Glinate-MF

Metformin:

• Glinate-MF (Metformin) reviews

Glinate-MF (Metformin) is a biguanide antihyperglycemic agent used for treating non-insulin-dependent diabetes mellitus (NIDDM). It improves glycemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake. Glinate-MF (Metformin) is the only oral antihyperglycemic agent that is not associated with weight gain. Glinate-MF (Metformin) may induce weight loss and is the drug of choice for obese NIDDM patients. When used alone, Glinate-MF (Metformin) does not cause hypoglycemia; however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin. Its main side effects are dyspepsia, nausea and diarrhea. Dose titration and/or use of smaller divided doses may decrease side effects. Glinate-MF (Metformin) should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis. Lower doses should be used in the elderly and those with decreased renal function. Glinate-MF (Metformin) decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Glinate-MF (Metformin) may also have a positive effect on lipid levels.

Indication: For use as an adjunct to diet and exercise in adult patients (18 years and older) with NIDDM. May also be used for the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome (PCOS).

Glinate-MF (Metformin) is an oral antihyperglycemic agent that improves glucose tolerance in patients with NIDDM, lowering both basal and postprandial plasma glucose. Glinate-MF (Metformin) is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. Unlike sulfonylureas, Glinate-MF (Metformin) does not produce hypoglycemia in either patients with NIDDM or healthy subjects and does not cause hyperinsulinemia. Glinate-MF (Metformin) does not affect insulin secretion.

Nateglinide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Glinate-MF (Nateglinide) reviews

1 INDICATIONS AND USAGE

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

Limitations of Use:

Glinate-MF (Nateglinide) should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Glinate-MF (Nateglinide) is a glinide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)

Limitations of use: Not for treating type 1 diabetes mellitus or diabetes ketoacidosis (1)

2 DOSAGE AND ADMINISTRATION

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

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

Instruct patients to take Glinate-MF (Nateglinide) tablets 1 to 30 minutes before meals.

In patients who skip meals, instruct patients to skip the scheduled dose of nateglinide tablets to reduce the risk of hypoglycemia .

• Recommended dose is 120 mg three times daily.
• In patients who are near glycemic goal when treatment is initiated, 60 mg three times daily may be administered. (2)
• Administer 1 to 30 minutes before meals. (2)
• If a meal is skipped, skip the scheduled dose to reduce the risk of hypoglycemia. (2, 5.1)

3 DOSAGE FORMS AND STRENGTHS

• 60 mg tablets: pink, circular, biconvex tablet with “WPI” debossed on one side and “3354” on the other.
• 120 mg tablets: pink, capsule-shaped, biconvex tablet with “WPI” debossed on one side and “3355” on the other.

Tablets: 60 mg and 120 mg (3)

4 CONTRAINDICATIONS

Glinate-MF (Nateglinide) is contraindicated in patients with a history of hypersensitivity to Glinate-MF (Nateglinide) or its active ingredients.

• History of hypersensitivity to Glinate-MF (Nateglinide) inactive ingredients (4)

5 WARNINGS AND PRECAUTIONS

• Hypoglycemia: Glinate-MF may cause hypoglycemia. Administer before meals to reduce the risk of hypoglycemia. Skip the scheduled dose of Glinate-MF (Nateglinide) if a meal is skipped to reduce the risk of hypoglycemia. (5.1)
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glinate-MF (Nateglinide). (5.2)

5.1 Hypoglycemia

All glinides, including Glinate-MF (Nateglinide), can cause hypoglycemia . 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) , 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 , and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia .

Patients should take Glinate-MF (Nateglinide) before meals and be instructed to skip the dose of Glinate-MF (Nateglinide) if a meal is skipped . 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.

5.2 MacrovascularOutcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glinate-MF (Nateglinide).

6 ADVERSE REACTIONS

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

Hypoglycemia

	Placebo	Glinate-MF (Nateglinide)
	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 Glinate-MF (Nateglinide). Non-severe hypoglycemia occurred in 2.4 % of Glinate-MF (Nateglinide) treated patients and 0.4 % of placebo treated patients .

Weight Gain

Patients treated with Glinate-MF (Nateglinide) had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with Glinate-MF (Nateglinide) 60 mg (3 times daily) and Glinate-MF (Nateglinide) 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 Glinate-MF (Nateglinide) alone, Glinate-MF (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.

