nateglinide 60 mg tablet generic starlix

Uses

Diabetes Mellitus

Nateglinide is used as monotherapy as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone and who have not been chronically treated with other oral antidiabetic agents. Nateglinide also may be used in combination with metformin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with metformin or a thiazolidinedione alone. However, in such patients, nateglinide should be added to, not substituted for, these drugs. In addition, the manufacturer states that nateglinide should not be added to or substituted for other insulin secretagogues (e.g., sulfonylureas) in patients whose hyperglycemia cannot be controlled adequately with such drugs.

The American Diabetes Association (ADA) currently classifies diabetes mellitus as type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes). Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus previously was described as adult-onset (AODM) diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on age of onset. Many patients' diabetes mellitus does not easily fit into a single classification. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.

Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. While children with immune-mediated type 1 diabetes generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population. Distinguishing between type 1 and type 2 diabetes mellitus in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).

Metformin generally is recommended as initial antidiabetic therapy in patients with type 2 diabetes mellitus, provided no contraindications exist, because of the absence of weight gain or hypoglycemia, generally low adverse effect profile, and relatively low cost of this drug. Some experts state that meglitinides may be appropriate choices in selected patients but are not preferred as second-line therapy after failure of metformin monotherapy because of their overall lower effectiveness, limited clinical data, and relative expense. In addition, use of meglitinides are not recommended in hospitalized patients with diabetes mellitus because of a lack of data in such patients.

Safety and efficacy of nateglinide as monotherapy for the management of type 2 diabetes mellitus were established in several randomized, double-blind studies of up to 24 weeks' duration. Nateglinide improved glycemic control as measured by fasting glucose and glycosylated hemoglobin (Hb A1_c) compared with placebo. In clinical studies, nateglinide generally was less effective in patients who previously were treated with other oral antidiabetic agents compared with treatment-naive patients.

Efficacy of nateglinide in combination with metformin was established in several studies of 24 weeks' duration in which combined therapy resulted in improved glycemic control compared with monotherapy with nateglinide or metformin. However, in a 12-week study in patients with type 2 diabetes mellitus inadequately controlled by glyburide monotherapy, the addition of nateglinide did not produce any improvement in glycemic control when compared with glyburide monotherapy.

Efficacy of nateglinide in combination with rosiglitazone was established in a study of 24 weeks' duration in patients inadequately controlled with rosiglitazone monotherapy. The addition of nateglinide (120 mg 3 times daily) to rosiglitazone monotherapy (8 mg once daily) resulted in improved glycemic control (as determined by reduction of HbA_1c from baseline, the primary clinical end point) compared with continuation of rosiglitazone monotherapy. The mean change in body weight from baseline was greater in patients receiving combination therapy than in those continuing to receive monotherapy.

For additional information on the management of type 2 diabetes mellitus, see Uses: Diabetes Mellitus in Repaglinide 68:20.16.

Dosage and Administration

General

Nateglinide is administered orally 3 times daily 1-30 minutes before meals.

The recommended initial or maintenance dosage of nateglinide as monotherapy or in combination with metformin or a thiazolidinedione is 120 mg 3 times daily prior to each meal. For patients who are near their goal HbA_1c when nateglinide therapy is initiated, a dosage of 60 mg of nateglinide 3 times daily prior to each meal is recommended as monotherapy or in combination with metformin or a thiazolidinedione.

For information on monitoring antidiabetic therapy, see Dosage: Diabetes Mellitus under Dosage and Administration in Repaglinide 68:20.16.

Special Populations

No special population dosage recommendations at this time.

Cautions

Contraindications

Known hypersensitivity to nateglinide or any ingredient in the formulation. Type 1 (insulin-dependent) diabetes mellitus or diabetic ketoacidosis.

Warnings/Precautions

General Precautions

Hypoglycemia

As with other oral antidiabetic agents, there is a risk of developing hypoglycemia in patients receiving nateglinide. In clinical studies, hypoglycemia occurred in 2.4% of patients receiving monotherapy with the drug, and 0.3% of patients discontinued nateglinide because of hypoglycemia. To reduce the risk of hypoglycemia, the drug should be administered before meals, and if a meal is to be skipped, the dose of nateglinide should be omitted.

The risk of hypoglycemia is related to the severity of diabetes mellitus, level of glycemic control, and other patient characteristics. Geriatric or malnourished patients and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effects of oral antidiabetic agents. The risk may be increased by strenuous exercise, alcohol ingestion, insufficient caloric intake, or combined therapy with other antidiabetic agents.

Loss of Glycemic Control

To maintain glycemic control during periods of stress (e.g., fever, trauma, infection, surgery), temporary discontinuance of nateglinide and administration of insulin may be required. The efficacy of nateglinide may decrease over time.

Metabolic Effects

In clinical studies, small increases in mean serum uric acid concentrations were observed in all study groups (e.g., nateglinide monotherapy, metformin monotherapy, nateglinide and metformin combination therapy, glyburide monotherapy). The clinical importance, if any, of these findings has not been established.

Specific Populations

Pregnancy

Category C.

Lactation

Nateglinide is distributed into milk in rats; use in nursing women is not recommended.

Pediatric Use

Safety and efficacy not established in children.

Geriatric Use

No substantial differences in safety and efficacy nor in pharmacokinetics relative to younger adults, but increased sensitivity cannot be ruled out, and this age group is at increased risk of hypoglycemia.

Hepatic Impairment

Use with caution in patients with moderate-to-severe hepatic impairment. No dosage adjustment is necessary in patients with mild hepatic impairment.

Renal Impairment

No dosage adjustment is necessary in patients with mild-to-severe renal impairment, but those with severe impairment may be at increased risk of hypoglycemia.

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving nateglinide include upper respiratory tract infection, back pain, flu-like symptoms, dizziness, arthropathy, diarrhea, accidental trauma, bronchitis, cough, and hypoglycemia.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of cytochrome P-450 (CYP) 2C9 and 3A4 isoenzymes; potential pharmacokinetic interaction (altered metabolism).

Drugs that May Potentiate Hypoglycemic Effects

Alcohol, monoamine oxidase inhibitors, nonselective β-adrenergic-blocking agents, nonsteroidal anti-inflammatory agents (NSAIAs), salicylates.

Drugs that May Antagonize Hypoglycemic Effects

Corticosteroids, sympathomimetic agents, thiazide diuretics, thyroid hormones.

Diclofenac, Digoxin, Glyburide, Metformin, Warfarin

No clinically important pharmacokinetic interaction observed.

Protein-Bound Drugs

Potential pharmacokinetic interaction. No important effects observed in vitro.