NDC 42291-636 Nateglinide

Nateglinide

NDC Product Code 42291-636

NDC CODE: 42291-636

Proprietary Name: Nateglinide What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Nateglinide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Nateglinide is used alone or with other medications to control high blood sugar along with a proper diet and exercise program. It is used in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke. It works by stimulating the body to produce more insulin. Insulin is a natural substance that allows the body to properly use sugar from the diet.

Product Characteristics

Color(s):
PINK (C48328)
Shape: ROUND (C48348)
Size(s):
1 MM
Imprint(s):
P;984
Score: 1

NDC Code Structure

NDC 42291-636-01

Package Description: 100 TABLET, COATED in 1 BOTTLE

NDC Product Information

Nateglinide with NDC 42291-636 is a a human prescription drug product labeled by Avkare, Inc.. The generic name of Nateglinide is nateglinide. The product's dosage form is tablet, coated and is administered via oral form.

Labeler Name: Avkare, Inc.

Dosage Form: Tablet, Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is covered with a designated coating.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Nateglinide Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • NATEGLINIDE 60 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • POVIDONE (UNII: FZ989GH94E)
  • POLYVINYL ALCOHOL (UNII: 532B59J990)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Glinide - [EPC] (Established Pharmacologic Class)
  • Potassium Channel Antagonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Avkare, Inc.
Labeler Code: 42291
FDA Application Number: ANDA077463 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-06-2016 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Nateglinide Oral

Nateglinide Oral is pronounced as (nuh tay' gli nide)

Why is nateglinide oral medication prescribed?
Nateglinide is used alone or in combination with other medications to treat type 2 diabetes (condition in which the body does not use insulin normally and therefore canno...
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* Please review the disclaimer below.

Nateglinide Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

Nateglinide Tablets, USP are an oral antidiabetic agent used in the management of Type 2 diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Nateglinide,(-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues.The structural formula is as shownNateglinide 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: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch. The 60 mg also contains iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. In addition, the 120 mg contains FD&C Yellow #6/Sunset Yellow Aluminum Lake, iron oxide yellow.

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.

Absorption

Following oral administration immediately prior to a meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (C


max) generally occurring within 1 hour (T


max) 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 C


max. T


max 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 C


max and a delay in time to peak plasma concentration (T


max). 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 α


1 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 1 mg dose of digoxin to healthy volunteers, there were no clinically relevant changes in the pharmacokinetics of either agent.


Warfarin: When healthy subjects were administered 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.

Nateglinide is highly bound to plasma proteins (98%), mainly albumin.


In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid and tolbutamide


in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting.


Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, and non-selective beta-adrenergic-blocking agents, 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.

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 C


max. 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 PlaceboIn 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%. Fifty-seven 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 monotherapyHbA1c (%)Placebo
N=168Nateglinide 60 mg
three times daily before meals
N=167Nateglinide 120 mg
three times daily before meals
N=168a p-value ≤0.004


Baseline (mean)
Change from baseline (mean)
Difference from placebo (mean8.0

+0.27.9

-0.3

-0.5


a8.1

-0.5

-0.7


aFPG (mg/dL)N=172N=171N=169Baseline (mean)
Change from baseline (mean)
Difference from placebo (mean)167.9

+9.1161.0

+0.4

-8.7


a166.5

-4.5

-13.6


aWeight (kg)N=170N=169N=166Baseline (mean)
Change from baseline (mean)
Difference from placebo (mean)85.8

-0.783.7

+0.3

+1.0


a86.3

+0.9

+1.6


aNateglinide Monotherapy Compared to Other Oral Antidiabetic AgentsGlyburideIn a 24-week, double-blind, active-controlled trial, patients with Type 2 diabetes who had been on a sulfonylurea for ≥ 3 months and who had a baseline HbA


1c ≥6.5% were randomized to receive 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 HbA


1c and mean FPG at endpoint compared to patients randomized to glyburide.


MetforminIn 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 HbA


1c ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization. The reductions in mean HbA


1c 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 HbA


1c 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, HbA


1c in the nateglinide monotherapy group increased slightly from baseline, whereas HbA


1c was reduced in the metformin monotherapy group (see


Table 2).


