Drug Interactions
Cationic Agents Secreted by Proximal Renal Tubules
Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).
Potential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).
Monitor carefully; consider dosage adjustment of either agent.
Protein-bound Drugs
Pharmacokinetic interaction unlikely.
Drugs That May Antagonize Hypoglycemic Effects
Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline); observe patient closely for evidence of altered glycemic control when such drugs are added to or withdrawn from therapy.
Specific Drugs
| Drug |
Interaction |
Comments |
| ACE inhibitors |
Potential risk of hypoglycemia/hyperglycemia when ACE inhibitor therapy is initiated/withdrawn |
Monitor blood glucose concentrations during dosage adjustments with either agent |
| Alcohol |
Increased risk of hypoglycemia and lactic acidosis |
Avoid excessive alcohol intake |
| β-Adrenergic blocking agents |
Impaired glucose tolerance; Increased frequency or severity of hypoglycemia and hypoglycemia-induced complications |
If concomitant therapy necessary, a β1-selective adrenergic blocking agent or β-adrenergic blocking agents with intrinsic sympathomimetic activity preferred |
| Cimetidine |
Possible decreased excretion of metformin |
|
| Clomiphene |
Possible resumption of ovulation in premenopausal patients with polycystic ovary syndrome |
|
| Furosemide |
Increased plasma concentrations of metformin and furosemide |
|
| Glyburide |
Variable decreases in AUC and peak blood concentration of glyburide |
Clinical importance uncertain |
| Nifedipine |
Enhanced absorption and increased urinary excretion of metformin |
|
| Thiazide diuretics |
May exacerbate diabetes mellitus |
Consider using less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing dosage of or discontinuing diuretic, or increasing dosage of oral antidiabetic agent |
Pharmacokinetics
Absorption
Bioavailability
Approximately 50–60% (absolute) with dosages of 0.5–1.5 g.
Fixed-combination preparation containing 500 mg of metformin hydrochloride and 4 mg of rosiglitazone is bioequivalent to mg-equivalent dosages of individual components administered separately under fasted conditions.
Onset
Therapeutic response usually apparent within a few days to 1 week. Maximal glycemic response within 2 weeks.
Duration
Blood glucose concentrations increase within 2 weeks following discontinuance of metformin therapy.
Food
Food decreases and slightly delays absorption of conventional tablets.
Food increases the extent of absorption of extended-release tablets (Glucophage® XR, Fortamet®). Peak plasma concentrations and time to achieve peak plasma concentrations not altered by administration of one extended-release preparation (Glucophage® XR) with food; food increases peak plasma concentrations and prolongs time to peak plasma concentrations of another extended-release tablet preparation (Fortamet®).
Food increases the extent of absorption and delays the time to peak plasma concentrations of the oral solution. Fat content of meals does not appreciably affect the pharmacokinetics of metformin hydrochloride oral solution.
Distribution
Extent
Rapidly distributed into peripheral body tissues and fluids, particularly GI tract.
Slowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).
Plasma Protein Binding
Negligible.
Elimination
Metabolism
Not metabolized in the liver or GI tract and not excreted into bile. No metabolites identified in humans.
Elimination Route
Excreted in urine (approximately 35–52%) and feces (20–33%). Eliminated as unchanged drug.
Half-life
3–6 hours.
Special Populations
Renal impairment may reduce clearance, including in geriatric patients with age-related decline in renal function. Renal impairment results in increased peak plasma concentrations, prolonged time to peak plasma concentration and half-life, and decreased volume of distribution.
Stability
Storage
Oral
Tablets
Conventional tablets: tight, light resistant containers at 20–25°C (may be exposed to 15–30°C).
Extended-release tablets: tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).
Fixed-combination preparations with glipizide or rosiglitazone: tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).
Solution
15–30°C.
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