip meals, instruct patients to skip the scheduled dose of STARLIX to reduce the risk of hypoglycemia [see WARNINGS AND PRECAUTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

• 60 mg tablets: pink, round, beveled edge film-coated tablet with “STARLIX” debossed on one side and “60” on the other
• 120 mg tablets: yellow, ovaloid film-coated tablet with “STARLIX” debossed on one side and “120” on the other

60 mg

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

Bottles of 100 - NDC 0078-0351-05

120 mg

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

Bottles of 100 - NDC 0078-0352-05

Storage And Handling

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Dispense in a tight container, USP.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: Oct 2021

SIDE EFFECTS

In clinical trials, approximately 2,600 patients with Type 2 diabetes were treated with 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 ateglinide patients discontinued due to hypoglycemia.Symptoms suggestive of hypoglycemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness.

Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of nateglinide and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of nateglinide and rosiglitazone than in patients receiving rosiglitazone alone. The following table lists events that occurred more frequently in nateglinide patients than placebo patients in controlled clinical trials.

Common Adverse Events ( ≥ 2% in nateglinide patients ) in Nateglinide Monotherapy Trials (% of patients )

	Placebo N=458	Nateglinide N=1441
Preferred Term
Upper Respiratory Infection	8.1	10.5
Back Pain	3.7	4.0
Flu Symptoms	2.6	3.6
Dizziness	2.2	3.6
Arthropathy	2.2	3.3
Diarrhea	3.1	3.2
Accidental Trauma	1.7	2.9
Bronchitis	2.6	2.7
Coughing	2.2	2.4
Hypoglycemia	0.4	2.4

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 nateglinide alone, nateglinide 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.

DRUG INTERACTIONS

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, non-selective beta-adrenergic-blocking agents, guanethidine, and CYP2C9 inhibitors (e.g. fluconazole, amiodarone, miconazole, oxandrolone) may potentiate the hypoglycemic action of nateglinide and other oral antidiabetic drugs.

Certain drugs including thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, rifampin, phenytoin and dietary supplements (St John's wort) may reduce the hypoglycemic action of nateglinide and other oral antidiabetic drugs. Somatostatin analogues may potentiate or attenuate the hypoglycemic action of nateglinide.

When these drugs are administered to or withdrawn from patients receiving nateglinide, 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 nateglinide was administered 10 minutes prior to a liquid meal. Nateglinide did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.

SIDE EFFECTS

The following serious adverse reaction is also described elsewhere in the labeling:

• Hypoglycemia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, approximately 2,600 patients with type 2 diabetes mellitus were treated with STARLIX. Of these, approximately 1,335 patients were treated for 6 months or longer and approximately 190 patients for one year or longer. Table 1 shows the most common adverse reactions associated with STARLIX.

Table 1: Adverse Reactions other than Hypoglycemia (%) occurring Greater than or Equal to 2% in STARLIX-Treated Patients from Pool of 12 to 64 week

	Placebo	STARLIX
	N=458	N=1441
Preferred Term
Upper Respiratory Infection	8.1	10.5
Back Pain	3.7	4.0
Flu Symptoms	2.6	3.6
Dizziness	2.2	3.6
Arthropathy	2.2	3.3
Diarrhea	3.1	3.2
Accidental Trauma	1.7	2.9
Bronchitis	2.6	2.7
Coughing	2.2	2.4

Hypoglycemia

Episodes of severe hypoglycemia (plasma glucose less than 36 mg/dL) were reported in two patients treated with STARLIX. Non-severe hypoglycemia occurred in 2.4 % of STARLIX treated patients and 0.4 % of placebo-treated patients [see WARNINGS AND PRECAUTIONS].

Weight Gain

Patients treated with STARLIX had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with STARLIX 60 mg (3 times daily) and STARLIX 120 mg (3 times daily) compared to placebo were 1.0 kg and 1.6 kg respectively.

Laboratory Test

Increases in 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of STARLIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity Reactions: Rash, itching, and urticaria

• Hepatobiliary Disorders: Jaundice, cholestatic hepatitis, and elevated liver enzymes

DRUG INTERACTIONS

Table 2 includes a list of drugs with clinically important drug interactions when concomitantly administered or withdrawn with STARLIX and instructions for managing or preventing them.

