NDC 0078-0351 Starlix

Nateglinide

NDC Product Code 0078-0351

NDC CODE: 0078-0351

Proprietary Name: Starlix What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Nateglinide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Nateglinide is used alone or with other medications to control high blood sugar along with a proper diet and exercise program. It is used in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke. It works by stimulating the body to produce more insulin. Insulin is a natural substance that allows the body to properly use sugar from the diet.

Product Characteristics

Color(s):
PINK (C48328)
Shape: ROUND (C48348)
Size(s):
10 MM
Imprint(s):
STARLIX;60
Score: 1

NDC Code Structure

  • 0078 - Novartis Pharmaceuticals Corporation

NDC 0078-0351-05

Package Description: 100 TABLET in 1 BOTTLE

NDC Product Information

Starlix with NDC 0078-0351 is a a human prescription drug product labeled by Novartis Pharmaceuticals Corporation. The generic name of Starlix is nateglinide. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Novartis Pharmaceuticals Corporation

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Starlix Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • NATEGLINIDE 60 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • HYPROMELLOSE 2208 (15000 MPA.S) (UNII: Z78RG6M2N2)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • POVIDONES (UNII: FZ989GH94E)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Glinide - [EPC] (Established Pharmacologic Class)
  • Potassium Channel Antagonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Novartis Pharmaceuticals Corporation
Labeler Code: 0078
FDA Application Number: NDA021204 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 12-04-2000 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 09-30-2021 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Nateglinide Oral

Nateglinide Oral is pronounced as (nuh tay' gli nide)

Why is nateglinide oral medication prescribed?
Nateglinide is used alone or in combination with other medications to treat type 2 diabetes (condition in which the body does not use insulin normally and therefore canno...
[Read More]

* Please review the disclaimer below.

Starlix Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1     Indications And Usage

STARLIX is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.Limitations of Use:STARLIX 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 STARLIX is 120 mg orally three times daily before meals.The recommended dose of STARLIX is 60 mg orally three times daily before meals in patients who are near glycemic goal when treatment is initiated.Instruct patients to take STARLIX 1 to 30 minutes before meals.In patients who skip meals, instruct patients to skip the scheduled dose of STARLIX to reduce the risk of hypoglycemia [see Warnings and Precautions (5.1)].

3     Dosage Forms And Strengths

  • 60 mg tablets: pink, round, beveled edge film-coated tablet with “STARLIX” debossed on one side and “60” on the other 120 mg tablets: yellow, ovaloid film-coated tablet with “STARLIX” debossed on one side and “120” on the other

4     Contraindications

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

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)]. 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     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 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. Table 1: Adverse Reactions other than Hypoglycemia (%) occurring Greater than or Equal to 2% in STARLIX-Treated Patients from Pool of 12 to 64 week Placebo Controlled TrialsPlaceboN=458STARLIXN=1441Preferred TermUpper Respiratory Infection8.110.5Back Pain3.74.0Flu Symptoms2.63.6Dizziness2.23.6Arthropathy2.23.3Diarrhea3.13.2Accidental Trauma1.72.9Bronchitis2.62.7Coughing2.22.4HypoglycemiaEpisodes 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 GainPatients 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 TestIncreases 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 urticariaHepatobiliary 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 STARLIX and instructions for managing or preventing them.Table 2: Clinically Significant Drug Interactions with STARLIXDrugs That May Increase the Blood-Glucose-Lowering Effect of STARLIX and Susceptibility to HypoglycemiaDrugs:Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, anabolic hormones (e.g. methandrostenolone), guanethidine, gymnema sylvestre, glucomannan, thioctic acid, and inhibitors of CYP2C9 (e.g. amiodarone, fluconazole, voriconazole, sulfinpyrazone), alcohol.Intervention:Dose reductions and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of STARLIX and Increase Susceptibility to HyperglycemiaDrugs:Thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), and CYP inducers (e.g. rifampin, phenytoin and St John’s Wort).Intervention:Dose increases and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.Drugs That May Blunt Signs and Symptoms of HypoglycemiaDrugs:beta-blockers, clonidine, guanethidine, and reserpineIntervention:Increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.

