Drug Interaction Report

MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE) inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia, agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever, myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case involving enalapril, a man who had been receiving enalapril without incident developed generalized pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100 mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril uneventfully without allopurinol. No pharmacokinetic interactions have been reported between allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant effect on the bioavailability of captopril.

MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor, particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell counts is recommended. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like symptoms.

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MONITOR CLOSELY: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers, especially verapamil and diltiazem, are used concomitantly with beta blockers. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. Ventricular asystole, sinus arrest, and heart block have also been reported. The risk is increased with high dosages, IV administration, left ventricular dysfunction, or AV conduction abnormalities. Beta blocker ophthalmic solutions may also interact, as they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Bradycardia (36 bpm) with wandering atrial pacemaker occurred in a patient taking oral verapamil and timolol ophthalmic drops. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, verapamil and diltiazem may decrease the clearance of some beta blockers and use of diltiazem with beta blockers has been associated with an increased risk of depression.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if these agents are used together, and the dosage of one or both agents adjusted as necessary. Patients should be advised to promptly report any symptoms including fatigue, headache, fainting, swelling of the extremities, weight gain, shortness of breath, chest pain, increased or decreased heartbeat, or irregular heartbeat.

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MONITOR CLOSELY: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers, especially verapamil and diltiazem, are used concomitantly with beta blockers. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. Ventricular asystole, sinus arrest, and heart block have also been reported. The risk is increased with high dosages, IV administration, left ventricular dysfunction, or AV conduction abnormalities. Beta blocker ophthalmic solutions may also interact, as they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Bradycardia (36 bpm) with wandering atrial pacemaker occurred in a patient taking oral verapamil and timolol ophthalmic drops. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, verapamil and diltiazem may decrease the clearance of some beta blockers and use of diltiazem with beta blockers has been associated with an increased risk of depression.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if these agents are used together, and the dosage of one or both agents adjusted as necessary. Patients should be advised to promptly report any symptoms including fatigue, headache, fainting, swelling of the extremities, weight gain, shortness of breath, chest pain, increased or decreased heartbeat, or irregular heartbeat.

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GENERALLY AVOID: Aspirin, even in small doses, may increase the risk of bleeding in patients on oral anticoagulants by inhibiting platelet aggregation, prolonging bleeding time, and inducing gastrointestinal lesions. Analgesic/antipyretic doses of aspirin increase the risk of major bleeding more than low-dose aspirin; however bleeding has also occurred with low-dose aspirin.

MANAGEMENT: This combination, especially with analgesic/antipyretic aspirin doses, should generally be avoided unless the potential benefit outweighs the risk of bleeding. If concomitant therapy is used for additive anticoagulant effects, monitoring for excessive anticoagulation and overt and occult bleeding is recommended. The INR should be checked frequently and the dosage adjusted accordingly when aspirin is added to an anticoagulant regimen. Be cognizant that bleeding may occur without INR or prothrombin time increases. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bruising, red or brown urine, or red or black stools. Patients should also be counseled to avoid any other over-the-counter oral or topical salicylate products.

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MONITOR CLOSELY: Fibric acid derivatives may enhance the hypoprothrombinemic effect of coumarin-type oral anticoagulants. The mechanism may involve displacement of anticoagulant from plasma protein binding sites.

MANAGEMENT: Caution should be exercised when fibrates are prescribed to patients receiving oral anticoagulant therapy. Frequent prothrombin determinations are advisable until prothrombin level has stabilized. Some experts recommend that the anticoagulant dose be reduced by approximately one-third to one-half initially, then gradually adjusted as necessary according to INR (International Normalized Ratio) monitoring. Patients should be advised to notify their physician if they experience potential signs of excessive anticoagulation such as unusual or prolonged bleeding, bruising, vomiting, change in stool or urine color, headache, dizziness, or weakness.

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MONITOR CLOSELY: Coadministration with potent or moderate inhibitors of CYP450 2C9 may significantly increase the plasma concentrations of sulfonylureas, many of which have been found to be substrates of the isoenzyme. Pharmacokinetic data are available for single-dose administration of chlorpropamide (250 mg), tolbutamide (500 mg), glipizide (2.5 mg), glyburide (5 mg), and glimepiride (0.5 mg) in combination with fluconazole, a moderate CYP450 2C9 inhibitor. In healthy study subjects, fluconazole 100 mg daily for 7 days increased the single-dose systemic exposures (AUCs) of various sulfonylureas by an average of nearly 30% (chlorpropamide, tolbutamide) to almost 50% (glipizide, glyburide). Mean changes in blood glucose levels were not statistically significant in these studies, although approximately 48% of patients treated with fluconazole experienced symptoms consistent with hypoglycemia compared to 40% of patients treated with placebo. One in four of the fluconazole-treated patients in the glyburide study also required oral glucose. A higher dosage of fluconazole (400 mg for one day, followed by 200 mg daily for 3 days) increased single-dose glimepiride AUC by 138% and prolonged its half-life from 2.0 to 3.3 hours in healthy volunteers. In another study, low-dose fluconazole (50 mg/day) given to treat vulvovaginal candidiasis in 14 postmenopausal diabetic women receiving gliclazide or glyburide therapy demonstrated no effect on blood glucose control; pharmacokinetic data were not included. Based on available data, fluconazole use does not appear to be associated with a significant risk of severe hypoglycemia at dosages <200 mg/day in sulfonylurea-treated patients. However, higher dosages may cause greater inhibition of sulfonylurea clearance and increased hypoglycemic effects, particularly in the elderly and patients with renal or hepatic impairment. There have been case reports of profound hypoglycemia, including coma and death, during treatment of sulfonylureas with fluconazole, oral miconazole, as well as voriconazole. Concomitant use of sulfonylureas with fluconazole has also been associated with increased risk of serum transaminase elevations.

MANAGEMENT: Caution is advised when sulfonylureas are used concomitantly with potent or moderate CYP450 2C9 inhibitors. Blood glucose should be closely monitored, and the sulfonylurea dosage adjusted as necessary. Patients should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately, discontinue the CYP450 2C9 inhibitor if possible, and contact their physician.

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MONITOR CLOSELY: Coadministration with potent or moderate inhibitors of CYP450 2C9 may significantly increase the plasma concentrations of sulfonylureas, many of which have been found to be substrates of the isoenzyme. Pharmacokinetic data are available for single-dose administration of chlorpropamide (250 mg), tolbutamide (500 mg), glipizide (2.5 mg), glyburide (5 mg), and glimepiride (0.5 mg) in combination with fluconazole, a moderate CYP450 2C9 inhibitor. In healthy study subjects, fluconazole 100 mg daily for 7 days increased the single-dose systemic exposures (AUCs) of various sulfonylureas by an average of nearly 30% (chlorpropamide, tolbutamide) to almost 50% (glipizide, glyburide). Mean changes in blood glucose levels were not statistically significant in these studies, although approximately 48% of patients treated with fluconazole experienced symptoms consistent with hypoglycemia compared to 40% of patients treated with placebo. One in four of the fluconazole-treated patients in the glyburide study also required oral glucose. A higher dosage of fluconazole (400 mg for one day, followed by 200 mg daily for 3 days) increased single-dose glimepiride AUC by 138% and prolonged its half-life from 2.0 to 3.3 hours in healthy volunteers. In another study, low-dose fluconazole (50 mg/day) given to treat vulvovaginal candidiasis in 14 postmenopausal diabetic women receiving gliclazide or glyburide therapy demonstrated no effect on blood glucose control; pharmacokinetic data were not included. Based on available data, fluconazole use does not appear to be associated with a significant risk of severe hypoglycemia at dosages <200 mg/day in sulfonylurea-treated patients. However, higher dosages may cause greater inhibition of sulfonylurea clearance and increased hypoglycemic effects, particularly in the elderly and patients with renal or hepatic impairment. There have been case reports of profound hypoglycemia, including coma and death, during treatment of sulfonylureas with fluconazole, oral miconazole, as well as voriconazole. Concomitant use of sulfonylureas with fluconazole has also been associated with increased risk of serum transaminase elevations.

MANAGEMENT: Caution is advised when sulfonylureas are used concomitantly with potent or moderate CYP450 2C9 inhibitors. Blood glucose should be closely monitored, and the sulfonylurea dosage adjusted as necessary. Patients should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately, discontinue the CYP450 2C9 inhibitor if possible, and contact their physician.

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MONITOR CLOSELY: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers, especially verapamil and diltiazem, are used concomitantly with beta blockers. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. Ventricular asystole, sinus arrest, and heart block have also been reported. The risk is increased with high dosages, IV administration, left ventricular dysfunction, or AV conduction abnormalities. Beta blocker ophthalmic solutions may also interact, as they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Bradycardia (36 bpm) with wandering atrial pacemaker occurred in a patient taking oral verapamil and timolol ophthalmic drops. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, verapamil and diltiazem may decrease the clearance of some beta blockers and use of diltiazem with beta blockers has been associated with an increased risk of depression.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if these agents are used together, and the dosage of one or both agents adjusted as necessary. Patients should be advised to promptly report any symptoms including fatigue, headache, fainting, swelling of the extremities, weight gain, shortness of breath, chest pain, increased or decreased heartbeat, or irregular heartbeat.

