and 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Dual Blockade of the Renin-Angiotensin-System (RAS). Fluconazole CT Concomitant administration of azilsartan and fluconazole (a potent CYP2C9/CYP2C19 inhibitor) increases azilsartan plasma AUC(0-inf) by 42%, Cmax by 14%, and urinary exposure XU (0-24) by 48%.
76 hr). CYP2C9/CYP2C19 may be involved in azilsartan medoxomil metabolism, but the clinical impact is unknown. Glyburide CT Concomitant administration of azilsartan and glyburide has no effect in glyburide AUC and Cmax. Glyburide Tmax is earlier by 30 minutes.
- PrEDARBYCLOR® Product Monograph Page 20 of 48 Ketoconazole CT Concomitant administration of azilsartan and ketoconazole (a potent CYP3A4 inhibitor) reduces azilsartan plasma AUC(0-inf) by 21% and Cmax by 32%. 06 hr). CYP3A4 may be involved in azilsartan medoxomil metabolism but the clinical impact is unknown.
Lithium salts T Lithium clearance may be reduced. Serum lithium levels should be monitored carefully if lithium salts are to be administered. Metformin CT Concomitant administration of azilsartan and metformin has no change in azilsartan AUC or Cmax.
Azilsartan Tmax is delayed by 30 minutes. Concomitant administration results in a 20% decrease in metformin AUC and a 18% decrease in metformin Cmax. There is no change in metformin Tmax. - PrEDARBYCLOR® Product Monograph Page 21 of 48 NSAIDs (Non- Steroidal Anti- Inflammatory Drugs) T In patients who are elderly, volume- depleted (including those on diuretic therapy), or with compromised renal function, co- administration of NSAIDs, including selective COX-2 inhibitors with ARBs, including azilsartan, may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible. The antihypertensive effect of ARBs, including azilsartan may be attenuated by NSAIDs including selective COX-2 inhibitors. Renal function should be monitored periodically in patients receiving azilsartan and NSAID therapy, including selective COX-2 inhibitors.
Pioglitazone CT Concomitant administration has no effect on azilsartan or pioglitazone AUC or Tmax. There is a 14% increase in pioglitazone Cmax; there is no change in azilsartan Cmax. - Warfarin CT Concomitant administration had no effect on warfarin AUC or Cmax.
No change is found in pharmacodynamics (PT or INR). S-warfarin Tmax was earlier by 15 minutes; there was no change in S-warfarin Tmax. - Legend: C = Case Study; CT = Clinical Trial; T = Theoretical PrEDARBYCLOR® Product Monograph Page 22 of 48 Chlorthalidone Chlorthalidone Source of Evidence Effect Clinical comment Alcohol, barbiturates, and narcotics C Potentiation of orthostatic hypotension may occur.
Avoid alcohol, barbiturates, or narcotics, especially with initiation of therapy. Amphotericin B T Amphotericin B increases the risk of hypokalemia induced by thiazide diuretics Monitor serum potassium level. , oral hypoglycemic agents and insulin) CT Thiazide-induced hyperglycemia may compromise blood sugar control.
Depletion of serum potassium augments glucose intolerance. Monitor glycemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required. Antineoplastic drugs, including cyclophosphamide and methotrexate C Concomitant use of thiazide Hematological status should be closely monitored in patients receiving this combination.
Dose adjustment of cytotoxic agents may be required. g. cholestyramine and colestipol resins CT Bile acid sequestrants bind thiazide diuretics in the gut and impair gastrointestinal absorption by 43-85%. Administration of thiazide 4 hours after a bile acid sequestrant reduced absorption of hydrochlorothiazide by 30-35%.
Give thiazide 2-4 hours before or 6 hours after the bile acid sequestrant. Maintain a consistent sequence of administration. Monitor blood pressure, and increase dose of thiazide, if necessary. There were no clinically significant changes in HDL and LDL cholesterol.
PrEDARBYCLOR® Product Monograph Page 23 of 48 Calcium or vitamin D supplements. C Increased risk of hypercalcemia and associated calcium toxicity. Thiazides decrease renal excretion of calcium and increase calcium release from bone. Hypercalcemia may occur with chronic high doses of calcium.
Monitor serum calcium, especially with concomitant use of high doses of calcium supplements, and signs of hypercalcemia. Dose reduction and/or withdrawal of calcium and/or Vitamin D supplements may be necessary. Carbamazepine C Carbamazepine may cause clinically significant hyponatremia.
Concomitant use with thiazide diuretics may potentiate hyponatremia. Monitor serum sodium levels. Use with caution. Corticosteroids and adrenocorticotropic hormone (ACTH) T Intensified electrolyte depletion, particularly hypokalemia may occur.
Monitor serum potassium, and adjust medications, as required. Digitalis T Hypokalemia caused by the action of chlorthalidone can exacerbate digitalis- induced cardiac arrhythmia. Concomitant administration of chlorthalidone and digitalis requires caution.
, hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events. Concomitant administration of chlorthalidone and digoxin requires caution. Monitor electrolytes and digoxin levels closely.
Supplement potassium or adjust doses of digoxin or thiazide, as required. , anti- cholinergic agents, such as atropine and prokinetic agents, such as metoclopramide, domperidone CT, T Bioavailability of thiazide diuretics may be increased by anticholinergic agents due to a decrease in gastrointestinal motility and gastric emptying.
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