Glyburide-Metformin Hcl (glyburide/metformin HCl)

Available as metformin hydrochloride; dosage expressed in terms of the salt.

Glyburide is administered orally. The drug (as conventional or micronized formulations) is usually administered as a single daily dose given each morning with breakfast, or with the first main meal. Once-daily dosing of glyburide provides adequate control of blood glucose concentration throughout the day in most patients with usual meal patterns; however, some patients, particularly those who require more than 10 mg of the drug daily (as conventional formulations) or more than 6 mg daily (as micronized glyburide), may have a more satisfactory response when glyburide is administered in 2 divided doses daily. There is some evidence that, when a divided-dosing regimen is used, blood glucose concentration following breakfast may be better controlled when the morning dose is administered 30 minutes before rather than with the meal; a similar tendency has been observed following the midday meal, but not the evening meal, when the remaining portions of the equally divided daily dose were administered 30 minutes before rather than with these meals.

When given concomitantly with colesevelam, glyburide should be administered at least 4 hours prior to colesevelam.

Patients who do not adhere to their prescribed dietary and drug regimens are more likely to have an unsatisfactory response to therapy. In patients usually well controlled by dietary management alone, short-term therapy with glyburide may be sufficient during periods of transient loss of diabetic control.

The fixed combination of glyburide and metformin hydrochloride should be taken once or twice daily with meals. See the full prescribing information for additional administration instructions for the combination product.

Store glyburide tablets at 20--25degreesC in a tightly closed container. Dispense in well-closed containers with safety closures.

Metformin hydrochloride is administered orally. In patients receiving metformin hydrochloride immediate-release tablets at a dosage of 2 g or less daily, the medication can usually be given as 2 divided doses daily; however, in patients who require more than 2 g daily, the medication may be better tolerated if administered in 3 divided doses daily. Although food decreases the extent and slightly delays absorption of metformin immediate-release tablets, the manufacturer recommends that the medication be taken with meals to decrease adverse GI effects. Immediate-release metformin hydrochloride in fixed combination with alogliptin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, linagliptin, pioglitazone, or sitagliptin is administered in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component. See the full prescribing information for additional administration instructions for the combination products.

Metformin hydrochloride oral solution is administered either once or twice daily with meals. Dosages above 2 g daily may be better tolerated if administered in 3 divided doses daily. Each dose should be measured using a metformin hydrochloride oral solution specific dosing cup.

Metformin hydrochloride extended-release tablets usually are taken with the evening meal. Extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin is administered once daily with the morning meal. The fixed combination of extended-release metformin hydrochloride and linagliptin should be administered once daily with a meal. The fixed combination of extended-release metformin hydrochloride and sitagliptin should be administered once daily with a meal, preferably with the evening meal. Extended-release metformin hydrochloride in fixed combination with saxagliptin should be administered once daily with the evening meal. Extended-release metformin hydrochloride tablets and fixed-combination preparations containing the extended-release form of the medication must be swallowed whole and not chewed, cut, or crushed; inactive ingredients occasionally may be eliminated in feces as a soft mass that may resemble the original tablet. See the full prescribing information for additional administration instructions for the combination products.

Store metformin hydrochloride immediate- and extended-release tablets at 20--25degreesC in light-resistant containers; excursions permitted to 15--30degreesC. Store metformin hydrochloride oral solution at 15--30degreesC.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Bcrp, Oatp1b1, And Oatp1b3 Substrates/Leniolisib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Leniolisib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1)

CLINICAL EFFECTS: Concurrent use of leniolisib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased toxicity of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid coadministration of leniolisib with substrates of BCRP, OATP1B1, and OATP1B3.(1)

DISCUSSION: When co-administered, leniolisib increased rosuvastatin (a substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: diclofenac, fluvastatin, glecaprevir, glyburide, imatinib, irinotecan, letermovir, lovastatin, methotrexate, mitoxantrone, momelotinib, paritaprevir, pitavastatin, pravastatin, repaglinide, simvastatin, and sulfasalazine.(1,2)

Glyburide/Bosentan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism behind the increased risk of elevated liver aminotransferases is unknown.

CLINICAL EFFECTS: Concurrent use of bosentan and glyburide may increase the risk of liver enzyme elevations.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of bosentan and glyburide state that the concurrent use of these agents is contraindicated(1,2) and that alternative hypoglycemic agents should be considered.(1)

DISCUSSION: An increased risk of liver enzyme elevation was seen in patients receiving concurrent bosentan and glyburide.(1,2)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Antidiabetic Agents/Gatifloxacin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of gatifloxacin may result in hypoglycemia and/or hyperglycemia.(1-4) Hypoglycemia is more common during the first three days of concurrent therapy. Hyperglycemia is more common after the first three days of concurrent therapy.(2)

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(2)

PATIENT MANAGEMENT: Patients receiving concurrent gatifloxacin should be closely monitored for hypoglycemia during the first three days of concurrent therapy and for hyperglycemia after the first three days of concurrent therapy. Patients should be instructed to discontinue gatifloxacin if hypoglycemia or hyperglycemia occur.(2)