• Common adverse reactions associated with Glinate-MF (Nateglinide) (3% or greater incidence) were upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, diarrhea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Glinate-MF (Nateglinide). 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 Glinate-MF (Nateglinide).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Glinate-MF (Nateglinide). 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

7 DRUG INTERACTIONS

Table 2 includes a list of drugs with clinically important drug interactions when concomitantly administered or withdrawn with Glinate-MF (Nateglinide) and instructions for managing or preventing them.

Drugs That May Increase the Blood-Glucose-Lowering Effect of Glinate-MF (Nateglinide) 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), alcohol.
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when Glinate-MF (Nateglinide) is coadministered with these drugs.
Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of Glinate-MF (Nateglinide) 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 Glinate-MF (Nateglinide) 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 Glinate-MF (Nateglinide) is coadministered with these drugs.

• Drugs That May Increase the Potential for Hypoglycemia: Glinate-MF (Nateglinide) dose reductions and increased frequency of glucose monitoring may be required when coadministered (7)
• Drugs That May Increase the Potential for Hyperglycemia: Glinate-MF (Nateglinide) dose increases and increased frequency of glucose monitoring may be required when coadministered (7)
• Drugs That May Blunt Signs and Symptoms of Hypoglycemia: Increased frequency of glucose monitoring may be required when coadministered (7)

8 USE IN SPECIFIC POPULATIONS

• Nursing mothers: Discontinue Glinate-MF or nursing (8.3)

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Glinate-MF (Nateglinide) in pregnant women. It is unknown whether Glinate-MF (Nateglinide) can cause fetal harm when administered to a pregnant woman. Glinate-MF (Nateglinide) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the rabbit, embryonic development was adversely affected and the incidence of gall bladder agenesis or small gallbladder was increased at a dose of 500 mg/kg (approximately 27 times the human therapeutic exposure of 120 mg three times daily, based on body surface area). Glinate-MF (Nateglinide) was not teratogenic in rats at doses up to 1,000 mg/kg (approximately 27 times the human therapeutic exposure based on body surface area).

8.3 Nursing Mothers

It is not known whether Glinate-MF is excreted in human milk. Glinate-MF (Nateglinide) is excreted in rat milk. Offspring of rats exposed to 1,000 mg/kg Glinate-MF (Nateglinide) (approximately 27 times the human therapeutic exposure of 120 mg three times daily, based on body surface area) had lower body weight. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made as to whether Glinate-MF (Nateglinide) should be discontinued in nursing mothers, or if mothers should discontinue nursing.

8.4 Pediatric Use

The safety and effectiveness of Glinate-MF (Nateglinide) have not been established in pediatric patients.

8.5 Geriatric Use

436 patients 65 years and older, and 80 patients 75 years and older were exposed to Glinate-MF in clinical studies. No differences were observed in safety or efficacy of Glinate-MF (Nateglinide) between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to Glinate-MF (Nateglinide) therapy cannot be ruled out.

8.6 Renal Impairment

No dosage adjustment is recommended in patients with mild to severe renal impairment .

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment. Use of Glinate-MF (Nateglinide) in patients with moderate-to-severe hepatic impairment has not been studied and therefore, should be used with caution in these patients .

10 OVERDOSAGE

There have been no instances of overdose with Glinate-MF (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 Glinate-MF (Nateglinide) is highly protein bound, dialysis is not an efficient means of removing it from the blood.

11 DESCRIPTION

Glinate-MF (Nateglinide), USP is an oral blood glucose-lowering drug of the glinide class. Glinate-MF (Nateglinide), (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues.

The structural formula is as shown:

Glinate-MF (Nateglinide), USP 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. Glinate-MF (Nateglinide) biconvex tablets contain 60 mg, or 120 mg, of Glinate-MF (Nateglinide), USP for oral administration.

Inactive Ingredients: colloidal silicon dioxide, fumaric acid, hypromellose, iron oxide (black and red), lactose monohydrate, alpha-lactose monohydrate, magnesium stearate, polysorbate 80, sodium starch glycolate, starch (maize), titanium dioxide, and FD&C red No. 40 aluminum lake.

1

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Glinate-MF lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Glinate-MF (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. Glinate-MF (Nateglinide) is highly tissue selective with low affinity for heart and skeletal muscle.

12.2 Pharmacodynamics

Glinate-MF (Nateglinide) stimulates pancreatic insulin secretion within 20 minutes of oral administration. When Glinate-MF (Nateglinide) 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.

