Repaglinide Tablets

Repaglinide Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitation of Use:

Repaglinide Tablets should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Repaglinide Tablets are contraindicated in patients with:

Hypoglycemia

All glinides, including Repaglinide Tablets, 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 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 co-administered 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 administer Repaglinide Tablets before meals and be instructed to skip the dose of Repaglinide Tablets if a meal is skipped. In patients who experience hypoglycemia, the dose of Repaglinide Tablets should be reduced [see Dosage and Administration (2.1)]. 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.

Serious Cardiovascular Adverse Reactions with Concomitant Use with NPH-insulin

Across seven controlled trials, there were six serious adverse events of myocardial ischemia in patients treated with Repaglinide Tablets plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [See Adverse Reactions (6.1)]. Repaglinide Tablets are not indicated for use in combination with NPH-insulin.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Repaglinide Tablets.

Clinically Important Drug Interactions with Repaglinide Tablets

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with Repaglinide Tablets and instructions for preventing or managing them.

Table 3: Clinically Important Drug Interactions with Repaglinide Tablets

Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. It is unknown whether Repaglinide Tablets can cause fetal harm when administered to a pregnant woman. Repaglinide Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Repaglinide was not teratogenic in rats or rabbits at doses 40 times (rats) and approximately 0.8 times (rabbit) clinical exposure (on a mg/m2 basis) throughout pregnancy. Offspring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation developed nonteratogenic skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of pregnancy. Relevant human exposure has not occurred to date and therefore the safety of repaglinide tablet administration throughout pregnancy or lactation cannot be established.

Nursing Mothers

Although it is not known whether repaglinide is excreted in human milk some oral agents are known to be excreted by this route. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, a decision should be made as to whether Repaglinide Tablets should be discontinued in nursing mothers, or if mothers should discontinue nursing. If Repaglinide Tablets are discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes [see Use in Specific Populations (8.1)] could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

In clinical studies of 24 weeks or greater duration, 415 patients were over 65 years of age and no patients were greater than 75 years of age. In one-year, active-controlled trials, no differences were seen in effectiveness or adverse events between these subjects and those less than 65. There was no increase in frequency or severity of hypoglycemia in older subjects, but greater sensitivity of some older individuals to repaglinide tablet therapy cannot be ruled out.

Renal Impairment

Pharmacokinetic studies of repaglinide were conducted in patients with mild to moderate renal function impairment (CrCl = 40 – 80 mL/min), and severe renal function impairment (CrCl = 20 – 40 mL/min). Initial dose adjustment is not required in patients with mild to moderate renal dysfunction. However, patients with severe renal function impairment should initiate repaglinide tablet therapy with the 0.5 mg dose and be carefully titrated [see Dosage and Administration (2.2)].

Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis.

Hepatic Impairment

A single-dose study was conducted 12 patients with chronic liver disease. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations. Therefore, Repaglinide Tablets should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments may be needed to allow full assessment of response.

Repaglinide Tablets, USP are an oral blood glucose-lowering drug of the glinide class. Repaglinide, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral sulfonylurea insulin secretagogues.

Structural Formula of Repaglinide

Repaglinide is a white to off-white powder with molecular formula C27H36N2O4 and a molecular weight of 452.6. Repaglinide Tablets, USP contain 0.5 mg, 1 mg, or 2 mg of repaglinide. In addition each tablet contains the following inactive ingredients: anhydrous dibasic calcium phosphate, microcrystalline cellulose, corn starch, polacrilin potassium, povidone, glycerin, magnesium stearate, meglumine, and poloxamer, and colloidal silicon dioxide. The 1 mg and 2 mg tablets contain ferric oxides (yellow and red, respectively) as coloring agents.