DISCUSSION: Hypoglycemia has been reported with gatifloxacin and glyburide(1,5,6) or glimepiride.(7) In a study in patients with type 2 diabetes mellitus, concurrent gatifloxacin (400 mg daily for 10 days) had no effect on the pharmacokinetics of glyburide (steady state daily regimen); however, pharmacodynamic interactions have been reported.(2) Health Canada has received 19 reports of hypoglycemia in patients taking gatifloxacin. Seventeen of these involved concurrent hypoglycemic agents. Health Canada has received 2 reports of hyperglycemia in patients taking gatifloxacin and hypoglycemic agents. Health Canada has received 2 reports of patients experiencing hypoglycemia and hyperglycemia during concurrent gatifloxacin and hypoglycemic agents.(3) In a study, 13 reports of dysglycemia were reported in patients taking gatifloxacin. Ten of these patients had diabetes mellitus and were on concurrent hypoglycemic agents. Of these ten patients, nine patients experienced hypoglycemia, while one patient experienced hyperglycemia.(8)

Metformin/Iodinated Contrast Materials

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Use of iodinated contrast materials may result in acute changes in renal function, resulting in a decrease in metformin clearance.(1-3)

CLINICAL EFFECTS: Use of iodinated contrast materials may increase levels of metformin, which may result in lactic acidosis.(1-3)

PREDISPOSING FACTORS: Pre-existing renal dysfunction may contribute to decreased clearance of metformin. Other factors which may increase the risk for lactic acidosis include age greater than 65 years, dehydration, metabolic acidosis, sepsis, a history of hepatic impairment, alcoholism, or heart failure.(1-4)

PATIENT MANAGEMENT: Evaluate renal function prior to contrast procedure. According to manufacturer recommendations, discontinue metformin at the time of, or prior to, the contrast imaging procedure in patients with a history of liver disease, alcoholism, heart failure, or if contrast is to be administered intra-arterially. When contrast is to be administered by other routes, discontinue metformin at the time of, or prior to, the procedure for patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Re-evaluate eGFR 48 hours after the imaging procedure and restart metformin if renal function is stable. Discontinuation of metformin is not required if eGFR is > 60 mL/min/1.73 m2.(4) According to American College of Radiology guidelines, discontinue metformin at the time of, or prior to, the contrast imaging procedure in patients with acute kidney injury or chronic kidney disease (Stage IV or V or eGFR < 30 mL/min/1.73 m2), or who are undergoing arterial catheter studies that might result in emboli (atheromatous or other) to the renal arteries. Re-evaluate eGFR 48 hours after the imaging procedure and restart metformin if renal function is normal. Discontinuation of metformin is not required in patients with no evidence of acute kidney injury and with eGFR >= 30 mL/min/m2.(5)

DISCUSSION: An FDA review of the medical literature showed that metformin may be safely used in patients with mild or moderate renal impairment, resulting in modifications of prescribing recommendations and method for evaluation of renal function.(4) A clinical review of 33 patients on metformin who had received contrast media showed elevations in serum creatinine of the four patients with baseline elevations. The 29 patients with normal baseline renal function showed no elevations after administration of contrast media. The authors recommend that a baseline serum creatinine is obtained for all patients and that metformin should only be discontinued in patients with baseline elevations.(6) A retrospective study of ninety-seven patients currently taking metformin underwent a radiologic procedure with contrast media. Of these patients, 4 developed contrast material associated nephropathy and eight patients had an increased risk of lactic acidosis, with a baseline serum creatinine <1.5mg/dl.(7) A prospective clinical trial with 50 diabetic patients on metformin with baseline serum creatinine <1.47mg/dl showed no statistical difference in renal function before and 48 hours after administration of contrast media. The authors recommend a baseline serum creatinine for all patients and suggest that temporary discontinuation of metformin may not be necessary when baseline renal function is <1.47mg/dl.(8) A systematic review of the literature reveals that 17 of 18 case reports of metformin-induced lactic acidosis involved patients with renal dysfunction prior to administration of contrast media. The authors recommend a baseline serum creatinine in all patients and if renal dysfunction is present, metformin should be discontinued for 48 hours before and after administration of contrast media. The authors recommend follow-up creatinine measurement in patients with prior renal impairment or known comorbidities affecting lactate levels.(9)

Metformin/Tafenoquine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine inhibits elimination by these pathways.(2)

CLINICAL EFFECTS: Use of tafenoquine may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin be adjusted as needed.(1) The manufacturer of tafenoquine states the concurrent administration of tafenoquine with OCT2 and MATE1 substrates, such as metformin, should be avoided. If coadministration cannot be avoided, monitor for drug-related toxicities.(2) Evaluate patient's renal function and consider discontinuation in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine is believed to inhibit the OCT2 and MATE1 pathways.(2)

Selected Bcrp Substrates/Capmatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Capmatinib inhibits BCRP, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of capmatinib with BCRP substrates may result in elevated levels of and toxicity from these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of capmatinib states that the concurrent use of narrow therapeutic index BCRP substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index BCRP substrate should be decreased according to the substrate prescribing information.(1)

DISCUSSION: In a study, capmatinib increased rosuvastatin (a BCRP substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax) by 204%.(1) BCRP substrates linked to this monograph include: glyburide, imatinib, irinotecan, lapatinib, methotrexate, and mitoxantrone.(1-2)

Selected Bcrp Substrates/Darolutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of darolutamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer recommends avoiding concurrent use of darolutamide with BCRP substrates when possible.

DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1) BCRP substrates linked to this monograph include: diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-3)

Selected Bcrp Substrates/Oteseconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oteseconazole is an inhibitor of the BCRP transporter, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of oteseconazole with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of oteseconazole states that the lowest possible starting dose of the BCRP substrate should be used and to consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1)

DISCUSSION: Oteseconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively.(1) BCRP substrates linked to this monograph include: diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, and sulfasalazine.(1-2)

Sulfonylureas/Miconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sulfonylureas are sensitive CYP2C9 substrates. Miconazole is a moderate CYP2C9 inhibitor and may inhibit the metabolism of sulfonylureas.(1)

CLINICAL EFFECTS: Concurrent use of miconazole may result in elevated levels and effects of the sulfonylureas, including severe hypoglycemia and coma.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian, Canadian, and UK manufacturers of gliclazide and the UK manufacturer of glipizide state that concurrent use with miconazole via systemic routes or oro-mucosal gel is contraindicated.(2-5) The manufacturers of other sulfonylureas and the Australian and UK manufacturers of miconazole advise caution when using the combination of sulfonylureas and miconazole. Monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted.(6-15)

DISCUSSION: A French pharmacovigilance study found that 98 cases of sulfonylurea-induced hypoglycemia were reported between 1985-1990, mostly with gliclazide (46 cases) and glyburide (40 cases). Miconazole was one of the most frequent causes of drug interactions (8 cases).(16) Other cases of severe hypoglycemia after miconazole was started in patients on sulfonylureas have been reported.(17-18)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Antidiabetics, Oral/Aspirin (> 100 MG); Salicylates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Complex. Salicylates appear to have intrinsic glucose lowering properties via several proposed mechanisms. Also, salicylates may cause protein binding displacement of antidiabetics. Decreased renal clearance may also occur.

CLINICAL EFFECTS: Potentiation of hypoglycemic effects may be observed.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed. Particular caution should be taken when salicylates are started or stopped in patients previously stabilized on antidiabetics.

DISCUSSION: Additional documentation is necessary to confirm this potential interaction.

Antidiabetics, Oral/Clofibrate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not defined.

CLINICAL EFFECTS: May observe enhanced hypoglycemic effects.

PREDISPOSING FACTORS: Hypoalbuminemia.

PATIENT MANAGEMENT: Monitor blood glucose and watch for signs of hypoglycemia. This is particularly important when clofibrate is started or stopped.

DISCUSSION: Additional documentation is necessary to confirm this potential interaction.

Antidiabetics, Oral/Oxy-Phenylbutazone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Phenylbutazone may displace antidiabetics from plasma protein binding sites. Renal elimination of the active metabolite of acetohexamide may be reduced. Finally, tolbutamide metabolism may be decreased.

CLINICAL EFFECTS: Potentiation of antidiabetic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed.

DISCUSSION: This interaction is well documented.

Antidiabetics, Oral/Sulfonamide Antibacterials

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. However, it is speculated that sulfonamides may inhibit hepatic metabolism and/or displace oral antidiabetics from plasma protein binding sites.

CLINICAL EFFECTS: Increased serum levels of antidiabetics with potentiation of hypoglycemic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed.

DISCUSSION: Additional documentation is necessary to confirm this interaction.

Antidiabetics/Epinephrine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gluconeogenesis, glycogenolysis, and lipolysis are increased by epinephrine. Also, insulin secretion and glucose uptake by peripheral tissues are decreased by epinephrine.

CLINICAL EFFECTS: Increased blood glucose resulting in decreased effectiveness of the antidiabetic agent.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Caution when starting or stopping epinephrine in diabetic patients. Adjust the antidiabetic dose as needed based on blood glucose levels.

DISCUSSION: This interaction is likely to occur based upon well documented properties of the interacting drugs. However, there is individual variability in its occurrence.

Antidiabetics/Slt Ophth Non-Cardioselective Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.(1,2)

CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(3) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(4) There have been case reports of hypoglycemia following the addition of ophthalmic timolol to a diabetic regimen.(5-7) Studies have shown that ophthalmic beta-blockers, especially the aqueous solution, have significant systemic absorption and do not undergo first-pass metabolism.(8,9)

Bcrp Or Oatp1b1 Substrates/Eltrombopag

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates.

CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1)

DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1)

Glimepiride; Glipizide; Glyburide/Colesevelam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Colesevelam may bind to glimepiride, glipizide, and glyburide in the gastrointestinal track, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of colesevelam may result in decreased levels and effectiveness of glimepiride,(1) glipizide,(1) or glyburide.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Glyburide,(1) glipizide,(3) and glimepiride(4) should be administered four hours before colesevelam.

DISCUSSION: When administered with colesevelam (3.75 g), the area-under-curve (AUC) and maximum concentration (Cmax) of glimepiride (4 mg) decreased by 18% and by 8%, respectively. When administered 4 hours prior to colesevelam, the AUC of glimepiride decreased by 6% and the Cmax increased 3%.(1) When administered with colesevelam (3.75 g), the AUC and Cmax of glipizide (20 mg) decreased by 12% and by 13%, respectively. When administered 4 hours prior to colesevelam, the AUC of glipizide decreased by 4%. There was no effect on glipizide Cmax when glipizide and colesevelam were separated by 4 hours.(1) When administered with colesevelam (3.75 g), AUC and Cmax of glyburide (3 mg) decreased by 32% and by 47%, respectively. When administered 1 hour prior to colesevelam, the AUC and Cmax of glyburide decreased by 20% and 15%, respectively. When administered 4 hours prior to colesevelam, the AUC and Cmax of glyburide decreased by 7% and 4%, respectively.(1,2)

Glinides; Sulfonylureas/Ethyl Alcohol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Alcohol can induce hypoglycemia and interfere with gluconeogenesis in the liver by means of intrinsic hypoglycemic activity.(1-3) Some alcoholic beverages may increase serum glucose levels from their high carbohydrate content.(4) Chronic alcohol intake may decrease half-life of sulfonylureas by increasing liver metabolism.(1, 5-8)

