NATEGLINIDE: 183 Adverse Event Reports & Safety Profile

Nateglinide, USP is an oral blood glucose-lowering drug of the glinide class. Nateglinide, USP (-)-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 or almost white powder with a molecular weight of 317.43 g/mol. It is freely soluble in methanol, methylene chloride and in alcohol, soluble in ether, sparingly soluble in acetonitrile and in octanol, practically insoluble in water. Nateglinide tablets contain 60 mg, or 120mg, of nateglinide for oral administration. Inactive ingredients : colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose, mannitol, iron oxide (yellow and red), polyethylene glycol, povidone, pre-gelatinized starch, sodium lauryl sulphate, sodium starch glycolate , sodium stearyl fumarate, talc and titanium dioxide. Film-coating material contains opadry pink and opadry yellow for the 60 mg and 120 mg. Opadry pink contains hypromellose, iron oxide red, macrogol and titanium dioxide. Opadry yellow contains hypromellose, iron oxides (yellow and red), macrogol, titanium dioxide, and talc. nate-spl-strc

AND USAGE Nateglinide Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use : Nateglinide Tablets should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Nateglinide

Tablets are a glinide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use : Not for treating type 1 diabetes mellitus or diabetes ketoacidosis ( 1 )

2 DOSAGE & ADMINISTRATION The recommended dose of nateglinide tablets is 120 mg orally three times daily before meals. The recommended dose of nateglinide tablets is 60 mg orally three times daily before meals in patients who are near glycemic goal when treatment is initiated. Instruct patients to take nateglinide tablets 1 to 30 minutes before meals. In patients who skip meals, instruct patients to skip the scheduled dose of nateglinide tablets to reduce the risk of hypoglycemia [ see Warnings and Precautions ( 5.1 ) ].

• Recommended dose is 120 mg three times daily. ( 2 )
• In patients who are near glycemic goal when treatment is initiated, 60 mg three times daily may be administered. ( 2 )
• Administer 1 to 30 minutes before meals. ( 2 )
• If a meal is skipped, skip the scheduled dose to reduce the risk of hypoglycemia. ( 2 , 5.1 )

Nateglinide Tablets are contraindicated in patients with a history of hypersensitivity to Nateglinide Tablets or its inactive ingredients. History of hypersensitivity to nateglinide or its inactive ingredients ( 4 )

REACTIONS The following serious adverse reaction is also described elsewhere in the labeling:

• Hypoglycemia [see Warnings and Precautions (5.1)]
• Common adverse reactions associated with nateglinide (3% or greater incidence) were upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cadila Pharmaceuticals Limited at 1-202-355-9785 (fax 1-202-355-9784) or www.cadilapharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 nateglinide. 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 nateglinide.

Table

1: Adverse Reactions other than Hypoglycemia (%) occurring Greater than or Equal to 2% in Nateglinide -Treated Patients from Pool of 12 to 64 week Placebo Controlled Trials Placebo Nateglinide N=458 N=1,441 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 Episodes of severe hypoglycemia (plasma glucose less than 36 mg/dL) were reported in two patients treated with nateglinide tablets. Non-severe hypoglycemia occurred in 2.4 % of nateglinide tablets treated patients and 0.4 % of placebo treated patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>.

Weight Gain

Patients treated with nateglinide tablets had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with nateglinide tablets 60 mg (3 times daily) and nateglinide tablets 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 nateglinide tablets alone, nateglinide tablets 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 nateglinide tablets. 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

AND PRECAUTIONS Hypoglycemia : Nateglinide Tablets may cause hypoglycemia. Administer before meals to reduce the risk of hypoglycemia. Skip the scheduled dose of Nateglinide Tablets if a meal is skipped to reduce the risk of hypoglycemia. ( 5.1 )

Macrovascular

Outcomes : There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Nateglinide Tablets. ( 5.2 )

5.1 Hypoglycemia All glinides, including Nateglinide Tablets, can cause hypoglycemia <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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) <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> , 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> , and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology (12.3) ]</span> . Patients should take Nateglinide Tablets before meals and be instructed to skip the dose of Nateglinide Tablets if a meal is skipped <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> . 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 Nateglinide Tablets.

INTERACTIONS Table 2 includes a list of drugs with clinically important drug interactions when concomitantly administered or withdrawn with nateglinide tablets and instructions for managing or preventing them.

Table

2: Clinically Significant Drug Interactions with Nateglinide Drugs That May Increase the Blood-Glucose-Lowering Effect of Nateglinide and Susceptibility to Hypoglycemia Drugs: 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), or in patients known to be poor metabolizers of CYP2C9 substrates, alcohol. Intervention: Dose reductions and increased frequency of glucose monitoring may be required when nateglinide tablets are coadministered with these drugs. Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of Nateglinide and Increase Susceptibility to Hyperglycemia Drugs : 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 nateglinide tablets are coadministered with these drugs.

Drugs That May Blunt

Signs and Symptoms of Hypoglycemia Drugs: beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when nateglinide tablets are co-administered with these drugs.Drugs: beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when nateglinide tablets are coadministered with these drugs.

• Drugs That May Increase the Potential for Hypoglycemia : Nateglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered ( 7 )
• Drugs That May Increase the Potential for Hyperglycemia : Nateglinide dose increases and increased frequency of glucose monitoring may be required when co-administered ( 7 )
• Drugs That May Blunt Signs and Symptoms of Hypoglycemia : Increased frequency of glucose monitoring may be required when co-administered ( 7 )