Starlix Tablet

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

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

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

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

Storage

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

Dispense in a tight container, USP.

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

Nateglinide tablets USP are oral antidiabetic agent used in the management of Type 2 diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Nateglinide, (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues. The structural formula is as shown

Nateglinide is a white powder with a molecular weight of 317.43. It is freely soluble in methan

Nateglinide
(nateglinide) Tablets USP

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

Hypoglycemia was relatively uncommon in all treatment arms of the clinical trials. Only 0.3% of ateglinide patients discontinued due to hypoglycemia.Symptoms suggestive of hypoglycemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness.

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

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

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

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.

Mechanism Of Action

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

Pharmacokinetics

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

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

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%).

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.

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.

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.

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

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.

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

Special Populations

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

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

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.

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

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

Pharmacodynamics

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

In a double-blind, controlled clinical trial in which nateglinide was administered before each of three meals, plasma glucose levels were determined over a 12-hour, daytime period after 7 weeks of treatment. Nateglinide was administered 10 minutes before meals. The meals were based on standard diabetic weight maintenance menus with the total caloric content based on each subject’s height.

Nateglinide produced statistically significant decreases in fasting and postprandial glycemia compared to placebo.

Clinical Studies

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

Nateglinide Monotherapy Compared To Placebo

In a randomized, double-blind, placebo-controlled, 24-week study, patients with Type 2 diabetes with HbA1C ≥ 6.8 % on diet alone were randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo. Baseline HbA1C ranged from 7.9% to 8.1% and 77.8% of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization. The addition of nateglinide before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 1). The reductions in HbA1C and FPG were similar for patients naïve to, and those previously exposed to, antidiabetic medications.

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

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive nateglinide (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of nateglinide 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fiftyseven percent of patients were previously untreated with oral antidiabetic therapy. Nateglinide monotherapy resulted in significant reductions in mean HbA1C and mean FPG compared to placebo that were similar to the results of the study reported above (see Table 2).

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

Nateglinide Monotherapy Compared To Other Oral Antidiabetic Agents

In a 24-week, double-blind, active-controlled trial, patients with Type 2 diabetes who had been on a sulfonylurea for ≥ 3 months and who had a baseline HbA1C ≥ 6.5 % were randomized to receive nateglinide (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to nateglinide had significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive nateglinide (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of nateglinide 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fiftyseven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization.The reductions in mean HbA1C and mean FPG at endpoint with metformin monotherapy were significantly greater than the reductions in these variables with nateglinide monotherapy (see Table 2). Relative to placebo, nateglinide monotherapy was associated with significant increases in mean weight whereas metformin monotherapy was associated with significant decreases in mean weight. Among the subset of patients naïve to antidiabetic therapy, the reductions in mean HbA1C and mean FPG for nateglinide monotherapy were similar to those for metformin monotherapy (see Table 2). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the nateglinide monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 2).

Nateglinide Combination Therapy

In the active and placebo-controlled study of metformin and nateglinide described above, the combination of nateglinide and metformin resulted in statistically significantly greater reductions in HbA1C and FPG compared to either nateglinide or metformin monotherapy (see Table2). Nateglinide, alone or in combination with metformin, significantly reduced the prandial glucose elevation from premeal to 2-hours post-meal compared to placebo and metformin alone.

In this study, one episode of severe hypoglycemia (plasma glucose ≤ 36 mg/dL) was reported in a patient receiving the combination of nateglinide and metformin and four episodes of severe hypoglycemia were reported in a single patient in the metformin treatment arm. No patient experienced an episode of hypoglycemia that required third party assistance. Compared to placebo, nateglinide monotherapy was associated with a statistically significant increase in weight, while no significant change in weight was observed with combined nateglinide and metformin therapy (see Table2).

In another 24-week, double-blind, placebo-controlled trial, patients with Type 2 diabetes with HbA1C ≥ 6.8% after treatment with metformin ( ≥ 1500 mg daily for ≥ 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive nateglinide (60 mg or 120 mg three times daily before meals) or placebo in addition to metformin. Combination therapy with nateglinide and metformin was associated with statistically significantly greater reductions in HbA1C compared to metformin monotherapy (-0.4% and -0.6% for nateglinide 60 mg and nateglinide 120 mg plus metformin, respectively).

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

A 24-week, double blind multicenter, placebo-controlled trial was performed in patients with Type 2 diabetes not adequately controlled after a therapeutic response to rosiglitazone monotherapy 8 mg daily. The addition of nateglinide (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1Ccompared to rosiglitazone monotherapy. The difference was -0.77% at 24 weeks. The mean change in weight from baseline was about +3 kg for patients treated with nateglinide plus rosiglitazone vs about +1 kg for patients treated with placebo plus rosiglitazone.

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.

Administration

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

Hypoglycemia

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

Drug Interactions

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

Do not use this medication if you are allergic to nateglinide, if you have type 1 diabetes, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Take care not to let your blood sugar get too low. Low blood sugar (hypoglycemia) can occur if you skip a meal, exercise too long, drink alcohol, or are under stress. Symptoms include headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating. Carry hard candy or glucose tablets with you in case you have low blood sugar. Other sugar sources include orange juice and milk. Be sure your family and close friends know how to help you in an emergency.

Nateglinide is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.