12.3 Pharmacokinetics

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

Absorption

Absolute bioavailability of Glinate-MF (Nateglinide) is approximately 73%. Plasma profiles are characterized by multiple plasma concentration peaks when Glinate-MF (Nateglinide) is administered under fasting conditions. This effect is diminished when Glinate-MF (Nateglinide) is taken prior to a meal. Following oral administration immediately prior to a meal, the mean peak plasma Glinate-MF (Nateglinide) concentrations (C_max) generally occur within 1 hour (T_max) after dosing. T_max is independent of dose.

The pharmacokinetics of Glinate-MF (Nateglinide) are not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels are significantly reduced when Glinate-MF (Nateglinide) is administered 10 minutes prior to a liquid meal as compared to solid meal. When given with or after meals, the extent of Glinate-MF (Nateglinide) absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in C_max and a delay in time to peak plasma concentration (T_max).

Glinate-MF (Nateglinide) did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.

Distribution

Following intravenous (IV) administration of Glinate-MF (Nateglinide), the steady-state volume of distribution of Glinate-MF (Nateglinide) is estimated to be approximately 10 L in healthy subjects. Glinate-MF (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, Glinate-MF (Nateglinide) plasma concentrations declined with an average elimination half-life of approximately 1.5 hours.

Metabolism

In vitro drug metabolism studies indicate that Glinate-MF (Nateglinide) 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 Glinate-MF (Nateglinide). The isoprene minor metabolite possesses potency similar to that of the parent compound Glinate-MF (Nateglinide).

Excretion

Glinate-MF (Nateglinide) and its metabolites are rapidly and completely eliminated following oral administration. 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.

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 to 50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and C_max. Patients with type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure (C_max decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.

Hepatic Impairment

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

Gender

No clinically significant differences in Glinate-MF (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 Glinate-MF (Nateglinide).

Age

Age does not influence the pharmacokinetic properties of Glinate-MF (Nateglinide).

Drug Interactions:

In vitro assessment of drug interactions

Glinate-MF (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.

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 Glinate-MF (Nateglinide) protein binding. Similarly, Glinate-MF (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 Glinate-MF (Nateglinide) and the effect of Glinate-MF (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 Glinate-MF (Nateglinide) was coadministered with glyburide, metformin, digoxin, warfarin, and diclofenac.

Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of Glinate-MF (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 dose	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

Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of Glinate-MF (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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Mutagenesis: Glinate-MF (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 Glinate-MF (Nateglinide) to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure with a recommended Glinate-MF (Nateglinide) dose of 120 mg three times daily before meals).

14 CLINICAL STUDIES

14.1 Monotherapy

In a 24-week, double-blind, placebo-controlled study, patients with type 2 diabetes were randomized to receive either Glinate-MF (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 Glinate-MF (Nateglinide) before meals resulted in statistically significant reductions in mean HbA_1C and mean fasting plasma glucose (FPG) compared to placebo. The reductions in HbA_1C and FPG were similar for patients naïve to, and those previously exposed to, antidiabetic medications.

HbA 1C (%)	Placebo N=168	Glinate-MF (Nateglinide) 60 mg three times daily before meals N=167	Glinate-MF (Nateglinide) 120 mg three times daily before meals N=168
Baseline (mean) Change from baseline (mean) Difference from placebo (mean) FPG (mg/dL)	8.0 +0.2 N=172	7.9 -0.3 -0.5 a N=171	8.1 -0.5 -0.7 a N=169
Baseline (mean) Change from baseline (mean) Difference from placebo (mean)	167.9 +9.1	161.0 +0.4 -8.7 a	166.5 -4.5 -13.6 a
a p-value ≤ 0.004

14.2 MonotherapyCompared 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 Glinate-MF (Nateglinide) (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to Glinate-MF (Nateglinide) had significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.

	Glyburide 10 mg Once daily	Glinate-MF (Nateglinide) 60 mg three times daily before meals	Glinate-MF (Nateglinide) 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		1.0 a	0.9 a
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		2.87 a	2.66 a

^a p-value <0.001

14.3 Monotherapy and in Combination withMetformin

In a 24-week, double-blind, active- and placebo-controlled study, patients with type 2 diabetes were randomized to receive either Glinate-MF alone (120 mg three times daily before meals), metformin alone (500 mg three times daily), a combination of Glinate-MF (Nateglinide) 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 HbA_1c and FPG were observed with metformin monotherapy compared to Glinate-MF (Nateglinide) monotherapy, and the combination of Glinate-MF (Nateglinide) and metformin compared to either Glinate-MF (Nateglinide) or metformin monotherapy.