Table 2: Clinically Significant Drug Interactions with STARLIX

Drugs That May Increase the Blood-Glucose-Lowering Effect of STARLIX and Susceptibility to Hypoglycemia
Drugs:	Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, anabolic hormones (e.g., methandrostenolone), guanethidine, gymnema sylvestre, glucomannan, thioctic acid, and inhibitors of CYP2C9 (e.g., amiodarone, fluconazole, voriconazole, sulfinpyrazone) or in patients known to be poor metabolizers of CYP2C9 substrates, alcohol.
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.
Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of STARLIX and Increase Susceptibility to Hyperglycemia
Drugs:	Thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g., lanreotide, octreotide), and CYP inducers (e.g., rifampin, phenytoin and St John’s Wort).
Intervention:	Dose increases and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	beta-blockers, clonidine, guanethidine, and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.

WARNINGS

No information provided.

PRECAUTIONS

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide 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. Nateglinide should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of nateglinide to reduce the risk of hypoglycemia.

Hepatic Impairment

Nateglinide should be used with caution in patients with moderate-to-severe 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 nateglinide therapy at such times. Secondary failure, or reduced effectiveness of nateglinide over a period of time, may occur.

Laboratory Tests

Response to therapies should be periodically assessed with glucose values and HbA1Clevels

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 nateglinide 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 nateglinide 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 (approximately16 times the human therapeutic exposure with a recommended nateglinide 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 nateglinide 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 nateglinide dose of 120 mg, three times daily before meals). There are no adequate and well-controlled studies in pregnant women. Nateglinide should not be used during pregnancy.

Labor And Delivery

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

Nursing Mothers

Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC0-48h 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 nateglinide dose of 120 mg, three times daily before meals). It is not known whether nateglinide is excreted in human milk. Because many drugs are excreted in human milk, nateglinide should not be administered to a nursing woman.

Pediatric Use

Clinical trials to demonstrate the safety and effectiveness in pediatric patients have not been conducted.

Geriatric Use

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

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Hypoglycemia

All glinides, including STARLIX, can cause hypoglycemia [see ADVERSE REACTIONS]. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy (nerve disease), in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see DRUG INTERACTIONS], or in patients who experience recurrent hypoglycemia.

Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in level of physical activity, changes to coadministered medication [see DRUG INTERACTIONS], and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use In Specific Populations , CLINICAL PHARMACOLOGY].

Patients should take STARLIX before meals and be instructed to skip the dose of STARLIX if a meal is skipped [see DOSAGE AND ADMINISTRATION]. Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with STARLIX.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Nateglinide did not increase tumors in two year carcinogenicity studies conducted in mice and rats. Oral doses of Nateglinide up to 900 mg/kg in rats and 400 mg/kg in mice were tested, which produced exposures in rats approximately 30-40 times and in mice 10-30 times the human therapeutic exposure of nateglinide at a dose of 120 mg three times daily, based on AUC.

Mutagenesis

Nateglinide was not genotoxic in the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay 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 (corresponding to 16 times the MRHD of 120 mg three times per day, based on BSA).).

Use In Specific Populations

Pregnancy

Risk Summary

The available data from published literature and the applicant’s pharmacovigilance with use of Starlix in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). STARLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal reproduction studies, there was no teratogenicity in rats and rabbits administered oral nateglinide during organogenesis at approximately 27 and 8 times the maximum recommended human dose (MRHD), respectively, based on body surface area (BSA).

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c > 7 and has been reported to be as high as 20% to 25% in women with a HbA1c > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Animal data

In embryofetal development studies, nateglinide administered orally during the period of organogenesis was not teratogenic in rats at doses up to 1,000 mg/kg (corresponding to 27 times the MRHD of 120 mg three times per day, based on BSA). In rabbits, embryonic development was adversely affected at 500 mg/kg/day and the incidence of gallbladder agenesis or small gallbladder was increased at a dose of 300 and 500 mg/kg (corresponding to 16 and 27 times the MRHD). No such effects were observed at 150 mg/kg/day (corresponding to 8 times the MRHD). In a pre-and postnatal development study in rats, nateglinide administered by oral gavage at doses of 100, 300, and 1000 mg/kg/day from gestation day 17 to lactation day 21 resulted in lower body weight in offspring of rats administered nateglinide at 1,000 mg/kg/day (corresponding to 27 times the MHRD).

