Glyburide and Metformin Hydrochloride (Page 4 of 8)

8.2 Lactation

Risk Summary

Breastfed infants of lactating women using glyburide and metformin hydrochloride should be monitored for symptoms of hypoglycemia [see Clinical Considerations]. Although glyburide was negligible in human milk in one small clinical lactation study; this result is not conclusive because of the limitations of the assay used in the study. There are no data on the effects of glyburide on milk production. Limited published studies report that metformin is present in human milk [see Data] . However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for glyburide and metformin hydrochloride and any potential adverse effects on the breastfed child from glyburide and metformin hydrochloride or from the underlying maternal condition.

Clinical Considerations

Monitoring for adverse reactions

Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with glyburide and metformin hydrochloride may result in ovulation in some anovulatory women.

8.4 Pediatric Use

Safety and effectiveness of glyburide and metformin hydrochloride have not been established in pediatric patients.

8.5 Geriatric Use

Of the 642 patients who received glyburide and metformin hydrochloride in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are particularly susceptible to the hypoglycemic action of anti-diabetic agents. Hypoglycemia may be difficult to recognize in these patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of hypoglycemia and lactic acidosis. Assess renal function more frequently in elderly patients [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Glyburide and metformin hydrochloride is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Glyburide and metformin hydrochloride is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

10 OVERDOSAGE

Glyburide

Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated with oral glucose. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment are medical emergencies requiring immediate treatment. The patient should be treated with glucagon or intravenous glucose. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glyburide from plasma may be prolonged in persons with liver disease. Because of the extensive protein binding of glyburide, dialysis is unlikely to be of benefit.

Metformin

Overdose of metformin has occurred, including ingestion of amounts greater than 50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

11 DESCRIPTION

Glyburide and metformin hydrochloride tablets, USP for oral use contain glyburide USP and metformin hydrochloride USP.

Glyburide USP is a sulfonylurea and its chemical name is 1-[[p-[2-(5-chloro- o -anisamido) ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide USP is a white to off-white crystalline compound with molecular formula of C 23 H 28 ClN 3 O 5 S and a molecular weight of 494.01. The structural formula is represented below.

Glyburide Chemical Structure

Metformin hydrochloride USP is a biguanide in hydrochloride salt form and its chemical name is N,N-dimethylimidodicarbonimidic diamide monohydrochloride. It is a white to off-white crystalline compound with molecular formula of C 4 H 12 ClN 5 (monohydrochloride) and a molecular weight of 165.63. Metformin is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin is 6.68. The structural formula is as shown:

Metformin Hydrochloride Chemical Structure

Glyburide and metformin hydrochloride tablets, USP are available in film-coated containing 1.25 mg glyburide USP with 250 mg metformin hydrochloride USP, 2.5 mg glyburide USP with 500 mg metformin hydrochloride USP, and 5 mg glyburide USP with 500 mg metformin hydrochloride USP. In addition, each film-coated tablet contains the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, hypromellose, propylene glycol, polysorbate 80, talc, titanium dioxide and FD&C Yellow#6 aluminum lake. The 1.25 mg/250 mg and 5 mg/500 mg strengths also contain D&C Yellow#10 aluminum lake; The 2.5 mg/500 mg strength also contains FD&C Red#40 aluminum lake.

Meets USP Dissolution Test 2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Glyburide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

Metformin is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may decrease.

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