Compared to placebo, Glinate-MF (Nateglinide) 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 Glinate-MF (Nateglinide) and metformin therapy. Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA_1C in the Glinate-MF (Nateglinide) monotherapy group increased slightly from baseline, whereas HbA_1C was reduced in the metformin monotherapy group.

HbA1C (%) All	Placebo N=160	Glinate-MF (Nateglinide) 120 mg three times daily before meals N=171	Metformin 500 mg three times daily N=172	Glinate-MF (Nateglinide) 120 mg before meals plus Metformin* N=162
Baseline (mean)	8.3	8.3	8.4	8.4
Change from baseline (mean)	+0.4	-0.4 bc	-0.8 c	-1.5
Difference from placebo		-0.8 a	-1.2 a	-1.9 a
Naïve	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		-1.0 a	-1.1 a	-1.9 a
Non-Naïve	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		-0.6 a	-1.4 a	-2.0 a
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	-13.1 bc	-30.0 c	-44.9
Difference from placebo		-21.1 a	-38.0 a	-52.9 a

^a p-value ≤ 0.05 vs. placebo

^b p-value ≤ 0.03 vs. metformin

^c p-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 HbA_1C 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 Glinate-MF (Nateglinide) (60 mg or 120 mg three times daily before meals) or placebo as add-on to metformin. At the end of treatment, Glinate-MF (Nateglinide) 60 mg and 120 mg three times daily resulted in a statistically significantly greater reductions in HbA_1C compared to placebo when added to metformin (-0.4% and -0.6% for Glinate-MF (Nateglinide) 60 mg and Glinate-MF (Nateglinide) 120 mg plus metformin, respectively).

	Placebo + metformin	Glinate-MF (Nateglinide) 60 mg + metformin	Glinate-MF (Nateglinide) 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		-0.4 a	-0.6 b
a p-value 0.003 vs. metformin b p-value < 0.001 vs. metformin All nateglinide/placebo taken three times daily before meals; all metformin 1000 mg twice daily.

14.4 Add-On Combination Therapy withRosiglitazone

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 Glinate-MF (Nateglinide) (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA_1C compared to placebo as add-on to rosiglitazone. The mean change in weight from baseline was +3 kg for patients treated with Glinate-MF (Nateglinide) compared to +1 kg for patients treated with placebo when added to rosiglitazone.

	Placebo + rosiglitazone 8 mg once daily	Glinate-MF (Nateglinide) 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)		-0.7 a
a p-value ≤ 0.0001

14.5 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 Glinate-MF (Nateglinide) (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

	Placebo + glyburide 10 mg once daily	Glinate-MF (Nateglinide) 60 mg before meals + glyburide 10 mg once daily	Glinate-MF (Nateglinide) 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)		-0.1 a	-0.3 b
Placebo or Glinate-MF (Nateglinide) given 10 minutes prior to breakfast, lunch, and dinner; glyburide given with the breakfast dose of Glinate-MF (Nateglinide) or placebo. a p-value 0.6959 b p-value 0.1246

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Glinate-MF (Nateglinide) tablets, USP

60 mg

Pink, circular, biconvex tablet with “WPI” debossed on one side and “3354” on the other.

Bottles of 100 NDC 0591-3354-01

120 mg

Pink, capsule-shaped, biconvex tablet with “WPI” debossed on one side and “3355” on the other.

Bottles of 100 NDC 0591-3355-01

Storage and Handling

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight container, USP.

17 PATIENT COUNSELING INFORMATION

Administration

Instruct patients to take Glinate-MF (Nateglinide) 1 to 30 minutes before meals. Instruct patients that skip meals to skip their dose of Glinate-MF (Nateglinide) .

Hypoglycemia

Inform patients that Glinate-MF (Nateglinide) 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 .

Drug Interactions

Discuss potential drug interactions with patients and inform them of potential drug-drug interactions with Glinate-MF (Nateglinide).

Manufactured by:

Cipla Ltd.

Verna Goa, INDIA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised: March 2017

NDC 0591-3354-01

Glinate-MF (Nateglinide) Tablets, USP

60 mg

100 Tablets

Actavis

Rx Only

1

NDC 0591-3355-01

Glinate-MF (Nateglinide) Tablets, USP

120 mg

100 Tablets

Actavis

Rx Only

1