5.1     Hypoglycemia

All glinides, including STARLIX, 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), Clinical Pharmacology (12.3)].

Patients should take STARLIX before meals and be instructed to skip the dose of STARLIX 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 STARLIX.

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 STARLIX. 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 STARLIX.

Hypoglycemia

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

Weight Gain

Patients treated with STARLIX had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with STARLIX 60 mg (3 times daily) and STARLIX 120 mg (3 times daily) compared to placebo were 1.0 kg and 1.6 kg, respectively.

Laboratory Test

Increases in Uric Acid: There were increases in mean uric acid levels for patients treated with STARLIX alone, STARLIX 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 STARLIX. 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

8.1     Pregnancy

Risk Summary

The available data from published literature and the applicant’s pharmacovigilance with use of Starlix in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). STARLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal reproduction studies, there was no teratogenicity in rats and rabbits administered oral nateglinide during organogenesis at approximately 27 and 8 times the maximum recommended human dose (MRHD), respectively, based on body surface area (BSA).

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c > 7 and has been reported to be as high as 20% to 25% in women with a HbA1c > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Animal data

In embryofetal development studies, nateglinide administered orally during the period of organogenesis was not teratogenic in rats at doses up to 1,000 mg/kg (corresponding to 27 times the MRHD of 120 mg three times per day, based on BSA). In rabbits, embryonic development was adversely affected at 500 mg/kg/day and the incidence of gallbladder agenesis or small gallbladder was increased at a dose of 300 and 500 mg/kg (corresponding to 16 and 27 times the MRHD). No such effects were observed at 150 mg/kg/day (corresponding to 8 times the MRHD). In a pre- and postnatal development study in rats, nateglinide administered by oral gavage at doses of 100, 300, and 1000 mg/kg/day from gestation day 17 to lactation day 21 resulted in lower body weight in offspring of rats administered nateglinide at 1,000 mg/kg/day (corresponding to 27 times the MHRD).

8.2     Lactation

Risk summary

There are no data on the presence of nateglinide in human milk, the effects on the breastfeeding infant, or the effects on milk production. The drug is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Because the potential for hypoglycemia in breast-fed infants, advise women that use of STARLIX is not recommended while breastfeeding.

Data

In rat reproduction studies, nateglinide and its metabolite are excreted in the milk following oral dose (300 mg/kg). The overall milk: plasma (M/P) concentration ratio of the total radioactivity was approximately 1.4 based on AUC0-48 values. The M/P ratio of unchanged nateglinide was approximately 2.2.

8.4     Pediatric Use

The safety and effectiveness of STARLIX 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 STARLIX in clinical studies. No differences were observed in safety or efficacy of STARLIX between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to STARLIX 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 STARLIX 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)].

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

STARLIX stimulates pancreatic insulin secretion within 20 minutes of oral administration. When STARLIX 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 area under the curve (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 (Cmax) generally occur within 1 hour (Tmax) after dosing. Tmax 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 STARLIX 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 Cmax and a delay in time to peak plasma concentration (Tmax).

STARLIX 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 STARLIX 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 15-50 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 (Cmax decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.

In a cohort of 8 patients with Type 2 diabetes and end-stage renal disease (ESRD) (eGFR < 15 mL/min/1.73m2) M1 metabolite accumulation up to 1.2 ng/mL occurred with a dosage of 90 mg once daily for 1 to 3 months. In another cohort of 8 patients with Type 2 diabetes on hemodialysis, M1 concentration decreased after a single session of hemodialysis. Although the hypoglycemic activity of the M1 metabolite is approximately 5 times lower than nateglinide, metabolite accumulation may increase the hypoglycemic effect of the administered dose.

Hepatic Impairment

In patients with mild hepatic impairment, the mean increase in Cmax and AUC of nateglinide were 37% and 30%, respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of STARLIX 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

STARLIX 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.

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 30-40 times and in mice 10-30 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 (corresponding to 16 times the MRHD of 120 mg three times per day, based on BSA).).

14.1     Monotherapy

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

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 STARLIX (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to STARLIX had statistically 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 STARLIX alone (120 mg three times daily before meals), metformin alone (500 mg three times daily), a combination of STARLIX 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 STARLIX monotherapy, and the combination of STARLIX and metformin compared to either STARLIX or metformin monotherapy (see Table 7).

Compared to placebo, STARLIX 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 STARLIX and metformin therapy (see Table 7). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1c in the STARLIX 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 1500 mg daily for at least 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive either STARLIX (60 mg or 120 mg three times daily before meals) or placebo as add-on to metformin. At the end of treatment, STARLIX 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 STARLIX 60 mg and STARLIX 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 STARLIX (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 STARLIX 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 STARLIX (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.