CLINICAL EFFECTS: Alcohol consumption while on a glinide or sulfonylureas may result in a range of reactions, from mild flushing to severe hypoglycemic reactions. Alcohol consumption during chlorpropamide therapy has resulted in a disulfiram-like reaction.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetics should be cautioned about the effects of alcohol consumption on diabetic control, possible flushing with concurrent use, and about unsuspected sources of alcohol such as medications. Patients on chlorpropamide therapy should be counseled about the possibility of a disulfiram-like reaction to alcohol consumption. Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (21): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: Chlorpropamide has been reported to induce facial flushing (5,9-18) and a disulfiram-like reaction(4,9,10,18,19) following alcohol consumption. Tolbutamide has been shown to interact with alcohol in nonalcoholic diabetic patients, alcoholics, and normal subjects.(2,3,6-8,16,17) There is one report of reduced tolerance for alcohol in a patient on tolazamide therapy.(20) In a study in 10 normal subjects, administration of ethanol with glipizide resulted in a delay in return to fasting glucose levels. The time of onset and the extent of hypoglycemia were not altered.(21) Glipizide and glyburide have been reported to have a very low incidence of disulfiram-like reactions with concurrent alcohol; however, in one study, 5 of 11 patients taking glyburide developed flushing after a test dose of alcohol.(18)

Glyburide/Safinamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates such as glyburide.(1) The exact mechanism by which MAO inhibitors such as safinamide affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: Administration of safinamide with glyburide may result in elevated levels of and toxicity from glyburide, including additive hypoglycemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The EMA and UK manufacturer of safinamide recommend monitoring patients who are on concomitant drugs that are substrates of BCRP, including glyburide. Dose adjustment of glyburide should be performed according to the prescribing information for glyburide.(1) Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.(1)

DISCUSSION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) In a clinical study, safinamide increased the AUC of rosuvastatin, a BCRP substrate, by 1.25- to 2-fold.(1,3)

Hypoglycemics; Insulin/Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion can lower the seizure threshold and when given concurrently with other medications that also lower the threshold there is an increased risk of seizure. Concurrent use of hypoglycemics or insulin increases the risk of hypoglycemia which can result in seizures.(1,2)

CLINICAL EFFECTS: Concurrent use of bupropion and hypoglycemics or insulin may increase the risk of seizure.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, systemic steroids, theophylline).(1,2)

PATIENT MANAGEMENT: The use of bupropion in patients treated with oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2)

Metformin/Bictegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transport. Bictegravir inhibits elimination by these pathways.(1,2)

CLINICAL EFFECTS: Use of bictegravir may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin be adjusted as needed.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Bictegravir is an inhibitor of OCT2 and MATE1.(2) Trimethoprim, an inhibitor of OCT2 and MATE1, was found to cause significant inhibition of net transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells. Chloroquine is eliminated by renal tubular secretion involving multidrug and toxin extrusion protein 1 (MATE1). Trimethoprim caused concentration-dependent inhibition of net metformin intake in HEK293-MATE1 cells (human embryonic kidney).(3) A randomized, open-label, two-phase crossover study found that trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of metformin. Trimethoprim increased metformin area-under-curve (AUC) by 29.4% and decreased metformin renal clearance by 26.4%.(4) In a study in 24 healthy volunteers received metformin 500 mg three times daily for ten days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration (Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate. (5)

Metformin/Carbonic Anhydrase Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbonic anhydrase inhibitors increase bicarbonate excretion which may cause metabolic acidosis.(1) High systemic concentrations of metformin may result in lactic acidosis.(2,3) Topiramate, a mild carbonic anhydrase inhibitor, may also increase systemic exposure to metformin.(1)

CLINICAL EFFECTS: Carbonic anhydrase inhibitors may increase the risk for metformin associated lactic acidosis.(1-3) Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low blood pH, increased anion gap and elevated blood lactate.(2) Carbonic anhydrase inhibitors linked to this monograph are acetazolamide, dichlorphenamide, methazolamide, sulthiame, topiramate, and zonisamide.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: For patients receiving concurrent therapy, monitor renal function and assure that patient does not have risk factors for metformin associated lactic acidosis. Discontinue metformin when risk factors are present. If both drugs are given, monitor renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Manufacturer recommendations: the manufacturer of metformin recommends caution with concomitant use of carbonic anhydrase inhibitors due to an increased risk for metformin associated lactic acidosis.(2) The manufacturer of topiramate notes that topiramate can frequently cause metabolic acidosis and that metformin should not be used in patients with metabolic acidosis.(1)

DISCUSSION: A literature search for lactic acidosis due solely to the combination of metformin and carbonic anhydrase inhibitors or topiramate did not reveal any case reports of symptomatic metabolic acidosis due to this combination. Never-the-less, since carbonic anhydrase inhibitors act by inhibiting the reabsorption of bicarbonate in the renal tubule, some lowering of systemic bicarbonate and pH is common and supports the plausibility of this interaction. In addition, a pharmacokinetic interaction has been described with topiramate. A study in healthy volunteers evaluated the effect of topiramate 100 mg every 12 hours on the kinetics of metformin 500 mg every 12 hours. Mean metformin exposure (area-under-curve or AUC) was increased 25%.(1)

Metformin/Cephalexin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cephalexin may inhibit the renal tubular secretion of metformin.(1,2)