Lactation

Risk summary

There are no data on the presence of nateglinide in human milk, the effects on the breastfeeding infant, or the effects on milk production. The drug is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Because the potential for hypoglycemia in breast-fed infants, advise women that use of STARLIX is not recommended while breastfeeding.

Data

In rat reproduction studies, nateglinide and its metabolite are excreted in the milk following oral dose (300 mg/kg). The overall milk: plasma (M/P) concentration ratio of the total radioactivity was approximately 1.4 based on AUC0-48 values. The M/P ratio of unchanged nateglinide was approximately 2.2.

Pediatric Use

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

Geriatric Use

436 patients 65 years and older, and 80 patients 75 years and older were exposed to STARLIX in clinical studies. 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.

Renal Impairment

No dosage adjustment is recommended in patients with mild to severe renal impairment [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment. Use of STARLIX in patients with moderate-to-severe hepatic impairment has not been studied and therefore, should be used with caution in these patients [see CLINICAL PHARMACOLOGY].

OVERDOSE

In a clinical study in patients with Type 2 diabetes, 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 nateglinide 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.

CONTRAINDICATIONS

Nateglinide tablets are contraindicated in patients with:

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

OVERDOSE

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 STARLIX is highly protein bound, dialysis is not an efficient means of removing it from the blood.

CONTRAINDICATIONS

STARLIX is contraindicated in patients with a history of hypersensitivity to STARLIX or its inactive ingredients.

CLINICAL PHARMACOLOGY

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 to 10 mcg/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 nateglinide is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Nateglinide 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 nateglinide 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 nateglinide 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 nateglinide 120 mg before meals was administered in combination with a single 1mg dose of digoxin to healthy volunteers, there were no clinically relevant changes in the pharmacokinetics of either agent.

Warfarin

When healthy subjects were administered nateglinide 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 nateglinide 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 to 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. Nateglinide should be used with caution in patients with chronic liver disease. (See PRECAUTIONS, Hepatic Impairment.)

Pharmacodynamics

Nateglinide is rapidly absorbed and stimulates pancreatic insulin secretion within 20 minutes of oral administration. When nateglinide 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 nateglinide was administered before each of three meals, plasma glucose levels were determined over a 12-hour, daytime period after 7 weeks of treatment. Nateglinide 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 height.

Nateglinide produced statistically significant decreases in fasting and 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 nateglinide. 3,513 patients had efficacy values beyond baseline. In these studies nateglinide was administered up to 30 minutes before each of three main meals daily.

Nateglinide Monotherapy Compared To Placebo

In a randomized, double-blind, placebo-controlled, 24-week study, patients with Type 2 diabetes with HbA1C ≥ 6.8 % on diet alone were randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo. Baseline HbA1C 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 nateglinide before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 1). The reductions in HbA1C 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 nateglinide 120 mg three times daily before meals. No patients experienced hypoglycemia that required third party assistance. Patients treated with nateglinide 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 nateglinide (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of nateglinide 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fiftyseven percent of patients were previously untreated with oral antidiabetic therapy. Nateglinide monotherapy resulted in significant reductions in mean HbA1C 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 nateglinide monotherapy

HbA1C (%)	Placebo N=168	Nateglinide 60 mg three times daily before meals N=167	Nateglinide 120 mg three times daily before meals N=168
Baseline (mean)	8	7.9	8.1
Change from baseline (mean)	+0.2	-0.3	-0.5
Difference from placebo (mean)		-0.5 a	-0.7 a
FPG(mg/dL)	N=172	N=171	N=169
Baseline (mean)	167.9	161	166.5
Change from baseline (mean)	+9.1	+0.4	-4.5
Difference from placebo (mean)		-8.7 a	-13.6 a
Weight (kg)	N=170	N=169	N=166
Baseline (mean)	85.8	83.7	86.3
Change from baseline (mean)	-0.7	+0.3	+0.9
Difference from placebo (mean)		+1 a	+1.6 a
ap-value ≤ 0.004

Nateglinide 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 HbA1C ≥ 6.5 % were randomized to receive nateglinide (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to nateglinide had significant increases in mean HbA1C 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 nateglinide (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of nateglinide 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fiftyseven 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 reductions in mean HbA1C and mean FPG at endpoint with metformin monotherapy were significantly greater than the reductions in these variables with nateglinide monotherapy (see Table 2). Relative to placebo, nateglinide 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 HbA1C and mean FPG for nateglinide monotherapy were similar to those for metformin monotherapy (see Table 2). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the nateglinide monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 2).