8.1     Pregnancy

Pregnancy Category C
There are no adequate and well-controlled studies of nateglinide in pregnant women. It is unknown whether STARLIX can cause fetal harm when administered to a pregnant woman. STARLIX 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 STARLIX should be discontinued in nursing mothers, or if mothers should discontinue nursing.

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)].

10     Overdosage

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 STARLIX is highly protein bound, dialysis is not an efficient means of removing it from the blood.

11     Description

STARLIX (nateglinide) is an oral blood glucose-lowering drug of the glinide class. 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.

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 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. AbsorptionAbsolute 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.DistributionFollowing 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.ExcretionNateglinide 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 PopulationsRenal ImpairmentNo 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.Hepatic ImpairmentIn 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. RaceResults 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.AgeAge does not influence the pharmacokinetic properties of nateglinide. Drug Interactions:In vitro assessment of drug interactionsSTARLIX 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 interactionsThe 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. Table 3: Effect of Coadministered Drugs on Pharmacokinetics of NateglinideAM: after morning dose; PM: after evening dose; * after second dose; ↑: increase in the parameter; ↓: decrease in the parameterCoadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange in CmaxChange in AUCGlyburide10 mg once daily for 3 weeks120 mg three times a day, single dose8.78% ↓3.53 % ↓Metformin500 mg three times a day for 3 weeks120 mg three times a day, single doseAM: 7.14% ↑PM: 11.4% ↓AM: 1.51% ↑PM: 5.97% ↑Digoxin1 mg, single dose120 mg three times a day, single doseAM: 2.17% ↓PM: 3.19% ↑AM: 7.62% ↑PM: 2.22% ↑Warfarin30 mg, single dose120 mg three times a day for 4 days2.65% ↑3.72% ↓Diclofenac75 mg, single dose120 mg twice daily, single doseAM: 13.23% ↓*PM: 3.76% ↑AM: 2.2% ↓*PM: 7.5% ↑Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered DrugsAM: after morning dose; PM: after evening dose; SD: single dose; ↑: increase in the parameter; ↓: decrease in the parameterCoadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange in CmaxChange in AUCGlyburide10 mg once daily for 3 weeks120 mg three times a day, single dose3.18% ↓7.34% ↓Metformin500 mg three times a day for 3 weeks120 mg three times a day, single doseAM: 10.7% ↑PM: 0.40% ↑AM: 13.3% ↑PM: 2.27% ↓Digoxin1 mg, single dose120 mg three times a day, single dose5.41% ↓6.58 % ↑Warfarin30 mg, single dose120 mg three times a day for 4 daysR-warfarin: 1.03% ↓S-warfarin: 0.85% ↓R-warfarin: 0.74% ↑S-warfarin: 7.23% ↑Diclofenac75 mg, single dose120 mg twice daily, single dose2.19% ↑7.97% ↑

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 (approximately 16 times the human therapeutic exposure with a recommended STARLIX 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 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. Table 5: Endpoint Results for a 24-week, Fixed Dose Study of STARLIX Monotherapya p-value ≤ 0.004 PlaceboSTARLIX 60 mg three times daily before mealsSTARLIX 120 mg three times daily before mealsHbA1C (%)N=168N=167N=168Baseline (mean)8.07.98.1Change from baseline (mean)+0.2-0.3-0.5Difference from placebo (mean)-0.5 a-0.7 aFPG (mg/dL)N=172N=171N=169Baseline (mean)167.9161.0166.5Change from baseline (mean)+9.1+0.4-4.5Difference from placebo (mean)-8.7 a-13.6 a

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 significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.Table 6: Endpoint Results for a 24-week Study of STARLIX Monotherapy Compared to Glyburidea p-value < 0.001Glyburide10 mgOnce dailySTARLIX 60 mg three times daily before mealsSTARLIX 120 mg three times daily before mealsHbA1C (%)N=183N=178N=179Baseline (mean)7.88.07.9Change from baseline (mean)0.31.31.1Difference from glyburide1.0 a0.9 aFPG (mmol/L)N=184N=182N=180Baseline (mean)9.449.679.61Change from baseline (mean)0.193.062.84Difference from glyburide2.87 a2.66 a