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ADJUST DOSE: Coadministration with verapamil may significantly increase the plasma concentrations of simvastatin and lovastatin and potentiate the risk of statin-induced myopathy. In 12 healthy volunteers, verapamil (240 mg/day for 2 days) increased the mean peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of unchanged simvastatin (40 mg single dose) by 2.6-fold and 4.6-fold, respectively, compared to placebo. The proposed mechanism is verapamil inhibition of simvastatin metabolism via intestinal and hepatic CYP450 3A4. Although not studied, the interaction is also expected to occur with lovastatin due to its similar metabolic profile to simvastatin. Clinically, high levels of statin or HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. In an analysis of clinical trials involving over 25,000 patients treated with simvastatin 20 mg to 80 mg, the incidence of myopathy was higher in patients receiving concomitant verapamil than in those not receiving a calcium channel blocker (0.63% vs 0.061%). There is also a reported case of rhabdomyolysis and acute renal failure in a patient receiving multiple drugs that inhibit CYP450 3A4, including verapamil.

MANAGEMENT: Simvastatin dosage should not exceed 10 mg daily and lovastatin dosage not exceed 20 mg daily when used in combination with verapamil. The benefits of this combination should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving verapamil, since they are not metabolized by CYP450 3A4. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark-colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

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CONTRAINDICATED: Severe myopathy and rhabdomyolysis have been reported during concomitant use of HMG-CoA reductase inhibitors and fibric acid derivatives, especially gemfibrozil. Gemfibrozil has been reported to significantly increase the plasma concentrations of some HMG-CoA reductase inhibitors and/or their active metabolites, including lovastatin, simvastatin, pravastatin, cerivastatin, and rosuvastatin (but not fluvastatin). High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. Other fibrates have not been shown to significantly affect the pharmacokinetics of HMG-CoA reductase inhibitors. However, the use of fibrates alone has also been associated with development of myopathy, thus a pharmacodynamic interaction could conceivably occur.

MANAGEMENT: Concomitant use of simvastatin and gemfibrozil is considered contraindicated by the manufacturer of simvastatin.

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ADJUST DOSE: Coadministration with amlodipine may significantly increase the plasma concentrations of simvastatin and its active metabolite, simvastatin acid, and potentiate the risk of statin-induced myopathy. The proposed mechanism is amlodipine inhibition of simvastatin metabolism via intestinal and hepatic CYP450 3A4. When a single 80 mg dose of simvastatin was administered on day 10 of amlodipine given at a dosage of 10 mg once daily, simvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 1.5- and 1.8-fold, respectively, while simvastatin acid Cmax and AUC increased by an average of 1.6-fold each. High levels of statin or HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

MANAGEMENT: Simvastatin dosage should not exceed 20 mg daily when used in combination with amlodipine. The benefits of this combination should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving amlodipine, since they are not metabolized by CYP450 3A4. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

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GENERALLY AVOID: Beta-blockers may antagonize the effects of beta-2 adrenergic bronchodilators and precipitate acute, life-threatening bronchospasm in patients with asthma or other obstructive airway diseases. The mechanism involves increased airway resistance and reduced bronchodilation due to blockade of beta-2 adrenergic receptors. The interaction may also occur with ophthalmically applied beta-blockers, which are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Due to opposing effects on beta-2 adrenergic receptors, propranolol has been used in the treatment of albuterol overdose. Likewise, beta-2 adrenergic agonists may interfere with the pharmacologic effects of beta-blockers.

MANAGEMENT: Concomitant use of beta-2 adrenergic bronchodilators with beta-blockers, including ophthalmic formulations, should generally be avoided. If coadministration is required, a cardioselective beta-blocker (e.g., acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nebivolol) is usually preferred. Nevertheless, caution is advised and respiratory status should be closely monitored, as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. In general, nonselective beta-blockers are considered contraindicated in patients with obstructive airways disease.

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MONITOR CLOSELY: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers, especially verapamil and diltiazem, are used concomitantly with beta blockers. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. Ventricular asystole, sinus arrest, and heart block have also been reported. The risk is increased with high dosages, IV administration, left ventricular dysfunction, or AV conduction abnormalities. Beta blocker ophthalmic solutions may also interact, as they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Bradycardia (36 bpm) with wandering atrial pacemaker occurred in a patient taking oral verapamil and timolol ophthalmic drops. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, verapamil and diltiazem may decrease the clearance of some beta blockers and use of diltiazem with beta blockers has been associated with an increased risk of depression.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if these agents are used together, and the dosage of one or both agents adjusted as necessary. Patients should be advised to promptly report any symptoms including fatigue, headache, fainting, swelling of the extremities, weight gain, shortness of breath, chest pain, increased or decreased heartbeat, or irregular heartbeat.

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GENERALLY AVOID: Beta-blockers may antagonize the effects of beta-2 adrenergic bronchodilators and precipitate acute, life-threatening bronchospasm in patients with asthma or other obstructive airway diseases. The mechanism involves increased airway resistance and reduced bronchodilation due to blockade of beta-2 adrenergic receptors. The interaction may also occur with ophthalmically applied beta-blockers, which are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Due to opposing effects on beta-2 adrenergic receptors, propranolol has been used in the treatment of albuterol overdose. Likewise, beta-2 adrenergic agonists may interfere with the pharmacologic effects of beta-blockers.

MANAGEMENT: Concomitant use of beta-2 adrenergic bronchodilators with beta-blockers, including ophthalmic formulations, should generally be avoided. If coadministration is required, a cardioselective beta-blocker (e.g., acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nebivolol) is usually preferred. Nevertheless, caution is advised and respiratory status should be closely monitored, as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. In general, nonselective beta-blockers are considered contraindicated in patients with obstructive airways disease.

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MONITOR CLOSELY: Coadministration with potent or moderate inhibitors of CYP450 2C9 may significantly increase the plasma concentrations of sulfonylureas, many of which have been found to be substrates of the isoenzyme. Pharmacokinetic data are available for single-dose administration of chlorpropamide (250 mg), tolbutamide (500 mg), glipizide (2.5 mg), glyburide (5 mg), and glimepiride (0.5 mg) in combination with fluconazole, a moderate CYP450 2C9 inhibitor. In healthy study subjects, fluconazole 100 mg daily for 7 days increased the single-dose systemic exposures (AUCs) of various sulfonylureas by an average of nearly 30% (chlorpropamide, tolbutamide) to almost 50% (glipizide, glyburide). Mean changes in blood glucose levels were not statistically significant in these studies, although approximately 48% of patients treated with fluconazole experienced symptoms consistent with hypoglycemia compared to 40% of patients treated with placebo. One in four of the fluconazole-treated patients in the glyburide study also required oral glucose. A higher dosage of fluconazole (400 mg for one day, followed by 200 mg daily for 3 days) increased single-dose glimepiride AUC by 138% and prolonged its half-life from 2.0 to 3.3 hours in healthy volunteers. In another study, low-dose fluconazole (50 mg/day) given to treat vulvovaginal candidiasis in 14 postmenopausal diabetic women receiving gliclazide or glyburide therapy demonstrated no effect on blood glucose control; pharmacokinetic data were not included. Based on available data, fluconazole use does not appear to be associated with a significant risk of severe hypoglycemia at dosages <200 mg/day in sulfonylurea-treated patients. However, higher dosages may cause greater inhibition of sulfonylurea clearance and increased hypoglycemic effects, particularly in the elderly and patients with renal or hepatic impairment. There have been case reports of profound hypoglycemia, including coma and death, during treatment of sulfonylureas with fluconazole, oral miconazole, as well as voriconazole. Concomitant use of sulfonylureas with fluconazole has also been associated with increased risk of serum transaminase elevations.

MANAGEMENT: Caution is advised when sulfonylureas are used concomitantly with potent or moderate CYP450 2C9 inhibitors. Blood glucose should be closely monitored, and the sulfonylurea dosage adjusted as necessary. Patients should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately, discontinue the CYP450 2C9 inhibitor if possible, and contact their physician.

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MONITOR CLOSELY: Concomitant use of clopidogrel and oral anticoagulants such as warfarin may increase the risk of bleeding. Although often prescribed (with or without low-dose aspirin) in patients with atrial fibrillation following percutaneous coronary intervention (PCI) or revascularization surgery to prevent myocardial ischemic events, the safety and efficacy of these agents in combination have not been thoroughly evaluated. In a retrospective analysis of registry data derived from a Dutch record linkage system for a cohort of new coumarin (acenocoumarol or phenprocoumon) users, investigators found that use of antiplatelet agents was associated with a significantly increased risk of hospitalization for major bleeding during coumarin therapy, and the greatest risk was observed with clopidogrel. The odds ratio of major bleeding in coumarin users was 2.9 for clopidogrel (75 mg/day), 1.6 for aspirin (30 to 100 mg/day), and 1.5 for dipyridamole (150 to 450 mg/day), even after adjustment for use of nonsteroidal anti-inflammatory drugs, antibiotic usage, corticosteroids, and gastroprotective agents. A third of the bleeding events were gastrointestinal, with adjusted odd ratios of 3.6, 2.2 and 2.1 for clopidogrel, dipyridamole and aspirin, respectively. Approximately 20% of the nongastrointestinal bleeding events were intracranial. Other studies have also reported an increased risk of bleeding complications during coadministration of antiplatelet and oral anticoagulant therapy. However, most of the data involve aspirin alone or dual antiplatelet therapy with aspirin, thus the actual risk attributed to clopidogrel is usually unknown. In contrast, a study of 43 patients with atrial fibrillation who had been stabilized on warfarin for at least 2 months reported no bleeding and no significant changes in average INR or R(+) and S(-) warfarin levels when clopidogrel 75 mg/day was added for 8 days.

MANAGEMENT: Caution and close monitoring of the INR and other bleeding parameters are recommended if clopidogrel is used in combination with an oral anticoagulant. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

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GENERALLY AVOID: Coadministration of an ACE inhibitor in combination with an angiotensin II receptor antagonist may increase the risk of hyperkalemia, hypotension, syncope, and renal dysfunction due to additive or synergistic effects on the renin-angiotensin system.

MANAGEMENT: Dual blockade of the renin-angiotensin-aldosterone system by adding an ACE inhibitor to an angiotensin II receptor antagonist is not recommended, especially in patients with diabetic nephropathy. Most patients receiving the combination do not obtain any additional benefit compared to monotherapy. However, if the combination is considered medically necessary, serum electrolytes, blood pressure, and renal function should be closely monitored. Routine monitoring of electrolytes and renal function may be indicated in the elderly or patients with worsening heart failure or a risk for dehydration. Potassium supplementation should generally be avoided unless it is closely monitored, and patients should be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as weakness, listlessness, confusion, tingling of the extremities, and irregular heartbeat.

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MONITOR: Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect. Allopurinol may interact in a similar manner with other oral anticoagulants.

MANAGEMENT: Patients on concomitant therapy should be monitored for excessive anticoagulation. The INR should be checked frequently and dosage adjusted accordingly when allopurinol is added to an anticoagulant regimen. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Although they are frequently combined in clinical practice, diuretics and angiotensin converting enzyme (ACE) inhibitors may have additive effects. Coadministration makes hypotension and hypovolemia more likely than does either drug alone. Some ACE inhibitors may attenuate the increase in the urinary excretion of sodium caused by some loop diuretics. Some patients on diuretics, especially those on dialysis or a dietary salt restriction, may experience acute hypotension with lightheadedness and dizziness after receiving the first dose of the ACE inhibitor. In addition, ACE inhibitors may cause renal insufficiency or acute renal failure in patients with sodium depletion or renal artery stenosis.

MANAGEMENT: Monitoring of blood pressure, diuresis, electrolytes, and renal function is recommended during coadministration. The possibility of first-dose hypotensive effects may be minimized by initiating therapy with small doses of the ACE inhibitor, or either discontinuing the diuretic temporarily or increasing the salt intake approximately one week prior to initiating an ACE inhibitor. Alternatively, the patient may remain under medical supervision for at least two hours after the first dose of the ACE inhibitor, or until blood pressure has stabilized.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Methyldopa and beta-blockers may have additive hypotensive effects. In addition, potentiation of hypertensive rebound associated with withdrawal of methyldopa or beta-blockers may occur if both drugs are withdrawn at the same time. The proposed mechanism may involve increased catecholamine release after methyldopa and/or a beta-blocker are withdrawn, which may lead to unopposed alpha-adrenergic effects and vasoconstriction.

MANAGEMENT: Close monitoring of blood pressure is recommended during concomitant use, and if methyldopa or the beta blocker are withdrawn from therapy. The manufacturer's product labeling may be consulted for the procedure to gradually discontinue a beta blocker. Methyldopa manufacturers recommend adjusting the beta blocker dose if methyldopa is added to therapy, and not exceeding a methyldopa dose of 500 mg/day when it is first added to therapy. Patients should be instructed to notify their doctor if they have a reduced heart rate, dizziness, fainting or headaches, chest pain or vision problems.

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MONITOR: Some investigators suggest that coadministration with aspirin may attenuate the vasodilator and hypotensive effects of ACE inhibitors. In addition, some have found that the benefits of ACE inhibitors on morbidity and mortality in post-acute myocardial infarction, coronary heart disease, and particularly congestive heart failure may be compromised or even nullified by aspirin. The proposed mechanism is aspirin inhibition of cyclooxygenase, resulting in suppression of prostaglandin synthesis and prostaglandin-mediated hemodynamic effects of ACE inhibitors. However, evidence of a negative interaction is largely contradictory, and interpretation of relevant data has often been complicated by multiple confounding elements as well as the retrospective or post hoc nature of most studies. Available data seem to indicate that low-dose aspirin (less than 236 mg/day, and especially less than 100 mg/day) is unlikely, or at least significantly less likely, to interfere with ACE inhibitor effects, although susceptibility to the interaction may be subject to some degree of interpatient variability.

MANAGEMENT: Based on current data, it is difficult to determine the likelihood of a negative interaction between aspirin and ACE inhibitors and its clinical relevance during long-term therapy, particularly in congestive heart failure. Current recommendations generally do not preclude combination use in patients with cardiovascular diseases or risk factors that might otherwise benefit from the drugs independently. However, patients receiving long-term therapy with the combination should undergo regular blood pressure and other appropriate clinical monitoring such as renal function assessments. The lowest therapeutic dosage of aspirin should be used.

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MONITOR: Several case reports have suggested that verapamil and aspirin may have synergistic antiplatelet effects. The mechanism of this interaction has not been fully elucidated. Also, one study of five patients has suggested that aspirin may reverse the antihypertensive effect of verapamil. The mechanism may be related to antagonism of the effect of verapamil on prostacyclin. Diltiazem has been shown to interact with aspirin in a similar manner.

MANAGEMENT: Close observation for prolonged bleeding time and reduced antihypertensive effect is recommended if these drugs must be used together. Patients should be advised to notify their physician if they experience unusual bleeding, bruising, or petechiae. Aspirin should be discontinued if an interaction is suspected.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: Oral sulfonylureas may enhance or reduce the hypoprothrombinemic response to oral anticoagulants. The mechanism may be related to displacement from plasma protein binding sites. In addition, coumarin anticoagulants may cause an increase in blood levels of hypoglycemic agents, possibly by inhibiting their hepatic metabolism. Clinical data have been highly variable.

MANAGEMENT: The patient should be monitored for altered anticoagulation (PT/INR) and altered glycemic effect when either of these drugs is added to or removed from a patient's regimen. Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations), and to promptly report any signs of bleeding (pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, vaginal bleeding, nosebleeds, bleeding of gums from brushing, red or brown urine, or red or black stools) to their physician.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: Oral sulfonylureas may enhance or reduce the hypoprothrombinemic response to oral anticoagulants. The mechanism may be related to displacement from plasma protein binding sites. In addition, coumarin anticoagulants may cause an increase in blood levels of hypoglycemic agents, possibly by inhibiting their hepatic metabolism. Clinical data have been highly variable.

MANAGEMENT: The patient should be monitored for altered anticoagulation (PT/INR) and altered glycemic effect when either of these drugs is added to or removed from a patient's regimen. Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations), and to promptly report any signs of bleeding (pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, vaginal bleeding, nosebleeds, bleeding of gums from brushing, red or brown urine, or red or black stools) to their physician.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Although they are frequently combined in clinical practice, diuretics and angiotensin converting enzyme (ACE) inhibitors may have additive effects. Coadministration makes hypotension and hypovolemia more likely than does either drug alone. Some ACE inhibitors may attenuate the increase in the urinary excretion of sodium caused by some loop diuretics. Some patients on diuretics, especially those on dialysis or a dietary salt restriction, may experience acute hypotension with lightheadedness and dizziness after receiving the first dose of the ACE inhibitor. In addition, ACE inhibitors may cause renal insufficiency or acute renal failure in patients with sodium depletion or renal artery stenosis.

MANAGEMENT: Monitoring of blood pressure, diuresis, electrolytes, and renal function is recommended during coadministration. The possibility of first-dose hypotensive effects may be minimized by initiating therapy with small doses of the ACE inhibitor, or either discontinuing the diuretic temporarily or increasing the salt intake approximately one week prior to initiating an ACE inhibitor. Alternatively, the patient may remain under medical supervision for at least two hours after the first dose of the ACE inhibitor, or until blood pressure has stabilized.

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MONITOR: Serious hypersensitivity reactions to allopurinol have been well-documented in the medical literature. Case reports have suggested that thiazide diuretics may increase the risk of allopurinol-induced hypersensitivity reactions, especially in patients with renal insufficiency. The mechanism is unknown and pharmacokinetic studies with hydrochlorothiazide have not demonstrated any effects on the disposition of allopurinol or oxipurinol (its major metabolite).

MANAGEMENT: Patients should be advised to promptly report any signs of hypersensitivity, including rash, pruritus, fever, or chills.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: The combination of a thiazide and loop diuretic may produce additive or synergistic effects on diuresis and excretion of electrolytes including sodium, potassium, magnesium, and chloride. Although these agents may be combined therapeutically in some patients with inadequate response to a single agent, the increased risk of dehydration, hypotension, hypokalemia, hypomagnesemia, and hyponatremia should be recognized. The exact mechanism of interaction is unclear but appears to be pharmacodynamic rather than pharmacokinetic.

MANAGEMENT: Caution is advised during concomitant use of a thiazide and loop diuretic. Dosages should be titrated slowly and carefully, and electrolytes, BUN, fluid status, blood pressure, and renal function should be monitored regularly. Patients should be advised to contact their physician if they experience signs and symptoms of fluid and electrolyte depletion such as dizziness, lightheadedness, dry mouth, thirst, fatigue, weakness, lethargy, muscle cramps, decreased urination, postural hypotension, and tachycardia.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The hypoglycemic effect of insulin may be potentiated by certain drugs, including ACE inhibitors, angiotensin receptor blockers (ARBs), 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinidine, quinine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, ARBs, fibrates, ginseng); stimulating insulin secretion (salicylates, disopyramide, pentoxifylline, propoxyphene, quinidine, quinine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or insulin secretagogues. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin, particularly in patients with advanced age and/or renal impairment. The insulin dosage may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: The hypoglycemic effect of insulin may be potentiated by certain drugs, including ACE inhibitors, angiotensin receptor blockers (ARBs), 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinidine, quinine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, ARBs, fibrates, ginseng); stimulating insulin secretion (salicylates, disopyramide, pentoxifylline, propoxyphene, quinidine, quinine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or insulin secretagogues. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin, particularly in patients with advanced age and/or renal impairment. The insulin dosage may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: The hypoglycemic effect of insulin may be potentiated by certain drugs, including ACE inhibitors, angiotensin receptor blockers (ARBs), 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinidine, quinine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, ARBs, fibrates, ginseng); stimulating insulin secretion (salicylates, disopyramide, pentoxifylline, propoxyphene, quinidine, quinine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or insulin secretagogues. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin, particularly in patients with advanced age and/or renal impairment. The insulin dosage may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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ADJUST DOSE: Coadministration of a sulfonylurea with insulin may potentiate the risk of hypoglycemia. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

MANAGEMENT: Caution and close blood glucose monitoring are advised during coadministration of these agents. A lower dosage of sulfonylurea or insulin may be required. Patients should be counseled to recognize the symptoms of hypoglycemia such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately and contact their physician. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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ADJUST DOSE: Coadministration of a sulfonylurea with insulin may potentiate the risk of hypoglycemia. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

MANAGEMENT: Caution and close blood glucose monitoring are advised during coadministration of these agents. A lower dosage of sulfonylurea or insulin may be required. Patients should be counseled to recognize the symptoms of hypoglycemia such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately and contact their physician. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers are used concomitantly with beta blockers, particularly in patients with ventricular or conduction abnormalities. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, some calcium channel blockers may inhibit the CYP450 metabolism of hepatically metabolized beta blockers, resulting in increased serum concentrations.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if a calcium channel blocker is prescribed with a beta blocker, and the dosage of one or both agents adjusted as necessary. The same precaution should be observed when beta blocker ophthalmic solutions are used, since they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels.

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MONITOR: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers are used concomitantly with beta blockers, particularly in patients with ventricular or conduction abnormalities. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, some calcium channel blockers may inhibit the CYP450 metabolism of hepatically metabolized beta blockers, resulting in increased serum concentrations.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if a calcium channel blocker is prescribed with a beta blocker, and the dosage of one or both agents adjusted as necessary. The same precaution should be observed when beta blocker ophthalmic solutions are used, since they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels.

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MONITOR: Coadministration with CYP450 3A4 inhibitors may increase the plasma concentrations of amlodipine, which is a substrate of the isoenzyme. In 8 elderly hypertensive patients, administration of a single 5 mg dose of amlodipine in combination with the moderate CYP450 3A4 inhibitor diltiazem (180 mg orally daily for 3 days) resulted in a nearly 60% increase in amlodipine peak plasma concentration (Cmax) and systemic exposure (AUC). Associated systolic, diastolic, and standing blood pressures decreased compared to those obtained with amlodipine alone. Erythromycin, another moderate inhibitor, did not significantly alter amlodipine systemic exposure in healthy volunteers. However, pharmacokinetic changes may be more pronounced in elderly patients.

MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if amlodipine is prescribed with potent or moderate CYP450 3A4 inhibitors. Dosage reduction may be required for amlodipine. Patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.

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MONITOR: Limited data indicate that some cyclooxygenase inhibitors may attenuate the antihypertensive effects of some calcium channel blockers. The mechanism appears to be related to an alteration of vascular tone, which is dependent on prostacyclins and other vasodilatory prostanoids. When a nonsteroidal anti-inflammatory drug (NSAID) is added to the regimen of a patient who is already taking a calcium channel blocker, increased blood pressure may result. Also, the clinician should be aware that the risk of hypotension is increased when NSAIDs are withdrawn from the regimen.

MANAGEMENT: Monitoring for altered blood pressure control is recommended.

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GENERALLY AVOID: Coadministration with other beta-blockers may increase the bradycardic and hypotensive effects of bisoprolol. Concomitant use of multiple drugs that can decrease heart rate and blood pressure is expected to increase the risk of clinically significant bradycardia and hypotension.

MANAGEMENT: Coadministration of bisoprolol with other beta-blockers should generally be avoided.

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GENERALLY AVOID: Coadministration with other beta-blockers may increase the bradycardic and hypotensive effects of bisoprolol. Concomitant use of multiple drugs that can decrease heart rate and blood pressure is expected to increase the risk of clinically significant bradycardia and hypotension.

MANAGEMENT: Coadministration of bisoprolol with other beta-blockers should generally be avoided.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Centrally acting antihypertensive agents and beta-blockers may have synergistic pharmacodynamic effects resulting in marked AV block, bradycardia, hypotension, and worsening of heart failure. In addition, potentiation of the hypertensive rebound associated with abrupt withdrawal of methyldopa and the beta blocker may occur.

MANAGEMENT: Caution and monitoring of the patient's hemodynamic status are recommended during coadministration or withdrawal of these drugs.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers are used concomitantly with beta blockers, particularly in patients with ventricular or conduction abnormalities. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, some calcium channel blockers may inhibit the CYP450 metabolism of hepatically metabolized beta blockers, resulting in increased serum concentrations.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if a calcium channel blocker is prescribed with a beta blocker, and the dosage of one or both agents adjusted as necessary. The same precaution should be observed when beta blocker ophthalmic solutions are used, since they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels.

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GENERALLY AVOID: Although cardioselective beta-blockers do not generally inhibit the bronchodilating effect of beta-2 adrenergic agonists, they may worsen pulmonary function in patients with asthma or other obstructive airway diseases. Cardioselective beta-blockers can occasionally precipitate acute bronchospasm in these patients, despite relative selectivity for beta-1 receptors in cardiac tissues. Presumably, beta-1 selectivity is dose-dependent and may be lost given a sufficient dose of the beta-blocker in susceptible patients. Other mechanisms may also be involved in bronchoconstriction that are unrelated to beta-2 blockade--for example, their effects on cholinergic M2 receptors and alpha-1 adrenoreceptors. Numerous single- and multiple-dose studies have been conducted in asthmatic and COPD patients with various cardioselective beta-blockers, including acebutolol, atenolol, bisoprolol, celiprolol, metoprolol, and nebivolol. Some reported no significant effects on pulmonary function or bronchodilator response to beta-2 agonists, while others reported some negative effects on pulmonary function and/or airway hyperresponsiveness. Overall, a meta-analysis of more than two dozen studies found that use of cardioselective beta-blockers in patients with mild to moderate reversible airway disease produced no adverse respiratory effects or decreased responsiveness to beta-2 agonists in the short term. A meta-analysis of 19 studies conducted in patients with COPD by the same group of investigators reported similar results. However, little data exist regarding their safety during chronic use or use in patients with severe respiratory disease. There have been reports of worsening asthma and bronchospasm in patients receiving cardioselective beta-blockers including betaxolol (both systemic and ophthalmic) and esmolol. Several studies have suggested enhanced bronchosparing effects of celiprolol over other cardioselective beta-blockers due to its partial beta-2 agonistic and alpha-2 blocking activities. However, one study found no difference between celiprolol and nebivolol. A few studies also suggested a lower degree of beta-1 selectivity for acebutolol compared to other cardioselective beta-blockers. The clinical significance is unknown.

MANAGEMENT: Beta-blockers, including those with relative cardioselectivity, should generally be avoided in patients with bronchospastic diseases. However, given their demonstrated benefit in such conditions as heart failure, myocardial infarction, cardiac arrhythmias and hypertension, cardioselective beta-blockers may be administered with caution to those who do not respond to or tolerate alternative treatment. The benefits generally outweigh the risks in patients with mild or moderate reactive airway disease that is well controlled on inhaled corticosteroids and beta-2 agonists, provided they have no prior history suggesting a predisposition to severe exacerbations. The dosage should start low, preferably in divided doses to avoid the higher plasma levels associated with longer dosing intervals, and titrated slowly according to therapeutic response and pulmonary function. Patients should be advised to contact their physician if they experience worsening of respiratory symptoms, which would warrant a reevaluation of the appropriateness of beta-blocker therapy. Cardioselective beta-blockers should be used with extreme caution, if at all, in patients prone to frequent exacerbations of their respiratory disease.

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MONITOR: Coadministration with beta-2 adrenergic agonists may potentiate the hypokalemic effects of potassium-wasting diuretics. Beta-2 agonists can cause clinically significant but usually transient decreases in serum potassium concentrations. Since QT prolongation is a possible side effect of beta-2 agonists, exacerbation of hypokalemia may increase the risk of torsade de pointes and other serious arrhythmias. The interaction may be more likely with systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or concomitant theophylline or corticosteroid therapy.

MANAGEMENT: Caution is advised when beta-2 agonists are used with potassium-wasting diuretics. Serum potassium level and cardiovascular status should be monitored, especially if the beta-2 agonist is administered systemically or by nebulizer. Patients should be advised to notify their physician if they experience potential signs and symptoms of hypokalemia such as fatigue, weakness, myalgia, muscle cramps, numbness, tingling, abdominal pain, constipation, palpitation, and irregular heartbeat.

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MONITOR: Limited data suggest that methyldopa and other sympatholytics may increase or prolong the pressor effect of sympathomimetics. Hypertension may result. Data exist for phenylpropanolamine and norepinephrine.

MANAGEMENT: If these drugs must be coadministered, blood pressure should be closely monitored. Discontinuation of the sympathomimetic may be necessary if hypertension develops.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: Coadministration with beta-2 adrenergic agonists may potentiate the hypokalemic effects of potassium-wasting diuretics. Beta-2 agonists can cause clinically significant but usually transient decreases in serum potassium concentrations. Since QT prolongation is a possible side effect of beta-2 agonists, exacerbation of hypokalemia may increase the risk of torsade de pointes and other serious arrhythmias. The interaction may be more likely with systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or concomitant theophylline or corticosteroid therapy.

MANAGEMENT: Caution is advised when beta-2 agonists are used with potassium-wasting diuretics. Serum potassium level and cardiovascular status should be monitored, especially if the beta-2 agonist is administered systemically or by nebulizer. Patients should be advised to notify their physician if they experience potential signs and symptoms of hypokalemia such as fatigue, weakness, myalgia, muscle cramps, numbness, tingling, abdominal pain, constipation, palpitation, and irregular heartbeat.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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GENERALLY AVOID: Although cardioselective beta-blockers do not generally inhibit the bronchodilating effect of beta-2 adrenergic agonists, they may worsen pulmonary function in patients with asthma or other obstructive airway diseases. Cardioselective beta-blockers can occasionally precipitate acute bronchospasm in these patients, despite relative selectivity for beta-1 receptors in cardiac tissues. Presumably, beta-1 selectivity is dose-dependent and may be lost given a sufficient dose of the beta-blocker in susceptible patients. Other mechanisms may also be involved in bronchoconstriction that are unrelated to beta-2 blockade--for example, their effects on cholinergic M2 receptors and alpha-1 adrenoreceptors. Numerous single- and multiple-dose studies have been conducted in asthmatic and COPD patients with various cardioselective beta-blockers, including acebutolol, atenolol, bisoprolol, celiprolol, metoprolol, and nebivolol. Some reported no significant effects on pulmonary function or bronchodilator response to beta-2 agonists, while others reported some negative effects on pulmonary function and/or airway hyperresponsiveness. Overall, a meta-analysis of more than two dozen studies found that use of cardioselective beta-blockers in patients with mild to moderate reversible airway disease produced no adverse respiratory effects or decreased responsiveness to beta-2 agonists in the short term. A meta-analysis of 19 studies conducted in patients with COPD by the same group of investigators reported similar results. However, little data exist regarding their safety during chronic use or use in patients with severe respiratory disease. There have been reports of worsening asthma and bronchospasm in patients receiving cardioselective beta-blockers including betaxolol (both systemic and ophthalmic) and esmolol. Several studies have suggested enhanced bronchosparing effects of celiprolol over other cardioselective beta-blockers due to its partial beta-2 agonistic and alpha-2 blocking activities. However, one study found no difference between celiprolol and nebivolol. A few studies also suggested a lower degree of beta-1 selectivity for acebutolol compared to other cardioselective beta-blockers. The clinical significance is unknown.

MANAGEMENT: Beta-blockers, including those with relative cardioselectivity, should generally be avoided in patients with bronchospastic diseases. However, given their demonstrated benefit in such conditions as heart failure, myocardial infarction, cardiac arrhythmias and hypertension, cardioselective beta-blockers may be administered with caution to those who do not respond to or tolerate alternative treatment. The benefits generally outweigh the risks in patients with mild or moderate reactive airway disease that is well controlled on inhaled corticosteroids and beta-2 agonists, provided they have no prior history suggesting a predisposition to severe exacerbations. The dosage should start low, preferably in divided doses to avoid the higher plasma levels associated with longer dosing intervals, and titrated slowly according to therapeutic response and pulmonary function. Patients should be advised to contact their physician if they experience worsening of respiratory symptoms, which would warrant a reevaluation of the appropriateness of beta-blocker therapy. Cardioselective beta-blockers should be used with extreme caution, if at all, in patients prone to frequent exacerbations of their respiratory disease.

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MONITOR: Limited data suggest that ACE inhibitors may potentiate the hypoglycemic effects of oral antidiabetic drugs, including metformin. The mechanism is unknown. Symptomatic and sometimes severe hypoglycemia has occurred.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if ACE inhibitors are coadministered with metformin, particularly in patients with advanced age and/or renal impairment. Dosage adjustments may be required if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when ACE inhibitors are withdrawn.

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MONITOR: Coadministration with metformin may decrease the anticoagulant effects of vitamin K antagonists (VKAs). The mechanism has not been delineated, but it may involve metformin-mediated increase in the elimination rate of VKAs. In addition, concomitant use of VKAs with metformin may increase the risk of severe hypoglycemia. The clinical significance of this interaction is unknown.

MANAGEMENT: Until more information is available, patients receiving VKAs with metformin should be closely monitored during concomitant therapy. The INR or prothrombin time should be checked frequently and the VKA dosage adjusted accordingly, particularly following initiation, change of dosage, or discontinuation of metformin therapy. In addition, patients receiving this combination should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations) and to notify their physician if it occurs.

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MONITOR: Verapamil may decrease the glucose-lowering effects of metformin. The mechanism may involve verapamil inhibition of the organic cation transporter 1 (OCT1), thereby inhibiting hepatic uptake of metformin. In 12 healthy male subjects, sustained-release verapamil (180 mg a day for 3 days) significantly decreased the glucose-lowering effects of immediate-release metformin (1000 mg in the evening, 750 mg the following morning), as evidenced by a reduction in maximum blood glucose concentrations and the area under the glucose concentration-time curve by 62.5% and 238%, respectively.

MANAGEMENT: Caution is advised if verapamil and metformin are used concomitantly. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages may be adjusted as necessary.

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MONITOR: One study has suggested that furosemide may increase plasma concentrations of metformin by 22% (without changes in metformin clearance) and that metformin may decrease the peak concentration and elimination half-life of furosemide by 31% and 32%, respectively. The clinical implications of these findings are uncertain. Increased metformin levels may increase the risk of lactic acidosis.

MANAGEMENT: If furosemide and metformin must be used together, it is recommended that the clinician observe closely for evidence that the effects of either drug have been altered. Patients should be advised to monitor their blood glucose and to promptly notify their physician if they experience possible signs of lactic acidosis such as malaise, myalgia, respiratory distress, hyperventilation, slow or irregular heartbeat, somnolence, abdominal upset, or other unusual symptoms.

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MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea, meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplementation.

MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used with metformin. Blood glucose should be closely monitored, and patients should be educated on the potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea, meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplementation.

MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used with metformin. Blood glucose should be closely monitored, and patients should be educated on the potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Diuretic-induced renal impairment and dehydration may increase the risk of lactic acidosis in patients who are concomitantly taking metformin. In addition, thiazides and other diuretics may interfere with glucose control by causing hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Close clinical monitoring is recommended if diuretics are coadministered with antidiabetic agents. Patients should be advised to monitor their blood glucose and to promptly notify their doctor if they experience possible signs of lactic acidosis (such as malaise, myalgia, respiratory distress, hyperventilation, slow or irregular heartbeat, somnolence, abdominal upset) or loss of glycemic control. Dose adjustments of metformin may be required. Likewise, patients should be observed for hypoglycemia if diuretics are withdrawn from their therapeutic regimen.

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MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea, meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplementation.

MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used with metformin. Blood glucose should be closely monitored, and patients should be educated on the potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Methyldopa and beta-blockers may have additive hypotensive effects. In addition, potentiation of hypertensive rebound associated with withdrawal of methyldopa or beta-blockers may occur if both drugs are withdrawn at the same time. The proposed mechanism may involve increased catecholamine release after methyldopa and/or a beta-blocker are withdrawn, which may lead to unopposed alpha-adrenergic effects and vasoconstriction.

MANAGEMENT: Close monitoring of blood pressure is recommended during concomitant use, and if methyldopa or the beta blocker are withdrawn from therapy. The manufacturer's product labeling may be consulted for the procedure to gradually discontinue a beta blocker. Methyldopa manufacturers recommend adjusting the beta blocker dose if methyldopa is added to therapy, and not exceeding a methyldopa dose of 500 mg/day when it is first added to therapy. Patients should be instructed to notify their doctor if they have a reduced heart rate, dizziness, fainting or headaches, chest pain or vision problems.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers are used concomitantly with beta blockers, particularly in patients with ventricular or conduction abnormalities. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, some calcium channel blockers may inhibit the CYP450 metabolism of hepatically metabolized beta blockers, resulting in increased serum concentrations.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if a calcium channel blocker is prescribed with a beta blocker, and the dosage of one or both agents adjusted as necessary. The same precaution should be observed when beta blocker ophthalmic solutions are used, since they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels.

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GENERALLY AVOID: Coadministration with other beta-blockers may increase the bradycardic and hypotensive effects of bisoprolol. Concomitant use of multiple drugs that can decrease heart rate and blood pressure is expected to increase the risk of clinically significant bradycardia and hypotension.

MANAGEMENT: Coadministration of bisoprolol with other beta-blockers should generally be avoided.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: The hypoglycemic action of glimepiride may be potentiated by highly protein-bound drugs. The mechanism is displacement of glimepiride from protein-binding sites, resulting in higher plasma concentrations of unbound glimepiride available to act on pancreatic beta cells.

MANAGEMENT: Patients should be monitored closely for hypoglycemia during concomitant therapy, particularly following addition of a highly protein-bound drug to a stabilized glimepiride regimen. Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations) and to notify their physician if it occurs. Likewise, such patients should be observed for loss of glycemic control when the highly protein-bound drug is withdrawn.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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ADJUST DOSE: Coadministration of a sulfonylurea with insulin may potentiate the risk of hypoglycemia. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

MANAGEMENT: Caution and close blood glucose monitoring are advised during coadministration of these agents. A lower dosage of sulfonylurea or insulin may be required. Patients should be counseled to recognize the symptoms of hypoglycemia such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately and contact their physician. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs, including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors, sympathomimetic amines, thyroid hormones, L-asparaginase, alpelisib, copanlisib, danazol, diazoxide, isoniazid, megestrol, omacetaxine, phenytoin, sirolimus, tagraxofusp, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.

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MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea, meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplementation.

MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used with metformin. Blood glucose should be closely monitored, and patients should be educated on the potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be advised of the need for regular blood glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta-blockers.

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MONITOR: Clopidogrel has been shown to potentiate the inhibition of platelet aggregation due to aspirin. Single-dose studies have not shown a prolongation of bleeding time when aspirin was added to clopidogrel; however, the risk of gastrointestinal (GI) bleeding may be increased. A large clinical trial reported that clopidogrel 75 mg/day plus aspirin 75 to 325 mg/day for up to 1 year was associated with a higher incidence of major GI bleeding (1.3% vs 0.7% with aspirin alone). These two medications are routinely used together for their additive antiplatelet, antistroke effect. The safety of chronic administration of aspirin or other salicylates with clopidogrel has not been established.

MANAGEMENT: Until further data are available, caution is recommended, especially in patients at risk of bleeding (i.e., GI ulceration), if clopidogrel is coadministered on a long-term basis with drugs that may cause GI lesions. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, red or black stools, or bloody or coffee-ground emesis. Patients should also be counseled to avoid any other over-the-counter salicylate products.

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MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effects of angiotensin II receptor antagonists. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension. In addition, NSAIDs can cause fluid retention, which also affects blood pressure. Clinical data are limited.

MONITOR: Concomitant use of NSAIDs and angiotensin II receptor antagonists may cause deterioration in renal function, particularly in patients who are elderly or volume-depleted (including those on diuretic therapy) or have compromised renal function. Acute renal failure may occur, although effects are usually reversible. Chronic use of NSAIDs alone may be associated with renal toxicities, including elevations in serum creatinine and BUN, tubular necrosis, glomerulitis, renal papillary necrosis, acute interstitial nephritis, nephrotic syndrome, and renal failure. Additionally, in patients with prerenal conditions whose renal perfusion may be dependent on the function of prostaglandins, NSAIDs may precipitate overt renal decompensation via a dose-related inhibition of prostaglandin synthesis. Angiotensin II receptor antagonists can further worsen renal function by blocking the effect of angiotensin II-mediated efferent arteriolar vasoconstriction, thereby decreasing glomerular filtration.

MANAGEMENT: Patients receiving angiotensin II receptor antagonists who require prolonged (greater than 1 week) concomitant therapy with an NSAID should have blood pressure monitored more closely following initiation, discontinuation, or change of dosage of the NSAID. Renal function should also be evaluated periodically during prolonged coadministration. The interaction is not expected to occur with low doses (e.g., low-dose aspirin) or intermittent short-term administration of NSAIDs.

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MONITOR: The hypoglycemic effect of insulin may be potentiated by certain drugs, including ACE inhibitors, angiotensin receptor blockers (ARBs), 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinidine, quinine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, ARBs, fibrates, ginseng); stimulating insulin secretion (salicylates, disopyramide, pentoxifylline, propoxyphene, quinidine, quinine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or insulin secretagogues. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin, particularly in patients with advanced age and/or renal impairment. The insulin dosage may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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Some oral beta-blockers may increase serum levels of oral anticoagulants and enhance anticoagulant effects. The mechanism is unknown . Data have been conflicting. Case reports exist for propranolol, while acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, esmolol, metoprolol, and pindolol reportedly do not interact. Hypoprothrombinemic effects are expected to be minimal. It is recommended that PT or INR be monitored when a beta-blocker is added to or deleted from the medical regimen of a patient receiving an oral anticoagulant. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

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Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive hypotensive effects. While these drugs are often safely used together, careful monitoring of the systemic blood pressure is recommended during coadministration, especially during the first one to three weeks of therapy.

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High doses of salicylates may blunt the antihypertensive effects of beta-blockers. The proposed mechanism is inhibition of prostaglandin synthesis. Low-dose aspirin does not appear to affect blood pressure. In addition, beta-blockers may exert an antiplatelet effect, which may be additive with the effects of some salicylates. Metoprolol may also increase aspirin absorption and/or plasma concentrations of salicylates; however, the clinical significance of this effect is unknown. Data have been conflicting. Until more information is available, patients who require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.

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High doses of salicylates may blunt the antihypertensive effects of beta-blockers. The proposed mechanism is inhibition of prostaglandin synthesis. Low-dose aspirin does not appear to affect blood pressure. In addition, beta-blockers may exert an antiplatelet effect, which may be additive with the effects of some salicylates. Metoprolol may also increase aspirin absorption and/or plasma concentrations of salicylates; however, the clinical significance of this effect is unknown. Data have been conflicting. Until more information is available, patients who require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.

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Salicylates in anti-inflammatory dosages may blunt the diuretic and natriuretic response to loop diuretics. The interaction has been demonstrated in patients with ascites secondary to liver cirrhosis and in normal volunteers. Investigators theorize that salicylates may inhibit the renal effects of loop diuretics that are mediated by prostaglandins, including increases in sodium excretion, renal blood flow, and plasma renin activity. Since renal prostaglandins are believed to play a major role in the maintenance of renal blood flow and glomerular filtration rate in cirrhotics with ascites, the interaction may be particularly important in this population. No clinical interventions are generally required, but the possibility of a potential interaction should be considered in patients with ascites treated with a loop diuretic and salicylate or salicylate-related product.

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Methyldopa may inhibit the metabolism of some antidiabetic agents. The serum half-life and the effectiveness of those agents may be increased, and unexpected hypoglycemia could result. When methyldopa is added to or deleted from a medical regimen that includes antidiabetic agents, the patient should be made aware of this interaction. Blood glucose should be checked more frequently, if necessary.

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The concomitant use of verapamil therapy may modestly increase serum levels of glyburide; however, glucose lowering effects are not altered. The mechanism has not been determined.

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Methyldopa may inhibit the metabolism of some antidiabetic agents. The serum half-life and the effectiveness of those agents may be increased, and unexpected hypoglycemia could result. When methyldopa is added to or deleted from a medical regimen that includes antidiabetic agents, the patient should be made aware of this interaction. Blood glucose should be checked more frequently, if necessary.

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Thiazide diuretics may reduce intravascular volume. Higher plasma levels of clotting factors and decreased anticoagulant effect may result; however the effects may not be clinically significant. Management consists of monitoring coagulation parameters during the initial phase of coadministration. Patients should be advised to promptly report any signs of blood clots (e.g. chest pain, shortness of breath, sudden loss of vision, or pain, redness or swelling in an extremity).

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Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive hypotensive effects. While these drugs are often safely used together, careful monitoring of the systemic blood pressure is recommended during coadministration, especially during the first one to three weeks of therapy.

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The antihypertensive effect of amlodipine and thiazide diuretics may be additive. Management consists of monitoring blood pressure during coadministration, especially during the first 1 to 3 weeks of therapy.

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High doses of salicylates may blunt the antihypertensive effects of beta-blockers. The proposed mechanism is inhibition of prostaglandin synthesis. Low-dose aspirin does not appear to affect blood pressure. In addition, beta-blockers may exert an antiplatelet effect, which may be additive with the effects of some salicylates. Metoprolol may also increase aspirin absorption and/or plasma concentrations of salicylates; however, the clinical significance of this effect is unknown. Data have been conflicting. Until more information is available, patients who require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.

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Simvastatin may slightly increase the anticoagulant response to warfarin. The mechanism may be warfarin displacement from protein binding sites. The clinical significance of this interaction has not been established, however, clinical monitoring of patient warfarin response and tolerance is recommended. Simvastatin may interact in a similar way with other oral anticoagulants. In addition, a case study has reported reversible rhabdomyolysis and acute renal failure 7 days following initiation of warfarin in a patient stabilized on simvastatin. Pravastatin, another HMG-CoA reductase inhibitor, does not appear to affect anticoagulation. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

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Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.

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High doses of salicylates may blunt the antihypertensive effects of beta-blockers. The proposed mechanism is inhibition of prostaglandin synthesis. Low-dose aspirin does not appear to affect blood pressure. In addition, beta-blockers may exert an antiplatelet effect, which may be additive with the effects of some salicylates. Metoprolol may also increase aspirin absorption and/or plasma concentrations of salicylates; however, the clinical significance of this effect is unknown. Data have been conflicting. Until more information is available, patients who require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.

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Methyldopa may inhibit the metabolism of some antidiabetic agents. The serum half-life and the effectiveness of those agents may be increased, and unexpected hypoglycemia could result. When methyldopa is added to or deleted from a medical regimen that includes antidiabetic agents, the patient should be made aware of this interaction. Blood glucose should be checked more frequently, if necessary.

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In vitro studies have shown that high concentrations of clopidogrel inhibit CYP450 2C9 isoenzymes. The metabolism of drugs which are substrates for this enzyme may be decreased, potentiating toxicity of the substrate drug. The clinical significance and magnitude of this interaction is not known. Dose adjustments may be necessary if an interaction is suspected.

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GENERALLY AVOID: Alcohol can potentiate the effect of metformin on lactate metabolism and increase the risk of lactic acidosis. In addition, alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Although hypoglycemia rarely occurs during treatment with metformin alone, the risk may increase with acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

Food may have varying effects on the absorption of metformin from immediate-release versus extended-release formulations. When a single 850 mg dose of immediate-release metformin was administered with food, mean peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 40% and 25%, respectively, and time to peak plasma concentration (Tmax) increased by 35 minutes compared to administration under fasting conditions. By contrast, administration of extended-release metformin with food increased AUC by 50% without affecting Cmax or Tmax, and both high- and low-fat meals had the same effect. These data may not be applicable to formulations that contain metformin with other oral antidiabetic agents.

MANAGEMENT: Metformin should be taken with meals, and excessive alcohol intake should be avoided during treatment. Diabetes patients in general should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Alcohol should not be consumed on an empty stomach or following exercise, as it may increase the risk of hypoglycemia. Patients should contact their physician immediately if they experience potential signs and symptoms of lactic acidosis such as malaise, myalgia, respiratory distress, increasing somnolence, and nonspecific abdominal distress (especially after stabilization of metformin therapy, when gastrointestinal symptoms are uncommon). With more marked acidosis, there may also be associated hypothermia, hypotension, and resistant bradyarrhythmias. Metformin should be withdrawn promptly if lactic acidosis is suspected. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful in establishing a diagnosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

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GENERALLY AVOID: Coadministration with grapefruit juice may significantly increase the plasma concentrations of lovastatin and simvastatin and their active acid metabolites. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. When a single 60 mg dose of simvastatin was coadministered with 200 mL of double-strength grapefruit juice three times a day, simvastatin systemic exposure (AUC) increased by 16-fold and simvastatin acid AUC increased by 7-fold. Administration of a single 20 mg dose of simvastatin with 8 ounces of single-strength grapefruit juice increased the AUC of simvastatin and simvastatin acid by 1.9-fold and 1.3-fold, respectively. The interaction has also been reported with lovastatin, which has a similar metabolic profile to simvastatin. Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal tract.

Coadministration with green tea may increase the plasma concentrations of simvastatin. The mechanism of interaction has not been established, but may involve inhibition of organic anion transporting polypeptide (OATP) 1B1- and/or 2B1-mediated hepatic uptake of simvastatin by catechins in green tea. The interaction was suspected in a 61-year-old man who experienced muscle intolerance during treatment with simvastatin while drinking an average of 3 cups of green tea daily. He also experienced similar muscle intolerance (leg cramps without creatine phosphokinase elevation) during treatments with atorvastatin and rosuvastatin while drinking green tea. Pharmacokinetic studies performed during his usual green tea intake demonstrated an approximately two-fold higher exposure to simvastatin lactone (the administered form of simvastatin) than that observed after stopping green tea intake for a month. He was also able to tolerate simvastatin after discontinuing green tea consumption. The authors of the report subsequently conducted two independent studies to assess the effect of different green tea preparations on simvastatin pharmacokinetics. One study was conducted in 12 Italian subjects and the other in 12 Japanese subjects. In the Italian study, administration of a single 20 mg dose of simvastatin following pretreatment with 200 mL of a hot green tea standardized infusion 3 times daily for 14 days (estimated daily intake of 335 mg total catechins and 173 mg epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea) was found to have no significant effect on mean peak plasma concentration (Cmax) or systemic exposure (AUC) of simvastatin lactone and simvastatin acid relative to administration with water. However, green tea increased simvastatin lactone AUC (0-6h) by about two-fold in 3 of the study subjects. In the Japanese study, administration of a single 10 mg dose of simvastatin following pretreatment with 350 mL of a commercial green tea beverage twice daily for 14 days (estimated daily intake of 638 mg total catechins and 322 mg EGCG) did not affect mean simvastatin lactone Cmax or AUC to a statistically significant extent compared to administration with water, but increased mean simvastatin acid Cmax and AUC by 42% and 22%, respectively. Similar to the first study, green tea increased simvastatin lactone AUC (0-6h) by two- to three-fold in 4 of the study subjects. Although not studied, the interaction may also occur with lovastatin due to its similar metabolic profile to simvastatin.

MANAGEMENT: Patients receiving therapy with lovastatin, simvastatin, or red yeast rice (which contains lovastatin) should be advised to avoid the consumption of grapefruit and grapefruit juice. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by other enzymes and may be preferable alternatives in some individuals. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. Also, patients should either refrain from the use of oat bran and pectin, or separate the administration times by at least 2 to 4 hours if concurrent use cannot be avoided. Caution may be advisable when coadministered with green tea or green tea extracts. Dosing reduction of the statin and/or limiting consumption of green tea and green tea products may be required if an interaction is suspected.

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GENERALLY AVOID: Moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using angiotensin II receptor blockers (ARBs). ARBs can promote hyperkalemia through inhibition of angiotensin II-induced aldosterone secretion. Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

MANAGEMENT: Patients should receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their physician. If salt substitutes are used concurrently, regular monitoring of serum potassium levels is recommended. Patients should also be advised to seek medical attention if they experience symptoms of hyperkalemia such as weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs.

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GENERALLY AVOID: Orange juice may moderately reduce the bioavailability of atenolol by interfering with its absorption from the gastrointestinal tract. In a pharmacokinetic study, subjects ingested 200 mL orange juice 3 times daily for 3 days and twice daily on the fourth day, and took 50 mg atenolol with 200 mL orange juice on day 3. The average peak plasma concentration (Cmax) of atenolol fell by 49% and the area under the concentration-time curve (AUC) fell by 40% in comparison to subjects who drank only water. In addition, the presence of food may reduce the bioavailability of atenolol by 20%. The clinical significance is unknown.

MANAGEMENT: Patients treated orally with atenolol should be advised to take atenolol at the same time each day and to avoid consumption of large amounts of orange juice to prevent any undue fluctuations in serum drug levels. Monitoring for altered efficacy of atenolol may be advisable.

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GENERALLY AVOID: Moderate-to-high dietary intake of potassium can cause hyperkalemia in some patients who are using angiotensin converting enzyme (ACE) inhibitors. In some cases, affected patients were using a potassium-rich salt substitute. ACE inhibitors can promote hyperkalemia through inhibition of the renin-aldosterone-angiotensin (RAA) system.

MANAGEMENT: It is recommended that patients who are taking ACE inhibitors be advised to avoid moderately high or high potassium dietary intake. Particular attention should be paid to the potassium content of salt substitutes.

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MONITOR: Vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants. Vitamin K is a cofactor in the synthesis of blood clotting factors that are inhibited by oral anticoagulants, thus intake of vitamin K through supplements or diet can reverse the action of oral anticoagulants. Resistance to oral anticoagulants has been associated with consumption of foods or enteral feedings high in vitamin K content. Likewise, a reduction of vitamin K intake following stabilization of anticoagulant therapy may result in elevation of the INR and bleeding complications. Foods rich in vitamin K include beef liver, broccoli, Brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and other green leafy vegetables. Moderate to high levels of vitamin K are also found in other foods such as asparagus, avocados, dill pickles, green peas, green tea, canola oil, margarine, mayonnaise, olive oil, and soybean oil. Snack foods containing the fat substitute, olestra, are fortified with 80 mcg of vitamin K per each one ounce serving so as to offset any depletion of vitamin K that may occur due to olestra interference with its absorption. Whether these foods can alter the effect of oral anticoagulants has not been extensively studied. One small study found that moderate consumption (1.5 servings/day) does not significantly affect the INR after one week in patients receiving long-term anticoagulation.