Nateglinide Combination Therapy

Metformin

In the active and placebo-controlled study of metformin and nateglinide described above, the combination of nateglinide and metformin resulted in statistically significantly greater reductions in HbA1C and FPG compared to either nateglinide or metformin monotherapy (see Table2). Nateglinide, alone or in combination with metformin, significantly reduced the prandial glucose elevation from premeal 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 nateglinide 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, nateglinide monotherapy was associated with a statistically significant increase in weight, while no significant change in weight was observed with combined nateglinide and metformin therapy (see Table2).

In another 24-week, double-blind, placebo-controlled trial, patients with Type 2 diabetes with HbA1C ≥ 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 nateglinide (60 mg or 120 mg three times daily before meals) or placebo in addition to metformin. Combination therapy with nateglinide and metformin was associated with statistically significantly greater reductions in HbA1C compared to metformin monotherapy (-0.4% and -0.6% for nateglinide 60 mg and nateglinide 120 mg plus metformin, respectively).

Table 2: End point results for a 24-week study of nateglinide monotherapy and combination with Metformin

	Placebo	Nateglinide 120 mg three times daily before meals	Metformin 500 mg three times daily	Nateglinide 120 mg before meals plus Metformin*
HbA1C (%)All	N=160	N=171	N=172	N=162
Baseline (mean)	8.3	8.3	8.4	8.4
Change from baseline (mean)	+0.4	-0.4bc	-0.8c	-1.5
Difference from placebo		-0.8a	-1.2a	-1.9a
Naive	N=98	N=99	N=98	N=81
Baseline (mean)	8.2	8.1	8.3	8.2
Change from baseline (mean)	+0.3	-0.7 c	-0.8 c	-1.6
Difference from placebo		-1 a	-1.1 a	-1.9 a
Non-Naive	N=62	N=72	N=74	N=81
Baseline (mean)	8.3	8.5	8.7	8.7
Change from baseline (mean)	+0.6	+0.004 bc	-0.8 c	-1.4
Difference from placebo FPG (mg/dL)		-0.6 a	-1.4 a	-2 a
All	N=166	N=173	N=174	N=167
Baseline (mean)	194	196.5	196	197.7
Change from baseline (mean)	+8	-13.1 bc	-30 c	-44.9
Difference from placebo		-21.1 a	-38 a	-52.9 a
Weight (kg)All	N=160	N=169	N=169	N=160
Baseline (mean)	85	85	86	87.4
Change from baseline (mean)	-0.4	+0.9 bc	-0.1	+0.2
Difference from placebo		+1.3 a	+0.3	+0.6
ap-value ≤ 0.05 vs. placebo bp-value ≤ 0.03 vs. metformin cp-value ≤ 0.05 vs. combination *Metformin was administered three times daily

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 nateglinide (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1Ccompared 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 nateglinide 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 nateglinide (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Nateglinide 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.

Pharmacodynamics

STARLIX stimulates pancreatic insulin secretion within 20 minutes of oral administration. When STARLIX is dosed before meals, the peak rise in plasma insulin occurs approximately 1 hour after dosing and falls to baseline by 4 hours after dosing.

Pharmacokinetics

In patients with Type 2 diabetes, multiple dose administration of nateglinide over the dosage range of 60 mg to 240 mg shows linear pharmacokinetics for both area under the curve (AUC) and Cmax. In patients with Type 2 diabetes, there is no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.

Absorption

Absolute bioavailability of nateglinide is approximately 73%. 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. Following oral administration immediately prior to a meal, the mean peak plasma nateglinide concentrations (Cmax) generally occur within 1 hour (Tmax) after dosing. Tmax is independent of dose.

