Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In double-blind clinical studies with glyburide and metformin hydrochloride as initial therapy or as second-line therapy of 20 and 14 weeks, respectively (see section 14), a total of 642 patients received glyburide and metformin hydrochloride, 312 received metformin HCl, 324 received glyburide, and 161 received placebo. Adverse reactions are listed in Table 1.
|Adverse Reaction||Number (%) of Patients|
|Placebo N=161||Glyburide N=324||Metformin HCl N=312||Glyburide and Metformin Hydrochloride N=642|
The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy study of glyburide and metformin hydrochloride are summarized in Table 2. For patients with a baseline HbA1c between 8% and 11% treated with glyburide and metformin hydrochloride 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with glyburide and metformin hydrochloride experienced hypoglycemic symptoms.
The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the glyburide and metformin hydrochloride initial therapy study are summarized in Table 2. Across all glyburide and metformin hydrochloride studies, GI symptoms were the most common adverse events with glyburide and metformin hydrochloride and were more frequent at higher dose levels. In controlled studies, <2% of patients discontinued glyburide and metformin hydrochloride therapy due to GI adverse events.
|Variable||Placebo N=161||Glyburide Tablets N=160||Metformin HCl Tablets N=159||Glyburide and Metformin Hydrochloride 1.25 mg/250 mg Tablets N=158||Glyburide and Metformin Hydrochloride 2.5 mg/500 mg Tablets N=162|
|Number (%) of patients with symptoms of hypoglycemia||3%||21%||3%||11%||38%|
|Number (%) of patients with gastrointestinal adverse events||24%||24%||43%||32%||38%|
Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These may be transient and may disappear despite continued use.
The following adverse reactions have been identified during post-approval use of glyburide and metformin hydrochloride. 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.
Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.
Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas.
Hepatic: Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin. Cholestatic jaundice and hepatitis may occur rarely with glyburide, which may progress to liver failure. Liver function abnormalities, including isolated transaminase elevations, have been reported.
Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.
Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.
Table 3 presents clinically significant drug interactions with glyburide and metformin hydrochloride.
Table 3: Clinically Significant Drug Interactions with Glyburide and Metformin Hydrochloride
|Carbonic Anhydrase Inhibitors|
|Clinical Impact:||Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with glyburide and metformin hydrochloride may increase the risk for lactic acidosis.|
|Intervention:||Consider more frequent monitoring of these patients.|
|Examples:||Topiramate, zonisamide, acetazolamide and dichlorphenamide.|
|Drugs that Reduce Metformin Clearance|
|Clinical Impact:||Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ].|
|Intervention:||Consider the benefits and risks of concomitant use with glyburide and metformin hydrochloride.|
|Examples:||Ranolazine, vandetanib, dolutegravir, and cimetidine.|
|Clinical Impact:||Alcohol is known to potentiate the effect of metformin on lactate metabolism.|
|Intervention:||Warn patients against excessive alcohol intake while receiving glyburide and metformin hydrochloride.|
|Drugs that potentiate the hypoglycemic action of glyburide and metformin hydrochloride|
|Clinical Impact:||Certain drugs may potentiate the hypoglycemic action of sulfonylureas, one of the components of glyburide and metformin hydrochloride.|
|Intervention:||Closely observe patient for hypoglycemia during co-administration and for loss of glycemic control when withdrawing these agents.|
|Examples:||Nonsteroidal anti-inflammatory agents and other highly protein-boind drugs, salicylcates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, beta-adrenergic blocking agents; potentially with ciprofloxacin, micronazole.|
|Clinical Impact:||Increased risk of liver enzyme elevations was observed.|
|Intervention:||Concomitant administration is contraindicated.|
|Clinical Impact:||Concomitant administration may led to reduced glyburide absorption (AUC and Cmax: -32% and -47%, respectively).|
|Intervention:||Glyburide and metformin hydrochloride should be administered at least 4 hours prior to colesevelam.|
|Drugs Reducing Glycemic Control|
|Clinical Impact:||Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.|
|Intervention:||When such drugs are administered to a patient receiving glyburide and metformin hydrochloride observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, observe the patient closely for hypoglycemia.|
|Examples:||Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.|
Available data from a small number of published studies and postmarketing experience with glyburide use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glyburide) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, glyburide and metformin hydrochloride should be discontinued at least two weeks before expected delivery [see Clinical Considerations]. Limited data with metformin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].
No evidence of harm to the fetus was observed when doses up to 500 times the maximum recommended human dose of 20 mg of glyburide, based on body surface area, were administered to rats and rabbits in reproduction studies.
No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 3- and 6- times, respectively, a 2000 mg clinical dose, based on body surface area [see Data ].
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Fetal/Neonatal Adverse Reactions
Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4 to 10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.
Dose adjustments during pregnancy and the postpartum period
Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glyburide and metformin hydrochloride should be discontinued at least two weeks before expected delivery [see Fetal/Neonatal Adverse Reactions].
Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Reproduction studies were performed in rats and rabbits at doses up to 500 times the maximum recommended human dose of 20 mg of glyburide based on body surface area comparisons and revealed no evidence of harm to the fetus.
Metformin did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 3 and 6 times a 2000 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
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