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Starlix®
T2006-110
5001036
5001037
Starlix®
(nateglinide) tablets
Rx only
Prescribing Information
DESCRIPTION
Starlix® (nateglinide) is 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]. Starlix, (-)-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 methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Starlix biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration.
Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, iron oxides (red or yellow), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
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
Pharmacodynamics
Starlix is rapidly absorbed and stimulates pancreatic insulin secretion within 20 minutes of oral administration. When Starlix 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 Starlix was administered before each of three meals, plasma glucose levels were determined over a 12-hour, daytime period after 7 weeks of treatment. Starlix was administered 10 minutes before meals. The meals were based on standard diabetic weight maintenance menus with the total caloric span based on each subject’s height. Starlix 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 Starlix® (nateglinide). 3,513 patients had efficacy values beyond baseline. In these studies Starlix was administered up to 30 minutes before each of three main meals daily.
Starlix® 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 Starlix (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 Starlix 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 Starlix 120 mg three times daily before meals. No patients experienced hypoglycemia that required third party assistance. Patients treated with Starlix 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 Starlix (120 mg three times daily before meals), metformin 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. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Starlix 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).
Placebo | Starlix® 60 mg three times daily before meals | Starlix® 120 mg three times daily before meals | |
| HbA1C (%) | N=168 | N=167 | N=168 |
| Baseline (mean) | 8.0 | 7.9 | 8.1 |
| Change from baseline (mean) | +0.2 | -0.3 | -0.5 |
| Difference from placebo (mean) | -0.5 a | -0.7 a | |
| FPG (mg/dL) | N=172 | N=171 | N=169 |
| Baseline (mean) | 167.9 | 161.0 | 166.5 |
| Change from baseline (mean) | +9.1 | +0.4 | -4.5 |
| Difference from placebo (mean) | -8.7 a | -13.6 a | |
| Weight (kg) | N=170 | N=169 | N=166 |
| Baseline (mean) | 85.8 | 83.7 | 86.3 |
| Change from baseline (mean) | -0.7 | +0.3 | +0.9 |
| Difference from placebo (mean) | +1.0 a | +1.6 a |
a p-value ≤ 0.004
Starlix® Monotherapy Compared to Other Oral Antidiabetic Agents
Starlix® Combination Therapy
INDICATIONS AND USAGE
Starlix® (nateglinide) is indicated as monotherapy to lower blood glucose in patients with Type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM) whose hyperglycemia cannot be adequately controlled by diet and physical exercise and who have not been chronically treated with other antidiabetic agents.
Starlix is also indicated for use in combination with metformin or a thiazolidinedione. In patients whose hyperglycemia is inadequately controlled with metformin or after a therapeutic response to a thiazolidinedione, Starlix may be added to, but not substituted for, those drugs.
Patients whose hyperglycemia is not adequately controlled with glyburide or other insulin secretagogues should not be switched to Starlix, nor should Starlix be added to their treatment regimen.
CONTRAINDICATIONS
Starlix® (nateglinide) is 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
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. Starlix® (nateglinide) should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of Starlix to reduce the risk of hypoglycemia.
Hepatic Impairment: Starlix should be used with caution in patients with moderate-to-severe liver disease because such patients have not been studied.
Loss of Glycemic Control
Transient loss of glycemic control may occur with fever, infection, trauma, or surgery. Insulin therapy may be needed instead of Starlix therapy at such times. Secondary failure, or reduced effectiveness of Starlix over a period of time, may occur.
Information for Patients
Patients should be informed of the potential risks and benefits of Starlix and of alternative modes of therapy. The risks and management of hypoglycemia should be explained. Patients should be instructed to take Starlix 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 Starlix.
Laboratory Tests
Response to therapies should be periodically assessed with glucose values and HbA1C levels.
Drug Interactions
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 may potentiate the hypoglycemic action of Starlix and other oral antidiabetic drugs.
Certain drugs including thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce the hypoglycemic action of Starlix and other oral antidiabetic drugs.
When these drugs are administered to or withdrawn from patients receiving Starlix, the patient should be observed closely for changes in glycemic control.
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 Starlix was administered 10 minutes prior to a liquid meal. Starlix did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.
Carcinogenesis/Mutagenesis/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 Starlix 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 Starlix 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 Starlix dose of 120 mg three times daily before meals).
Pregnancy
Labor and Delivery
The effect of Starlix on labor and delivery in humans is not known.
Nursing Mothers
Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC0-48h 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 Starlix dose of 120 mg, three times daily before meals). It is not known whether Starlix is excreted in human milk. Because many drugs are excreted in human milk, Starlix should not be administered to a nursing woman.
Pediatric Use
The safety and effectiveness of Starlix in pediatric patients have not been established.
Geriatric Use
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.
ADVERSE REACTIONS
In clinical trials, approximately 2,600 patients with Type 2 diabetes were treated with Starlix® (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 Starlix patients discontinued due to hypoglycemia. Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of Starlix and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of Starlix and rosiglitazone than in patients receiving rosiglitazone alone. The following table uls events that occurred more frequently in Starlix patients than placebo patients in controlled clinical trials.
| Placebo | Starlix® | |
| N=458 | N=1441 | |
| Preferred Term | ||
| 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 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. The clinical significance of these findings is unknown.
OVERDOSAGE
In a clinical study in patients with Type 2 diabetes, Starlix® (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 Starlix 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
Starlix® (nateglinide) 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 Starlix, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.
The 60-mg dose of Starlix, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.
Dosage in Geriatric Patients
No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to Starlix 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, Starlix should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS, Hepatic Impairment).
HOW SUPPLIED
Starlix® (nateglinide) tablets
60 mg
Pink, round, beveled edge tablet with “STARLIX” debossed on one side and “60” on the other.
Bottles of 100……………………………………………….NDC 0078-0351-05
Bottles of 500……………………………………………….NDC 0078-0351-08
120 mg
Yellow, ovaloid tablet with “STARLIX” debossed on one side and “120” on the other.
Bottles of 100……………………………………………….NDC 0078-0352-05
Bottles of 500……………………………………………….NDC 0078-0352-08
Storage
Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF).
Dispense in a tight container, USP.
T2006-110
REV: November 2006 5001036
5001037
Manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis