Starlix

Absorption: Following oral administration prior to a meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (C_max) generally occurring within 1 hour to peak plasma concentration (T_max) after dosing. When administered to patients with Type 2 diabetes over the dosage range of 60 to 240 mg 3 times a day for 1 week, nateglinide demonstrated linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and C_max. T_max was found to be independent of dose in this patient population. Absolute bioavailability is estimated to be 73%. When given with 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 T_max. Nateglinide is usually taken immediately (1 minute) before a meal but may be taken up to 30 minutes before meals (see Dosage).

Distribution: Based on i.v. data, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 L. 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 µg/mL.

Metabolism: Nateglinide is extensively 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 than nateglinide. The isoprene minor metabolite possesses similar potency as the parent compound nateglinide.

Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly metabolized by cytochrome P450 isoenzyme CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%) (see Precautions, Drug Interactions).

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 is recovered in the urine. Most of the ¹⁴C-nateglinide (83%) is excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the ¹⁴C-nateglinide is 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 1.5 hours. Consistent with this short elimination half-life, there is no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg 3 times daily for 7 days.

Special Populations: Geriatrics: There was no difference in the safety and efficacy profile of nateglinide between the elderly and the general population. In addition, age did not influence the pharmacokinetic properties of nateglinide. Therefore, no special 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 needed.

Race: Results of a population pharmacokinetic analysis included subjects of Caucasian (n=255), black (n=12) and other ethnic origins (n=45). The results did not indicate any influence of race on the pharmacokinetics of nateglinide, but the numbers are small.

Renal Impairment: The systemic availability and the half-life of nateglinide in diabetic subjects with moderate to severe renal insufficiency (CrCl: 0.25 to 0.83 mL/sec/1.73 m² or 15 to 50 mL/min/1.73 m²), whether or not on dialysis, do not differ to a clinically significant extent from those in healthy subjects, therefore no dose adjustment is necessary.

Hepatic Impairment: The systemic availability and the half-life of nateglinide in non-diabetic subjects with mild to moderate hepatic insufficiency do not differ to a clinically significant extent from those in healthy subjects. Consequently, dose adjustment for patients with mild to moderate hepatic disease is not required. Since patients with moderate to severe hepatic disease were not studied, nateglinide should be used with caution in such patients.

Pharmacodynamics and Clinical Effects: In clinical studies, treatment with nateglinide resulted in an improvement in glycemic control, as measured by glycosylated hemoglobin A1c (HbA_lC) and post-meal glucose. Fasting plasma glucose (FPG) levels were also reduced. This is consistent with the mechanism of action of nateglinide which is to restore early insulin secretion and thereby reduce post-meal glucose. The improvement in glycemic control was durable, with maintenance of effect compared to baseline for at least 52 weeks. In the 24-week, placebo-controlled, clinical trials, the mean weight gain in patients treated with nateglinide was 1 kg or less.

Clinical Studies: Compared to repaglinide in healthy subjects, nateglinide was associated with a faster rise of insulin concentrations (within 30 minutes) and a shorter duration (return to placebo levels in 1.5 versus 4 hours) resulting in less total insulin exposure. Nateglinide was also more effective in blunting the post-meal plasma glucose excursion compared to repaglinide (89% vs 56%) without inducing prolonged hypoglycemia.

The loss of first phase insulin secretion is a hallmark of Type 2 diabetes. Nateglinide restores this response in patients with Type 2 diabetes.

The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated in patients with Type 2 diabetes that improved glycemic control, as reflected in HbA_1C and fasting glucose levels, was associated with a reduction in the diabetic complications retinopathy, neuropathy and nephropathy.

The DECODE study (Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe study published in 1999) and the Diabetes Intervention Study demonstrated the role of 2-hour plasma glucose as an independent risk factor for total and cardiovascular mortality whereas FPG did not significantly contribute to the prediction of mortality.

A total of 2122 patients with Type 2 diabetes were treated with nateglinide in double-blind, placebo or active controlled studies. These studies included two 24-week placebo controlled studies, two 24-week active controlled studies, and five additional efficacy studies with treatment durations of 8 weeks (2 studies), 12 weeks (2 studies) or 16 weeks. In addition, 3 controlled extension studies were carried out to 52 weeks. All 9 studies were characterized by a lengthy washout period of prior therapy so as to adequately evaluate the treatment effect of nateglinide by minimizing confounding effects of previous antidiabetic medications. In these studies, nateglinide was administered before main meals, usually breakfast, lunch and dinner.

Effect on Post-meal (prandial) Plasma Glucose: Restoration of early insulin release during meals, resulting in reduced post-meal plasma glucose, is an important component of optimal therapy in Type 2 diabetes.

In an 8-week study that compared the effect of nateglinide 120 mg taken with meals, glyburide 10 mg once daily, and placebo on daytime glucose and insulin profiles, treatment with nateglinide was associated with a greater reduction of the post-meal glucose excursion and less total insulin exposure.

The rapid rise and short duration of insulin release associated with nateglinide results in a reduction in glucose fluctuations throughout the day. Nateglinide significantly reduced the standard deviation of the plasma glucose levels compared to glyburide. The results illustrated in Figure 1 suggest that the postprandial insulin pattern in response to nateglinide approximates the physiological pattern.

After a liquid (Sustacal, Mead Johnson) meal, both nateglinide and glyburide reduced the incremental glucose exposure over 4 hours. This reduction was statistically significantly greater for nateglinide compared to glyburide (i.e., the percent change from baseline AUC_0-4 was -64%, -32% and -1% for nateglinide, glyburide and placebo respectively).

In a 24-week, placebo-controlled study conducted to evaluate the effect of nateglinide as monotherapy and in combination with metformin, there was a statistically significant reduction in incremental mealtime plasma glucose AUC_{(0-130 min)}. The post-meal glycemic excursion was reduced by 16% with metformin, 34% with nateglinide 120 mg before meals and by 40% with the combination of nateglinide 120 mg before meals plus metformin 500 mg t.i.d. These data confirm that the efficacy of nateglinide in lowering post-meal glucose is maintained when administered with a drug with a complementary mode of action.

Monotherapy: Two 24-week, placebo-controlled studies were conducted in patients with Type 2 diabetes that were inadequately controlled on diet alone. In Study A, statistically significant reductions in HbA_1C occurred in a dose-dependent manner over the range of 60 to 180 mg when nateglinide was administered just before breakfast, lunch, and dinner as monotherapy. The mean change from baseline for reduction of HbA_1C was 0.004 to 0.006 (0.4 to 0.6%). The difference from placebo was 0.006 to 0.01 (0.6 to 1.0%) for 120 mg nateglinide before breakfast, lunch, and dinner. Statistically significant reductions in fasting plasma glucose (FPG) over the range of 0.61 to 0.93 mmol/L were also observed.

In a second 24-week study (Study B) conducted to evaluate the effect of nateglinide monotherapy, the mean change from baseline for reduction of HbA_1C was 0.005 (0.5%). The difference from placebo was 0.009 (0.9%) for 120 mg nateglinide before breakfast, lunch, and dinner, which was statistically significant.

Combination with Metformin: The results of above study (Study B) suggest that nateglinide and metformin are synergistic when used in combination, due to complementary modes of action. The combination of the 2 drugs demonstrated an 84% responder rate based on a reduction of >10% from pretreatment baseline HbA_1C. The effect on HbA_1C and FPG was greater with nateglinide plus metformin combination therapy than with either agent alone. Virtually all of the post-meal glucose effect was due to nateglinide. Metformin had a greater effect on HbA_1C than nateglinide.

Other: In a 24-week active controlled study, patients who were stabilized on high dose sulfonylurea for at least 3 months and directly switched to monotherapy with nateglinide 60 or 120 mg before meals experienced reduced glycemic control as evidenced by increases in FPG and HbA_1C.

In a 12-week study of patients inadequately controlled on glyburide 10 mg once daily, the addition of nateglinide 120 mg before meals did not produce any additional benefit.

Data available from both in vitro and in vivo drug metabolism experiments indicate that nateglinide is predominantly metabolized by the cytochrome P450 isoenzyme CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Nateglinide has the ability to inhibit the in vitro metabolism of tolbutamide, a CYP2C9 substrate. No inhibition of CYP 3A4 metabolic reactions is expected based on in vitro experiments, suggesting a low potential for clinically significant pharmacokinetic drug interactions.

Glyburide: Concomitant administration of nateglinide (120 mg t.i.d.) and glyburide (10 mg/day) to healthy volunteers had no clinically relevant effect on the pharmacokinetics of either agent.

Metformin: In healthy volunteers, nateglinide (120 mg t.i.d.) taken with metformin (500 mg/day) did not alter the pharmacokinetics of either agent.