Nateglinide Combination TherapyMetforminIn 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 HbA


1c and FPG compared to either nateglinide or metformin monotherapy (see


Table 2). Nateglinide, alone or in combination with metformin, significantly reduced the prandial glucose elevation form pre-meal to 2-hours post-meal compared to placebo and metformin alone.


In this study, one episode of severe hypoglycemia (plasma glucose ≤36 mg/dL) was reported in a patient receiving the combination of 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


Table 2).


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: Endpoint results for a 24-week study of Nateglinide monotherapy and combination with metforminHbA1c (%)
All Placebo
N=160Nateglinide
120 mg
three times daily before meals
N=171Metformin
500 mg
three times daily N=172Nateglinide
120 mg before meals plus Metformin* N=162a p-value ≤0.05 vs. placebo


b p-value ≤0.03 vs. metforminc p-value ≤0.05 vs. combination* Metformin was administered three times dailyBaseline (mean)
Change from baseline (mean)
Difference from placebo
Naïve8.3

+0.4


N=988.3

-0.4


bc
-0.8


a

N=99


8.4

-0.8


c
-1.2


a

N=98


.4

-1.5
-1.9


a

N=81


Baseline (mean)
Change from baseline (mean)
Difference from placebo
Non-Naïve8.2

+0.3


N=628.1

-0.7


c
-1.0


a

N=72


8.3

-0.8


c
-1.1


a

N=74


8.2

-1.6
-1.9


a

N=81


Baseline (mean)
Change from baseline (mean)
Difference from placebo
FPG (mg/dL)
All8.3

+0.6



N=1668.5

+0.004


bc
-0.6


a


N=173


8.7

-0.8


c
-1.4


a


N=174


8.7

-1.4
-2.0


a


N=167


Baseline (mean)
Change from baseline (mean)
Difference from placebo
Weight (kg)
All194.0

+8.0



N=160196.5

-13.1


bc
-21.1


a


N=169


196.0

-30.0


c
-38.0


a


N=169


197.7

-44.9
-52.9


a


N=160


Baseline (mean)
Change from baseline (mean)
Difference from placebo85.0-0.485.0

+0.9


bc
+1.3


a86.0

-0.1
+0.3 87.4

+0.2
+0.6RosiglitazoneA 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 HbA


1c compared to rosiglitazone monotherapy. The difference was -0.77% at 24 weeks. The mean change in weight from baseline was about +3 kg for patients treated with nateglinide plus rosiglitazone vs about +1 kg for patients treated with placebo plus rosiglitazone.


GlyburideIn 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.

Indications And Usage

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

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.

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 ControlTransient 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.

Information For Patients

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.

Laboratory Tests

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


1c levels.

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.

Carcinogenesis And Mutagenesis And 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 (approximately 16 times the human therapeutic exposure with a recommended nateglinide dose of 120 mg three times daily before meals).

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 AUC


0-48h ratio in milk to plasma was approximately 1:4. During the peri- and postnatal period body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended 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.

Adverse Reactions

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 nateglinide 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)Preferred TermPlaceboN=458NateglinideN=1441 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.


To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage

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.

Dosage And Administration

Nateglinide Tablets USP 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, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.The 60 mg dose of nateglinide, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA


1c when treatment is initiated.

Dosage In Geriatric Patients

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

Dosage In Renal And Hepatic Impairment

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


PRECAUTIONS,


Hepatic Impairment).

How Supplied

Nateglinide Tablets, USP60 mgPink color coated, round biconvex, beveled edge tablet debossed with “P 984” on one side and plain on the other sideBottles of 100..........NDC 42291-636-01120 mgOrange color coated, oval shaped biconvex, tablet debossed with “P 985” on one side and plain on the other sideBottles of 100........NDC 42291-637-01StorageStore at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature].Dispense in a tight, light resistant containers.Manufactured for:AvKARE, Inc.                 


Pulaski, TN 38478Mfg. Rev. 02/16 


AV 04/16 (P)

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