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).Table 7: Endpoint results for a 24-week study of STARLIX Monotherapy and Combination with Metformina p-value ≤ 0.05 vs. placebob p-value ≤ 0.03 vs. metforminc p-value ≤ 0.05 vs. combination* Metformin was administered three times dailyPlaceboSTARLIX 120 mg three times daily before mealsMetformin500 mg three times dailySTARLIX120 mg before meals plus Metformin*HbA1C (%)AllN=160N=171N=172N=162Baseline (mean)8.38.38.48.4Change from baseline (mean)+0.4-0.4 bc-0.8 c-1.5Difference from placebo -0.8 a-1.2 a-1.9 aNaїveN=98N=99N=98N=81Baseline (mean)8.28.18.38.2Change from baseline (mean)+0.3-0.7 c-0.8 c-1.6Difference from placebo-1.0 a-1.1 a-1.9 aNon-NaїveN=62N=72N=74N=81Baseline (mean)8.38.58.78.7Change from baseline (mean)+0.6+0.004 bc-0.8 c-1.4Difference from placebo-0.6 a-1.4 a-2.0 aFPG (mg/dL)AllN=166N=173N=174N=167Baseline (mean)194.0196.5196.0197.7Change from baseline (mean)+8.0-13.1 bc-30.0 c-44.9Difference from placebo-21.1 a-38.0 a-52.9 aIn 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).Table 8: Endpoint Results for a 24-week Study of STARLIX Monotherapy as Add-on to Metformina p-value 0.003 vs. metforminb p-value < 0.001 vs. metforminAll STARLIX/placebo taken three times daily before meals; all metformin 1000 mg twice daily.
Placebo +metforminSTARLIX 60 mg+metforminSTARLIX 120 mg+ metforminHbA1C (%)N=150N=152N=154Baseline (mean)8.28.08.2Change from baseline (mean)0.01-0.4-0.6Difference from metformin-0.4 a-0.6 b

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.Table 9: Endpoint Results for a 24-week Study of the Effect of Adding STARLIX or Placebo to Rosiglitazonea p-value ≤ 0.0001Placebo +rosiglitazone8 mg once dailySTARLIX 120 mgbefore meals + rosiglitazone8 mg once dailyHbA1C (%)N=191N=194Baseline (mean)8.48.3Change from baseline (mean)0.03-0.7Difference from rosiglitazone (mean)-0.7 a

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.Table 10: Endpoint Results for a 12-week Study of the Effect of Adding STARLIX or Placebo to GlyburidePlacebo or STARLIX given 10 minutes prior to breakfast, lunch, and dinner; glyburide given with the breakfast dose of STARLIX or placebo.a p-value 0.6959b p-value 0.1246Placebo +glyburide10 mg once dailySTARLIX 60 mgbefore meals + glyburide10 mg once dailySTARLIX 120 mgbefore meals + glyburide10 mg once dailyHbA1C (%)N=58N=55N=54Baseline (mean)8.78.78.7Change from baseline (mean)0.30.2-0.02Difference from glyburide (mean)-0.1 a-0.3 b

16     How Supplied/Storage And Handling

How Supplied60 mgPink, round, beveled edge film-coated tablet with “STARLIX” debossed on one side and “60” on the other.Bottles of 100……………………………………………….NDC 0078-0351-05120 mgYellow, ovaloid film-coated tablet with “STARLIX” debossed on one side and “120” on the other.Bottles of 100……………………………………………….NDC 0078-0352-05Storage and HandlingStore at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF). Dispense in a tight container, USP.

17     Patient Counseling Information

AdministrationInstruct 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 (2)].HypoglycemiaInform 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 (5.1)].Drug Interactions Discuss potential drug interactions with patients and inform them of potential drug-drug interactions with STARLIX.Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisT2017-31March 2017

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