The pharmacokinetics of nateglinide are not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels are significantly reduced when STARLIX is administered 10 minutes prior to a liquid meal as compared to solid meal. 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).

STARLIX did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.

Distribution

Following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 L 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 to 10 mcg/mL.

Elimination

In healthy volunteers and patients with type 2 diabetes mellitus, nateglinide plasma concentrations declined with an average elimination half-life of approximately 1.5 hours.

Metabolism

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%).

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.

Excretion

Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Eighty-three percent of the 14^C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14^C-nateglinide was excreted in the urine as parent compound.

Specific Populations

Renal Impairment

No pharmacokinetic data are available in subjects with mild renal impairment (CrCl 60 to 89 mL/min). Compared to healthy matched subjects, patients with type 2 diabetes mellitus and moderate and severe renal impairment (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 (Cmax decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.

In a cohort of 8 patients with type 2 diabetes and end-stage renal disease (ESRD) (eGFR < 15 mL/min/1.73m²) M1 metabolite accumulation up to 1.2 ng/mL occurred with a dosage of 90 mg once daily for 1 to 3 months. In another cohort of 8 patients with type 2 diabetes on hemodialysis, M1 concentration decreased after a single session of hemodialysis. Although the hypoglycemic activity of the M1 metabolite is approximately 5 times lower than nateglinide, metabolite accumulation may increase the hypoglycemic effect of the administered dose.

Hepatic Impairment

In patients with mild hepatic impairment, the mean increase in Cmax and AUC of nateglinide were 37% and 30 % respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of STARLIX in patients with moderate-to-severe hepatic impairment.

Gender

No clinically significant differences in nateglinide pharmacokinetics were observed between men and women.

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.

Age

Age does not influence the pharmacokinetic properties of nateglinide.

Drug Interactions

In Vitro Assessment Of Drug Interactions

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.

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.

In Vivo Assessment Of Drug Interactions

The effect of coadministered drugs on the pharmacokinetics of nateglinide and the effect of nateglinide on pharmacokinetics of coadministered drugs are shown in Tables 3 and 4. No clinically relevant change in pharmacokinetic parameters of either agent was reported when nateglinide was coadministered with glyburide, metformin, digoxin, warfarin, and diclofenac.

Table 3: Effect of Coadministered Drugs on Pharmacokinetics of Nateglinide

Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of nateglinide	Change in Cmax	Change in AUC
Glyburide	10 mg once daily for 3 weeks	120 mg three times a day, single dose	8.78% ↓	3.53 % ↓
Metformin	500 mg three times a day for 3 weeks	120 mg three times a day, single dose	AM: 7.14% ↑ PM: 11.4% ↓	AM: 1.51% ↑ PM: 5.97% ↑
Digoxin	1 mg, single dose	120 mg three times a day, single dosec	AM: 2.17% ↓ PM: 3.19% ↑	AM: 7.62% ↑ PM: 2.22% ↑
Warfarin	30 mg, single dose	120 mg three times a day for 4 days	2.65% ↑	3.72% ↓
Diclofenac	75 mg, single dose	120 mg twice daily, single dose	AM: 13.23% ↓ *PM: 3.76% ↑	AM: 2.2% ↓ *PM: 7.5% ↑
AM: after morning dose; PM: after evening dose; *after second dose; ↑: increase in the parameter; ↓: decrease in the parameter

Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered Drugs

Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of nateglinide	Change in Cmax	Change in AUC
Glyburide	10 mg once daily for 3 weeks	120 mg three times a day, single dose	3.18% ↓	7.34% ↓
Metformin	500 mg three times a day for 3 weeks	120 mg three times a day, single dose	AM: 10.7% ↑ PM: 0.40% ↑	AM: 13.3% ↑ PM: 2.27% ↓
Digoxin	1 mg, single dose	120 mg three times a day, single dose	5.41% ↓	6.58 % ↑
Warfarin	30 mg, single dose	120 mg three times a day for 4 days	R-warfarin: 1.03% ↓ S-warfarin: 0.85% ↓	R-warfarin: 0.74% ↑ S-warfarin: 7.23% ↑
Diclofenac	75 mg, single dose	120 mg twice daily, single dose	2.19% ↑	7.97% ↑
AM: after morning dose; PM: after evening dose; SD: single dose; ↑: increase in the parameter; ↓: decrease in the parameter

Clinical Studies

Monotherapy

In a 24-week, double-blind, placebo-controlled study, patients with type 2 diabetes were randomized to receive either STARLIX (60 mg or 120 mg three times daily before meals) or placebo. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization.

At Week 24, treatment with STARLIX before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 5). The reductions in HbA1C and FPG were similar for patient’s naïve to, and those previously exposed to, antidiabetic medications.

Table 5: Endpoint Results for a 24-week, Fixed Dose Study of STARLIX Monotherapy

	Placebo	STARLIX 60 mg three times daily before meals	STARLIX 120 mg three times daily before meals
HbA1C (%)	N = 168	N = 167	N = 168
Baseline (mean)	8.0	7.9	8.1
Change from baseline (mean)	+0.2	-0.3	-0.5
Difference from placebo (mean)		-0.5a	-0.7a
FPG (mg/dL)	N = 172	N = 171	N = 169
Baseline (mean)	167.9	161.0	166.5
Change from baseline (mean)	+9.1	+0.4	-4.5
Difference from placebo (mean)		-8.7a	-13.6a
ap-value ≤ 0.004

Monotherapy Compared To Glyburide

In a 24-week, double-blind, active-controlled trial, patients with type 2 diabetes who had been on a sulfonylurea for 3 or more months and who had a baseline HbA1C greater than or equal to 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 statistically significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.

Table 6: Endpoint Results for a 24-Week Study of STARLIX Monotherapy Compared to Glyburide

	Glyburide 10 mg Once daily	STARLIX 60 mg three times daily before meals	STARLIX 120 mg three times daily before meals
HbA1C (%)	N = 183	N = 178	N = 179
Baseline (mean)	7.8	8.0	7.9
Change from baseline (mean)	0.3	1.3	1.1
Difference from glyburide		1.0a	0.9a
FPG (mmol/L)	N = 184	N = 182	N = 180
Baseline (mean)	9.44	9.67	9.61
Change from baseline (mean)	0.19	3.06	2.84
Difference from glyburide		2.87a	2.66a
ap-value < 0.001

Monotherapy And In Combination With Metformin

In a 24-week, double-blind, active-and placebo-controlled study, patients with type 2 diabetes were randomized to receive either STARLIX alone (120 mg three times daily before meals), metformin alone (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. 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.

At Week 24, statistically significant reductions in mean HbA1c and FPG were observed with metformin monotherapy compared to STARLIX monotherapy, and the combination of STARLIX and metformin compared to either STARLIX or metformin monotherapy (see Table 7).

Compared to placebo, STARLIX monotherapy was associated with a statistically significant increase in mean body weight, while no significant change in body weight was observed with metformin monotherapy or combination of STARLIX and metformin therapy (see Table 7). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the STARLIX monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 7).

Table 7: Endpoint Results for a 24-Week Study of STARLIX Monotherapy and Combination with Metformin

	Placebo	STARLIX 120 mg three times daily before meals	Metformin 500 mg three times daily	STARLIX 120 mg before meals plus Metformin*
HbA1C (%)
All	N = 160	N = 171	N = 172	N = 162
Baseline (mean)	8.3	8.3	8.4	8.4
Change from baseline (mean)	+0.4	-0.4bc	-0.8c	-1.5
Difference from placebo		-0.8a	-1.2a	-1.9a
Naive	N = 98	N = 99	N = 98	N = 81
Baseline (mean)	8.2	8.1	8.3	8.2
Change from baseline (mean)	+0.3	-0.7c	-0.8c	-1.6
Difference from placebo		-1.0a	-1.1a	-1.9a
Non-Naive	N = 62	N = 72	N = 74	N = 81
Baseline (mean)	8.3	8.5	8.7	8.7
Change from baseline (mean)	+0.6	+0.004bc	-0.8c	-1.4
Difference from placebo		-0.6a	-1.4a	-2.0a
FPG (mg/dL)
All	N = 166	N = 173	N = 174	N = 167
Baseline (mean)	194.0	196.5	196.0	197.7
Change from baseline (mean)	+8.0	-13.1bc	-30.0c	-44.9
Difference from placebo		-21.1a	-38.0a	-52.9a
ap-value ≤ 0.05 vs. placebo bp-value ≤ 0.03 vs. metformin cp-value ≤ 0.05 vs. combination *Metformin was administered three times daily

In another 24-week, double-blind, placebo-controlled trial, patients with type 2 diabetes with HbA1C greater than or equal to 6.8% after treatment with metformin (greater than or equal to 1500 mg daily for at least 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive either STARLIX (60 mg or 120 mg three times daily before meals) or placebo as add-on to metformin. At the end of treatment, STARLIX 60 mg and 120 mg three times daily resulted in a statistically significantly greater reductions in HbA1C compared to placebo when added to metformin (-0.4% and -0.6% for STARLIX 60 mg and STARLIX 120 mg plus metformin, respectively).

Table 8: Endpoint Results for a 24-week Study of STARLIX Monotherapy as Add-on to Metformin

	Placebo + metformin	STARLIX 60 mg + metformin	STARLIX 120 mg + metformin
HbA1C (%)	N = 150	N = 152	N = 154
Baseline (mean)	8.2	8.0	8.2
Change from baseline (mean)	0.01	-0.4	-0.6
Difference from metformin		-0.4a	-0.6b
ap-value 0.003 vs. metformin bp-value < 0.001 vs. metformin All STARLIX/placebo taken three times daily before meals; all metformin 1000 mg twice daily.

Add-On Combination Therapy With Rosiglitazone

A 24-week, double blind, multicenter, placebo-controlled trial was performed in patients with type 2 diabetes not adequately controlled on rosiglitazone 8 mg daily. The addition of STARLIX (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to placebo as add-on to rosiglitazone. The mean change in weight from baseline was +3 kg for patients treated with STARLIX compared to +1 kg for patients treated with placebo when added to rosiglitazone.

Table 9: Endpoint Results for a 24-week Study of the Effect of Adding STARLIX or Placebo to Rosiglitazone

	Placebo + rosiglitazone 8 mg once daily	STARLIX 120 mg before meals + rosiglitazone 8 mg once daily
HbA1C (%)	N = 191	N = 194
Baseline (mean)	8.4	8.3
Change from baseline (mean)	0.03	-0.7
Difference from rosiglitazone (mean)		-0.7a
ap-value ≤ 0.0001

Add-On Combination Therapy With 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.

Table 10: Endpoint Results for a 12-week Study of the Effect of Adding STARLIX or Placebo to Glyburide

	Placebo + glyburide 10 mg once daily	STARLIX 60 mg before meals + glyburide 10 mg once daily	STARLIX 120 mg before meals + glyburide 10 mg once daily
HbA1C (%)	N=58	N=55	N=54
Baseline (mean)	8.7	8.7	8.7
Change from baseline (mean)	0.3	0.2	-0.02
Difference from glyburide (mean)		-0.1a	-0.3b
Placebo or STARLIX given 10 minutes prior to breakfast, lunch, and dinner; glyburide given with the breakfast dose of STARLIX or placebo. ap-value 0.6959 bp-value 0.1246

PATIENT INFORMATION

Patients should be informed of the potential risks and benefits of nateglinide and of alternative modes of therapy. The risks and management of hypoglycemia should be explained. Patients should be instructed to take nateglinide 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 nateglinide.

PATIENT INFORMATION

Administration

Instruct patients to take STARLIX 1 to 30 minutes before meals. Instruct patients that skip meals to skip their dose of STARLIX [see DOSAGE AND ADMINISTRATION].

Hypoglycemia

Inform patients that STARLIX can cause hypoglycemia and instruct patients and their caregivers on self-management procedures including glucose monitoring and management of hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended [see WARNINGS AND PRECAUTIONS].

Lactation

Advise patients that use of Starlix is not recommended while breastfeeding [see Use In Specific Populations].

Drug Interactions

Discuss potential drug interactions with patients and inform them of potential drug-drug interactions with STARLIX.