FDA Label for Nateglinide

1 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.

Limitations of Use:

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

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 nateglinide tablets is 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 [see Warnings and Precautions (5.1)].

3 Dosage Forms And Strengths

• Nateglinide Tablets USP, 60 mg are white to off-white, round, biconvex with bevel-edge, film-coated tablets debossed '721' on one side and plain on the other side.
• Nateglinide Tablets USP, 120 mg are light-orange to orange, oval, biconvex with bevel-edge, film-coated tablets debossed '722' on one side and plain on the other side.

4 Contraindications

Nateglinide is contraindicated in patients with a history of hypersensitivity to nateglinide or its active ingredients.

5.1 Hypoglycemia

All glinides, including nateglinide, can cause hypoglycemia [see Adverse Reactions (6.1)]. 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 (7)], 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 (7)], 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 (8.6, 8.7)].

Patients should take nateglinide before meals and be instructed to skip the dose of nateglinide if a meal is skipped [see Dosage and Administration (2)]. 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 Macrovascular Outcomes

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

6 Adverse Reactions

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

Hypoglycemia [see Warnings and Precautions (5.1)]

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 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 nateglinide.

Hypoglycemia

Episodes of severe hypoglycemia (plasma glucose less than 36 mg/dL) were reported in two patients treated with nateglinide. Non-severe hypoglycemia occurred in 2.4 % of nateglinide treated patients and 0.4 % of placebo treated patients [see Warnings and Precautions (5.1)].

Weight Gain

Patients treated with nateglinide had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with nateglinide 60 mg (3 times daily) and nateglinide 120 mg (3 times daily) compared to placebo were 1kg and 1.6 kg respectively.

Laboratory Test

Increases in 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of 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 nateglinide and instructions for managing or preventing them.

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of nateglinide in pregnant women. It is unknown whether nateglinide can cause fetal harm when administered to a pregnant woman. 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). 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 nateglinide is excreted in human milk. Nateglinide is excreted in rat milk. Offspring of rats exposed to 1,000 mg/kg 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 nateglinide should be discontinued in nursing mothers, or if mothers should discontinue nursing.

8.4 Pediatric Use

The safety and effectiveness of 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 nateglinide in clinical studies. 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.

8.6 Renal Impairment

No dosage adjustment is recommended in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment. Use of nateglinide 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 (12.3)].

10 Overdosage

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.

11 Description

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

The structural formula is as shown:

Nateglinide, USP is a white powder with a molecular weight of 317.43. It is freely soluble in methanol and alcohol, soluble in ether, sparingly soluble in acetonitrile and octanol, practically insoluble in water.

Each nateglinide tablet, USP intended for oral administration contains nateglinide, USP 60 mg and 120 mg. In addition, each tablet contains the following inactive ingredients: citric acid anhydrous, colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polysorbate 80, polyethylene glycol, povidone, talc and titanium dioxide. Additionally, each 120 mg tablet contains iron oxide red and iron oxide yellow.

12.1 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.

12.2 Pharmacodynamics

Nateglinide stimulates pancreatic insulin secretion within 20 minutes of oral administration. When 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 nateglinide over the dosage range of 60 mg to 240 mg shows linear pharmacokinetics for both 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 (C_max) generally occur within 1 hour (T_max) after dosing. T_max 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 nateglinide 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 C_max and a delay in time to peak plasma concentration (T_max).

Nateglinide tablets 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 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 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 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 mL/min 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 nateglinide were 37% and 30 % respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of nateglinide 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

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 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.

AM: after morning dose; PM: after evening dose; * after second dose; ↑: increase in the parameter; ↓: decrease in the parameter

AM: after morning dose; PM: after evening dose; SD: single dose; ↑: increase in the parameter; ↓: decrease in the parameter

13.1 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 times to 40 times and in mice 10 times to 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 (approximately 16 times the human therapeutic exposure with a recommended nateglinide dose of 120 mg three times daily before meals).

14.1 Monotherapy

In a 24-week, double-blind, placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide (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 nateglinide 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 patients naïve to, and those previously exposed to, antidiabetic medications.

^ap-value ≤ 0.004              

14.2 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 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.

14.3 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 nateglinide alone (120 mg three times daily before meals), metformin alone (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. 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 nateglinide monotherapy, and the combination of nateglinide and metformin compared to either nateglinide or metformin monotherapy (see Table 7).

Compared to placebo, 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 nateglinide and metformin therapy (see Table 7). 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 7).

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 1,500 mg daily for at least 1 month) were first entered into a four week run-in period of metformin monotherapy (2,000 mg daily) and then randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo as add-on to metformin. At the end of treatment, nateglinide 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 nateglinide 60 mg and nateglinide 120 mg plus metformin, respectively).

14.4 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 nateglinide (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 nateglinide compared to +1 kg for patients treated with placebo when added to rosiglitazone.

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  nateglinide (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

16 How Supplied/Storage And Handling

How Supplied

Nateglinide Tablets USP, 60 mg are white to off-white, round, biconvex with bevel-edge,

film-coated tablets debossed '721' on one side and plain on the other side and are supplied as follows:

NDC 70771-1015-3 in bottle of 30 tablets

NDC 70771-1015-9 in bottle of 90 tablets

NDC 70771-1015-1 in bottle of 100 tablets

NDC 70771-1015-5 in bottle of 500 tablets

NDC 70771-1015-0 in bottle of 1000 tablets

NDC 70771-1015-4 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets

Nateglinide Tablets USP, 120 mg are light-orange to orange, oval, biconvex with bevel-edge, film-coated tablets debossed '722' on one side and plain on the other side and are supplied as follows:

NDC 70771-1016-3 in bottle of 30 tablets

NDC 70771-1016-9 in bottle of 90 tablets

NDC 70771-1016-1 in bottle of 100 tablets

NDC 70771-1016-5 in bottle of 500 tablets

NDC 70771-1016-0 in bottle of 1000 tablets

NDC 70771-1016-4 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets

Storage  and Handling

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in tightly closed container.

17 Patient Counseling Information

Administration

Instruct patients to take nateglinide tablets 1 to 30 minutes before meals. Instruct patients that skip meals to skip their dose of nateglinide tablets [see Dosage and Administration (2)].

Hypoglycemia

Inform patients that nateglinide tablets 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 (5.1)].

Drug Interactions

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

Other

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Rev.:07/17

Package Label.Principal Display Panel

NDC 70771-1015-9 in bottle of 90 tablets

Nateglinide Tablets USP, 60 mg

Rx only

90 tablets

NDC 70771-1016-9 in bottle of 90 tablets

Nateglinide Tablets USP, 120 mg

Rx only

90 tablets