CLINICAL EFFECTS: Concurrent use of cephalexin may result in increased levels and clinical effects of metformin,(1,2) as well as an increased risk of lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: Patients maintained on metformin should be closely monitored when cephalexin is initiated and discontinued. The dosage of metformin may need to be adjusted.(1)

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, concurrent metformin (500 mg) and cephalexin (500 mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metformin by 34% and 24%, respectively. Metformin renal clearance decreased by 14%.(1,2)

Metformin/Dolutegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dolutegravir may inhibit the renal organic cation transporter, OCT2, responsible for the elimination of metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: With concomitant use, assess the benefit and risk of metformin in patients on dolutegravir. When starting or stopping dolutegravir, the metformin dose may require an adjustment. Monitor blood glucose when initiating concomitant use and after stopping dolutegravir.(1) Monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio.(1)

DISCUSSION: Dolutegravir has been shown to inhibit OCT2 in vitro and in vivo and is expected to inhibit the excretion of metformin.(1) In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of metformin by 66% and 79%, respectively. In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg twice daily) increased the Cmax and AUC of metformin by 111% and 145%, respectively.(1)

Metformin/Mate Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal tubular secretion of metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: Use an alternative agent if possible. If both drugs are given, monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Dosage of either agent may need to be adjusted.(1)

DISCUSSION: In a study of normal healthy volunteers, concurrent metformin and oral cimetidine increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2) MATE inhibitors include: brepocitinib, cimetidine, pyrimethamine, and risdiplam.(3)

Metformin/Oct2 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of metformin by OCT2 in the kidneys.(1)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from metformin.(1)

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels higher than 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of metformin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of metformin and consider dosage reduction of metformin.(1)

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) OCT2 inhibitors linked to this monograph include: arimoclomol, givinostat, trilaciclib, and vimseltinib.(2)

Metformin/Patiromer

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Patiromer may bind to metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in decreased gastrointestinal absorption and loss of efficacy of metformin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of patiromer recommends that you administer patiromer at least 3 hours before or 3 hours after metformin.(1)

DISCUSSION: A study in healthy volunteers showed that patiromer decreased the systemic exposure of coadministered metformin. No interaction was seen when these drugs were taken 3 hours apart.(1)

Metformin/Ranolazine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ranolazine may decrease renal elimination of metformin by inhibiting OCT-2.(1)

CLINICAL EFFECTS: Concurrent ranolazine may result in elevated levels of and toxicity from metformin.(1)

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metformin and ranolazine. In patients receiving 1000 mg ranolazine twice daily, limit the dose of metformin to 1700 mg daily.(1)

DISCUSSION: In healthy subjects, ranolazine (1000 mg twice daily) increased exposure of metformin by 80%. Ranolazine (500 mg BID) increased metformin exposure by 40%.(1)

Metformin/Trimethoprim

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transport. Trimethoprim inhibits elimination by these pathways.

CLINICAL EFFECTS: Use of trimethoprim may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin and/or trimethoprim be adjusted as needed. Consider the benefits and risks of concomitant use.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Trimethoprim was found to cause significant inhibition of net transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells. Chloroquine is eliminated by renal tubular secretion involving multidrug and toxin extrusion protein 1 (MATE1). Trimethoprim caused concentration-dependent inhibition of net metformin intake in HEK293-MATE1 cells (human embryonic kidney). (2) A randomized, open-label, two-phase crossover study found that trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of metformin. Trimethoprim increased metformin area under the curve (AUC) by 29.4% and decreased metformin renal clearance by 26.4%. (3) 24 healthy volunteers received metformin 500 mg three times daily for ten days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration (Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate. (4)

Metformin/Vandetanib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Renal tubular secretion of metformin is mediated by organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein (MATE) transporter. Vandetanib inhibits elimination by the OCT2 and MATE pathways.(1)

CLINICAL EFFECTS: Use of vandetanib may increase levels of metformin. Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.(1)

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: Use an alternative agent if possible. The US labeling for vandetanib recommends caution with concomitant use of metformin and close monitoring for metformin toxicity.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: A study in 13 healthy subjects receiving a single 1,000 mg dose of metformin 3 hours after a single 800 mg dose of vandetanib resulted in increases in metformin area-under-curve (AUC) of 74% and maximum concentration (Cmax) of 50% with coadministration compared to metformin alone.(1) In a study of normal healthy volunteers, concurrent metformin and oral cimetidine (MATE inhibitor) increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2)

Oatp1b1 Substrates/Midostaurin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Midostaurin has been shown to inhibit OATP1B1.(1) Inhibition of OATP1B1 may decrease hepatic uptake of substrates.

CLINICAL EFFECTS: Simultaneous use of midostaurin with OATP1B1 substrates may result in increased levels and side effects from the substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of midostaurin states that concomitant OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects as dose adjustments of the substrate may be necessary.(1)

DISCUSSION: In a study, single dose midostaurin 100 mg increased the area-under-curve (AUC) of single dose rosuvastatin by 48%. With a 50 mg twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1 substrate by up to 2-fold.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, rosuvastatin and simvastatin.

Selected Antidiabetic Agents/Chloroquine; Hydroxychloroquine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Chloroquine and hydroxychloroquine may increase insulin sensitivity by inhibiting insulin metabolism and inflammation and increasing cellular uptake of glucose and glycogen synthesis.(1,2) These effects may result in additive hypoglycemia with anti-diabetic agents.

CLINICAL EFFECTS: Concurrent use of chloroquine or hydroxychloroquine and antidiabetic agents may result in severe hypoglycemia.(3) Hypoglycemia can lead to coma.

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.

PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with chloroquine or hydroxychloroquine should be closely monitored for hypoglycemia. A decrease in the dose of insulin or other anti-diabetic medications may be required. Patients should be advised of the risk and symptoms of hypoglycemia and to contact their doctor if hypoglycemia occurs.(3) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety.

DISCUSSION: Hydroxychloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening.(3) Concomitant hypoglycemic agents may increase the risk and/or severity of this effect. A 77 year old man who was stable on twice daily insulin suffered two episodes of hypoglycemic coma 2 weeks after starting prednisone 5 mg daily and hydroxychloroquine 400 mg daily for rheumatoid arthritis. His insulin dosage required a decrease of 37%.(4) Many studies have investigated the glucose-lowering effect of hydroxychloroquine. In a clinical trial of type II diabetics on maximal doses of sulfonylureas, addition of hydroxychloroquine lowered hemoglobin A1C (HbA1C) up to 1% more than placebo.(5) Another clinical trial of type II diabetics on metformin and glimepiride or gliclazide found that hydroxychloroquine 400 mg daily reduced fasting blood glucose (FBG), post-prandial glucose (PPG), and HbA1C to a similar degree as pioglitazone 15 mg daily at 24 weeks.(6) In a prospective observational study, 250 uncontrolled type II diabetics on metformin, glimepiride, pioglitazone, sitagliptin, and a SGLT-2 inhibitor received hydroxychloroquine 400 mg daily for 48 weeks. HbA1C decreased from 8.83% to 6.44%, FBG decreased by 40.78%, and PPG decreased by 58.95%. The doses of metformin were reduced by 50%, glimepiride and sitagliptin by 75%, and SGLT-2 inhibitors were discontinued in most patients.(7)

Selected Antidiabetic Agents/Clarithromycin; Telithromycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clarithromycin and telithromycin may inhibit the metabolism of glipizide(1) and glyburide(1,2) by CYP3A4.

CLINICAL EFFECTS: Concurrent use of glipizide or glyburide and clarithromycin or telithromycin may result in elevated levels of and effects from glipizide and glyburide, including hypoglycemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on glipizide or glyburide should be closely monitored if clarithromycin or telithromycin is added to or withdrawn from concurrent therapy. A dosage adjustment of the antidiabetic agent may be required during macrolide therapy.

DISCUSSION: In a study in 12 healthy subjects, clarithromycin (250 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of glyburide (0.875 mg) by 1.35-fold and 1.25-fold, respectively.(2) Severe hypoglycemia has been reported in patients following the addition of clarithromycin to glipizide and glyburide therapy.(1)

Selected Antidiabetic Agents/Selected Quinolones

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of quinolones and antidiabetic agents may result in severe hypoglycemia.(1-7) Hypoglycemia can lead to coma.

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(5)

PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with a quinolone should be closely monitored for hypoglycemia.(1-4) Patients should be instructed to discontinue quinolone use and contact their doctor if hypoglycemia occurs.(2,4) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety.

DISCUSSION: Hypoglycemia has been reported with concurrent ciprofloxacin and glyburide,(1,8,9) levofloxacin and glyburide,(2,10,11) norfloxacin and glyburide,(3) levofloxacin and glipizide (12) as well as levofloxacin and metformin-glibenclamide.(14) There has been one report of fatal hypoglycemia with concurrent levofloxacin and glyburide(9) and one of the above reports of hypoglycemia with concurrent levofloxacin and glyburide resulted in hypoxic brain injury.(11) A review of postmarketing adverse event data for the fluoroquinolones and hypoglycemic coma identified 56 reports in FAERS search from October 1987- April 2017 and 11 additional cases in the medical literature. Most patients had risk factors for hypoglycemia. 41 patients were taking one or more hypoglycemic drugs. 13 deaths occurred (some of these patients had renal insufficiency). 9 patients did not fully recover and had resultant disability.(13)

Selected Antidiabetics/Maois

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism by which MAO inhibitors affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: The hypoglycemic response to both insulin and glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylurea may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.

DISCUSSION: This interaction is likely to occur. The interaction between MAOIs and insulin is well documented. Additional documentation is necessary to confirm the potential interaction of MAOI's with other glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylureas but is expected to occur based on pharmacologic similarity. It may take several weeks for the full hypoglycemic effect of the MAOI to occur. Conversely, it may take several weeks for the effect to dissipate after stopping the MAOI. Furazolidone is known to be a monoamine oxidase inhibitor. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Selected Bcrp Substrates/Momelotinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Momelotinib is an inhibitor of the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of momelotinib with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of momelotinib states concurrent use with BCRP substrates should be approached with caution. If concurrent use is warranted, consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1)

DISCUSSION: Momelotinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 220% and 170%, respectively.(1) BCRP substrates linked to this monograph include: glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and sulfasalazine.(1-2)

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

Sulfonylureas/Amiodarone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amiodarone may decrease the metabolism of sulfonylureas by inhibiting CYP2C9. Amiodarone is a moderate CYP2C9 inhibitor.(1-5)

CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia.

PREDISPOSING FACTORS: This interaction may be more likely in patients using higher doses of amiodarone and who use amiodarone for greater than 180 days.(6)

PATIENT MANAGEMENT: Closely monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted when initiating or discontinuing amiodarone therapy.

DISCUSSION: In a nested case control study, concurrent use of amiodarone and sulfonylureas increased the risk of severe hypoglycemia by 56% (95% CI:0.98-2.46). In patients on sulfonylureas, amiodarone use greater than 180 days and at higher daily doses was associated with a 2.08-fold and a 2.21-fold increase in severe hypoglycemia, respectively, which was statistically significant.(6)

Sulfonylureas/Azole Antifungals

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Azole antifungals inhibit the metabolism of sulfonylureas.

CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted.

DISCUSSION: Prospective and retrospective studies in healthy subjects have documented an interaction between the sulfonylureas and fluconazole and ketoconazole. In vitro studies have shown the metabolism of sulfonylureas to be inhibited by ketoconazole and clotrimazole. In 13 healthy males, fluconazole increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of glipizide (2.5 mg) by 19% and 49%, respectively. In 20 healthy males, fluconazole increased the Cmax and AUC of a single dose of glyburide (5 mg) by 19% and 44%, respectively. In 13 healthy males, fluconazole increased the Cmax and AUC of a single dose of tolbutamide (500 mg) by 11% and 26%, respectively. Although itraconazole was found to have no effect on tolbutamide clearance in a study in rats, additional information is needed to determine if an interaction occurs. In healthy subjects, glucose concentrations decreased during concurrent therapy with glipizide and posaconazole. Voriconazole has been shown to inhibit CYP2C9.

Sulfonylureas/Diazoxide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: In a patient stabilized on a sulfonylurea hypoglycemic agent, hyperglycemia may occur following the addition of diazoxide to the treatment.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood glucose and adjust the dose of the sulfonylurea hypoglycemic agent as needed.

DISCUSSION: The concurrent administration of a sulfonylurea hypoglycemic agent and diazoxide has been beneficial in treating chlorpropamide-induced hypoglycemia and diazoxide-induced hyperglycemia. These reports indicate a potential problem if these agents are administered without proper monitoring of the patient's blood glucose.

Sulfonylureas/Systemic Non-Cardioselective Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.

CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and sulfonylureas. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)

*Known hypersensitivity or allergy to any ingredient in the respective formulations.

*Diabetic ketoacidosis with or without coma. Diabetic ketoacidosis should be treated with insulin.

*Type 1 diabetes mellitus.

*Concomitant therapy with bosentan.

*Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

*Severe renal impairment (estimated glomerular filtration rate (eGFR) <30 mL/minute per 1.73 m2).

*Known hypersensitivity to metformin hydrochloride.

• Alcohol intoxication
• Alcohol use disorder
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Dehydration
• Metabolic acidosis
• Mitochondrial disease
• Sepsis
• Shock

• Acute decompensated heart failure
• Acute myocardial infarction
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Debilitation
• Disease of liver
• Hepatic porphyria
• High fever >101 degrees fahrenheit
• Hypoglycemic disorder
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Severe diarrhea
• Severe hypoxemia
• Severe vomiting

• Alcohol use disorder
• Debilitation
• Disease of liver
• Fever
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemolytic anemia
• Hypothyroidism
• Infection
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Pituitary insufficiency
• Primary adrenocortical insufficiency
• Severe hepatic disease
• Vitamin b12 deficiency

The most common adverse effects of glyburide (conventional and micronized formulations) are GI disturbances (e.g., nausea, epigastric fullness, heartburn).

The most common adverse effects of glyburide in fixed combination with metformin hydrochloride (>5% of patients) include diarrhea, headache, nausea/vomiting, abdominal pain, and dizziness.

The most common adverse effects of immediate-release metformin hydrochloride tablets (>5%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

The most common adverse effects of metformin hydrochloride oral solution are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

The most common adverse effects of extended-release metformin hydrochloride tablets (>5%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

More Frequent

• Hypoglycemic disorder
• Weight gain

Less Frequent

• Dyspnea
• Erythema multiforme
• Exfoliative dermatitis

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Accommodation disorder
• Acute respiratory distress syndrome
• Agranulocytosis
• Angioedema
• Aplastic anemia
• Autoimmune hemolytic anemia
• Autoimmune hepatitis
• Bullous dermatitis
• Cholestasis
• Cholestatic hepatitis
• Eosinophilia
• Hemolytic anemia
• Hepatic failure
• Hepatic porphyria
• Hepatitis
• Hepatocellular damage
• Hypoglycemic disorder
• Hyponatremia
• Lactic acidosis
• Leukopenia
• Maculopapular rash
• Megaloblastic anemia
• Obstructive hyperbilirubinemia
• Pancreatitis
• Pancytopenia
• Porphyria cutanea tarda
• Thrombocytopenic disorder
• Vasculitis

More Frequent

• Abdominal distension
• Constipation
• Diarrhea
• Dysgeusia
• Epigastric fullness
• Flatulence
• Headache disorder
• Heartburn
• Nausea
• Nausea
• Upper respiratory infection
• Vitamin b12 deficiency
• Vomiting
• Weight loss

Less Frequent

• Acute abdominal pain
• Chills
• Constipation
• Dizziness
• Dyspepsia
• Flu-like symptoms
• Flushing
• General weakness
• Hyperhidrosis
• Myalgia
• Nail disorders
• Palpitations
• Rhinitis

Rare or Very Rare

• Anticholinergic toxicity
• Arthralgia
• Drowsy
• Myalgia
• Pruritus of skin
• Pruritus of skin
• Skin photosensitivity
• Skin rash
• Skin rash
• Urticaria
• Urticaria
• Visual changes

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Safety and efficacy of glyburide in pediatric patients have not been established.

Safety and effectiveness of immediate-release metformin hydrochloride tablets and oral solution have been established in pediatric patients 10--16 years of age. Safety and effectiveness of immediate-release metformin hydrochloride tablets and oral solution have not been established in pediatric patients <10 years of age. Use of immediate-release metformin hydrochloride tablets and oral solution is supported by evidence from adequate and well-controlled studies in adults with additional data from a controlled clinical study in pediatric patients 10--16 years of age with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults. In this study, adverse effects were similar to those described in adults. A maximum daily dosage of 2 g of immediate-release metformin hydrochloride tablets or oral solution is recommended.

Safety and effectiveness of extended-release metformin hydrochloride tablets in pediatric patients have not been established.

There is insufficient evidence with glyburide in pregnant women to evaluate a drug-associated risk of adverse outcomes. Reproduction studies in rats and rabbits at up to 500 times the human dose have revealed no evidence of harm to the fetus. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration. Use of glyburide in pregnant women is generally not recommended, and the drug should be used during pregnancy only when clearly necessary (e.g., when insulin therapy is infeasible). Glyburide has been used in some pregnant women without unusual adverse effects. In a prospective, comparative clinical trial in women with gestational diabetes, treatment with glyburide (mean daily dosage 9 mg, range 2.5-20 mg) initiated in the second trimester (11-33 weeks gestation) and continued until delivery resulted in similar degrees of glycemic control and perinatal outcomes as treatment with human insulin (mean daily dosage: 85 units). The incidence of hypoglycemia in neonates whose mothers received either insulin or glyburide therapy also was similar. In a retrospective study, hypoglycemia occurred and persisted for up to 2 days or longer in a few neonates whose mothers had received glyburide up to the time of delivery. Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving other sulfonylurea antidiabetic agents up to the time of delivery; this effect has been reported more frequently with the use of agents with prolonged elimination half-lives. To minimize the risk of neonatal hypoglycemia if glyburide is used during pregnancy, the manufacturers recommend that the drug be discontinued at least 2 weeks before the expected delivery date.

Limited data with metformin hydrochloride in pregnant females are not sufficient to determine a medication-associated risk for major birth defects or miscarriage. Available studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g., congenital malformations) and mortality.

Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 3 and 6 times the maximum recommended human daily dosage of extended-release tablets (2 g) based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm (e.g., teratogenicity) to the fetus. Determination of fetal concentrations of metformin suggest that a partial placental barrier to the medication exists.

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. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.

Although it is not known whether glyburide is distributed into human milk, some sulfonylurea antidiabetic agents are distributed into human milk. Because of the potential for hypoglycemia in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If glyburide is discontinued, and if dietary management alone is inadequate for controlling blood glucose concentration, administration of insulin should be considered.

Metformin is distributed into milk in lactating rats. Limited data indicate that metformin is distributed into breast milk in humans. However, there is insufficient information to determine the effects of metformin on the breast-fed infant and no available information on the effects of metformin on milk production.

Published clinical lactation studies report that metformin present in human milk resulted in infant doses approximately 0.11--1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, these studies were not designed to establish the risk of metformin use during lactation; limited adverse event data were collected in infants. In a study in 7 nursing females who received metformin hydrochloride (median dosage 1500 mg daily), the mean milk-to-plasma ratio for metformin was 0.35 and the overall average concentration in milk over the dosing interval was 0.27 mg/L. Metformin was present in low or undetectable amounts in the plasma of 4 breast-fed infants, and no adverse effects were noted in 6 infants that were evaluated. In another study, mean peak and trough metformin concentrations in 4 nursing women receiving metformin hydrochloride 500 mg twice daily were 1.06 and 0.42 mcg/mL, respectively, in serum and 0.42 and 0.39 mcg/mL, respectively, in breast milk. The mean milk-to-serum ratio was 0.63 and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65%. Blood glucose concentrations obtained in 3 infants 4 hours after breastfeeding were within normal limits (47-77 mg/dL).

The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for the medication and potential adverse effects on the breast-fed child (e.g., hypoglycemia). Breast-fed infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Metformin should be used with caution in geriatric patients since aging is associated with a greater frequency of reduced renal, hepatic, and cardiac function, and of concomitant disease or other therapy, resulting in a higher risk of lactic acidosis. Initial dosages of metformin hydrochloride in geriatric patients should be conservative (initiated at the low end of the dosage range) and should be titrated carefully; limited data suggest reducing dosage by approximately 33% in geriatric patients. In addition, renal function should be monitored more frequently in geriatric patients to determine the appropriate dosage of metformin hydrochloride. Any dosage adjustment in geriatric patients should be based on a careful assessment of renal function.

Geriatric patients are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Geriatric patients are prone to develop renal insufficiency, which may put them at risk for hypoglycemia; dosage selection should include assessment of renal function. Hypoglycemia may be difficult to recognize in geriatric patients. Initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.

Controlled clinical trials evaluating metformin hydrochloride immediate-release and extended-release tablets did not include sufficient numbers of geriatric patients to determine whether geriatric patients respond differently to metformin than younger patients, although other reported clinical experience has not identified any differences in response between geriatric and younger patients.

In general, dosage selection for a geriatric patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medication therapy and the higher risk of lactic acidosis. In addition, renal function should be monitored more frequently in geriatric patients and care should be taken in dosage selection; such patients generally should not receive the maximum recommended dosage of metformin hydrochloride.