Digoxin: Nateglinide (120 mg t.i.d.) when administered with digoxin (1 mg/day) to healthy volunteers, did not alter the steady-state pharmacokinetic properties of either agent.

Warfarin: Nateglinide (120 mg t.i.d.) taken with warfarin (30 mg/day) by healthy volunteers had no clinically relevant effect on the pharmacokinetics of either agent.

Diclofenac: Administration of nateglinide (120 mg b.i.d.) with diclofenac (75 mg/day) to healthy volunteers did not alter the pharmacokinetics of either agent.

In an interaction trial with sulfinpyrazone, a potent and selective CYP2C9 inhibitor, a modest increase in nateglinide AUC (28%) was observed in healthy volunteers, with no changes in the mean C_max and elimination half-life. A more prolonged effect and possibly a risk of hypoglycemia cannot be excluded in patients when nateglinide is co-administered with CYP2C9 inhibitors.

Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In an in vitro displacement study with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, ASA, tolbutamide, and metformin, there was no influence by these drugs on the extent of nateglinide protein binding. In a separate in vitro study, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, ASA and tolbutamide.

Certain drugs, including NSAID agents, salicylates, MAOIs and nonselective beta-adrenergic-blocking agents may potentiate the hypoglycemic action of oral antidiabetic drugs.

Certain drugs including thiazides, corticosteroids, thyroid products and sympathomimetics may reduce the hypoglycemic action of oral antidiabetic drugs.

When these drugs are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycemic control.

Among patients receiving nateglinide as monotherapy in controlled clinical studies ranging from 8 weeks to 1 year in duration, 436 patients (30%) were 65 or older and 80 patients (5.4%) were 75 or older. No differences in safety or efficacy between these subjects and those less than 65 were observed for nateglinide. There was no increase in frequency of hypoglycemia in patients over the age of 65. However, greater sensitivity of some older individuals to nateglinide therapy cannot be ruled out.

Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC_0-48h ratio in milk to plasma was about 1.4. Body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg during the peri- and postnatal period. 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.

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

Nateglinide was not teratogenic in rats at doses up to 1000 mg/kg (20 times the maximum daily human dose when compared on the basis of body surface area). In the rabbit, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at a dose which also resulted in maternal toxicity (i.e., 500 mg/kg, which is 21 times the maximum daily human dose based on body surface area).

There are no adequate and well-controlled studies in pregnant women. Nateglinide is not recommended for use in pregnancy.

Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Since the primary mechanism of action for nateglinide is reducing post-meal glucose (an essential contributor to HbA_1C), the therapeutic response to nateglinide may be monitored with 1 to 2 hour post-meal glucose measurements. In addition, glycosylated hemoglobin (HbA_1C) should also be measured periodically.

The pharmacokinetics of nateglinide are not affected by the composition of a meal (high protein, fat or carbohydrate). Nateglinide does not have any effect on gastric emptying.

Patients should be informed of the following: Management of Type 2 diabetes should include adherence to dietary instructions, regular exercise and routine testing of blood glucose and glycosylated hemoglobin (HbA_1C).

All oral antidiabetic treatments have the potential to cause hypoglycemia. Geriatric patients, malnourished patients and those with adrenal or pituitary insufficiency are more susceptible to the glucose lowering effects of these treatments. A missed or delayed meal, strenuous physical exercise, or concomitant use of oral antidiabetic agents may increase the risk of hypoglycemia. Patients experiencing hypoglycemia should not drive or operate machinery. Hypoglycemia may be difficult to recognize in elderly patients and in patients receiving β-blockers.

Nateglinide should be taken before meals and is usually taken immediately (1 minute) before meals but may be taken up to 30 minutes before meals. Patients who skip a meal should be instructed to skip a dose for that meal.

Each pink, round, beveled-edged, film-coated tablet with “Starlix” debossed on one side and “60” on the other side, contains: nateglinide 60 mg. Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, iron oxide (red or yellow), lactose (hydrous), magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. Cartons of 7 blister strips of 12 tablets. Store between 15 and 30°C. Keep bottles tightly closed.

Each yellow, ovaloid, film-coated tablet, with “Starlix” debossed on one side and “120” on the other side, contains: nateglinide 120 mg. Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, iron oxide (red or yellow), lactose (hydrous), magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. Cartons of 7 blister strips of 12 tablets. Store between 15 and 30°C. Keep bottles tightly closed.

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 i.v. glucose. As nateglinide is highly protein bound, dialysis is not an efficient means of removing it from the blood.