Consumption of large amounts of mango fruit has been associated with enhanced effects of warfarin. The exact mechanism of interaction is unknown but may be related to the vitamin A content, which may inhibit metabolism of warfarin. In one report, thirteen patients with an average INR increase of 38% reportedly had consumed one to six mangos daily 2 to 30 days prior to their appointment. The average INR decreased by 17.7% after discontinuation of mango ingestion for 2 weeks. Rechallenge in two patients appeared to confirm the interaction.

Limited data also suggest a potential interaction between warfarin and cranberry juice resulting in changes in the INR and/or bleeding complications. The mechanism is unknown but may involve alterations in warfarin metabolism induced by flavonoids contained in cranberry juice. At least a dozen reports of suspected interaction have been filed with the Committee on Safety of Medicines in the U.K. since 1999, including one fatality. In the fatal case, the patient's INR increased dramatically (greater than 50) six weeks after he started drinking cranberry juice, and he died from gastrointestinal and pericardial hemorrhage. However, the patient was also taking cephalexin for a chest infection and had not eaten for two weeks prior to hospitalization, which may have been contributing factors. Other cases involved less dramatic increases or instabilities in INR following cranberry juice consumption, and a decrease was reported in one, although details are generally lacking. In a rare published report, a 71-year-old patient developed hemoptysis, hematochezia, and shortness of breath two weeks after he started drinking 24 ounces of cranberry juice a day. Laboratory test results on admission revealed a decrease in hemoglobin, an INR greater than 18, and prothrombin time exceeding 120 seconds. The patient recovered after warfarin doses were withheld for several days and he was given packed red blood cells, fresh-frozen plasma, and subcutaneous vitamin K. It is not known if variations in the constituents of different brands of cranberry juice may affect the potential for drug interactions.

There have been several case reports in the medical literature of patients consuming grapefruit, grapefruit juice, or grapefruit seed extract who experienced increases in INR. R(+) warfarin, the less active of the two enantiomers of warfarin, is partially metabolized by CYP450 3A4. Depending on brand, concentration, dose and preparation, grapefruit juice may be considered a moderate to strong inhibitor of CYP450 3A4, thus coadministration with warfarin may decrease the clearance of R(+) warfarin. However, the clinical significance of this effect has not been established. A pharmacokinetic study found no effect on the PT or INR values of nine warfarin patients given 8 oz of grapefruit juice three times a day for one week.

A patient who was stabilized on warfarin developed a large hematoma in her calf in association with an elevated INR of 14 following consumption of approximately 3 liters of pomegranate juice in the week prior to admission. In vitro data suggest that pomegranate juice can inhibit CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the biologically more active S(-) enantiomer of warfarin. In rats, pomegranate juice has also been shown to inhibit intestinal CYP450 3A4, the isoenzyme that contributes to the metabolism of R(+) warfarin.

Black currant juice and black currant seed oil may theoretically increase the risk of bleeding or bruising if used in combination with anticoagulants. The proposed mechanism is the antiplatelet effects of the gamma-linolenic acid constituent in black currants.

Soy protein in the form of soy milk was thought to be responsible for a case of possible warfarin antagonism in an elderly male stabilized on warfarin. The exact mechanism of interaction is unknown, as soy milk contains only trace amounts of vitamin K. Subtherapeutic INR values were observed approximately 4 weeks after the patient began consuming soy milk daily for the treatment of hypertriglyceridemia. No other changes in diet or medications were noted during this time. The patient's INR returned to normal following discontinuation of the soy milk with no other intervention.

An interaction with chewing tobacco was suspected in a case of warfarin therapy failure in a young male who was treated with up to 25 to 30 mg/day for 4.5 years. The inability to achieve adequate INR values led to eventual discontinuation of the chewing tobacco, which resulted in an INR increase from 1.1 to 2.3 in six days. The authors attributed the interaction to the relatively high vitamin K content in smokeless tobacco.

MANAGEMENT: Intake of vitamin K through supplements or diet should not vary significantly during oral anticoagulant therapy. The diet in general should remain consistent, as other foods containing little or no vitamin K such as mangos and soy milk have been reported to interact with warfarin. Some experts recommend that continuous enteral nutrition should be interrupted for one hour before and one hour after administration of the anticoagulant dose and that enteral formulas containing soy protein should be avoided. Patients should also consider avoiding or limiting the consumption of cranberry juice or other cranberry formulations (e.g., encapsulated dried cranberry powder), pomegranate juice, black currant juice, and black currant seed oil.

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ADJUST DOSING INTERVAL: The bioavailability of propranolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take propranolol at the same time each day, preferably with or immediately following meals.

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GENERALLY AVOID: Consumption of large quantities of grapefruit juice may be associated with significantly increased plasma concentrations of oral verapamil. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. One study reported no significant effect of a single administration of grapefruit juice on the pharmacokinetics of verapamil in ten hypertensive patients receiving chronic therapy. In another study conducted in nine healthy male volunteers, administration of 120 mg oral verapamil twice daily for 3 days following pretreatment with 200 mL grapefruit juice twice daily for 5 days resulted in a 57% increase in S-verapamil peak plasma concentration (Cmax), a 36% increase in S-verapamil systemic exposure (AUC), a 40% increase in R-verapamil Cmax, and a 28% increase in R-verapamil AUC compared to administration following orange juice. Elimination half-life and renal clearance of both S- and R-verapamil were not affected by grapefruit juice, and there were no significant effects on blood pressure, heart rate, or PR interval. A third study reported a 1.63-fold increase in Cmax and a 1.45-fold increase in AUC of (R,S)-verapamil in 24 young, healthy volunteers given verapamil sustained-release 120 mg twice daily for 7 days with 250 mL grapefruit juice four times daily on days 5 through 7. Two subjects developed PR interval prolongation of more than 350 ms during grapefruit juice coadministration. A high degree of interindividual variability has been observed in these studies. The interaction was also suspected in a case report of a 42-year-old woman who developed complete heart block, hypotension, hypoxic respiratory failure, severe anion gap metabolic acidosis, and hyperglycemia following accidental ingestion of three verapamil sustained-release 120 mg tablets over a span of six hours. The patient's past medical history was remarkable only for migraine headaches, for which she was receiving several medications including verapamil. Prior to admission, the patient had a 2-week history of poorly controlled migraine, and the six hours preceding hospitalization she suffered from worsening headache and palpitations progressing to altered sensorium. An extensive workup revealed elevated verapamil and norverapamil levels more than 4.5 times above the upper therapeutic limits. These levels also far exceeded those reported in the medical literature for patients taking verapamil 120 mg every 6 hours, or 480 mg in a 24-hour period. The patient recovered after receiving ventilator and vasopressor support. Upon questioning, it was discovered that the patient had been drinking large amounts of grapefruit juice (3 to 4 liters total) the week preceding her admission due to nausea. No other sources or contributing factors could be found for the verapamil toxicity.

MANAGEMENT: Patients treated with oral verapamil should avoid the consumption of large amounts of grapefruit or grapefruit juice to prevent any undue fluctuations in serum drug levels. Patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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MONITOR: Concomitant use of statin medication with substantial quantities of alcohol may increase the risk of hepatic injury. Transient increases in serum transaminases have been reported with statin use and while these increases generally resolve or improve with continued therapy or a brief interruption in therapy, there have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Active liver disease or unexplained transaminase elevations are contraindications to statin use.

MANAGEMENT: Patients should be counseled to avoid substantial quantities of alcohol in combination with statin medications and clinicians should be aware of the increased risk for hepatotoxicity in these patients.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Enhanced hypoprothrombinemic response to warfarin has been reported in patients with acute alcohol intoxication and/or liver disease. The proposed mechanisms are inhibition of warfarin metabolism and decreased synthesis of clotting factors. Binge drinking may exacerbate liver impairment and its metabolic ability in patients with liver dysfunction. The risk of bleeding may be increased. Conversely, reductions in INR/PT have also been reported in chronic alcoholics with liver disease. The proposed mechanism is that continual drinking of large amounts of alcohol induces the hepatic metabolism of anticoagulants. Effects are highly variable and significant INR/PT fluctuations are possible.

MANAGEMENT: Patients taking oral anticoagulants should be counseled to avoid large amounts of ethanol, but moderate consumption (one to two drinks per day) are not likely to affect the response to the anticoagulant in patients with normal liver function. Frequent INR/PT monitoring is recommended, especially if alcohol intake changes considerably. It may be advisable to avoid oral anticoagulant therapy in patients with uncontrollable drinking problems. Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

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GENERALLY AVOID: Verapamil may increase the blood concentrations and intoxicating effects of ethanol. The exact mechanism of interaction is unknown but may involve verapamil inhibition of ethanol metabolism. In 10 healthy, young volunteers, verapamil (80 mg orally every 8 hours for 6 days) increased the mean peak blood concentration (Cmax) and the 12-hour area under the concentration-time curve (AUC) of ethanol (0.8 g/kg single oral dose) by 17% and 30%, respectively, compared to placebo. Verapamil AUCs were positively correlated to increased ethanol blood AUC values. Subjectively (i.e. each subject's perception of intoxication as measured on a visual analog scale), verapamil also significantly increased the area under the ethanol effect versus time curve but did not change the peak effect or time to peak effect.

MANAGEMENT: Patients treated with verapamil should be counseled to avoid alcohol consumption.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

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ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

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MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

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ADJUST DOSING INTERVAL: The oral bioavailability and pharmacologic effects of methyldopa may be decreased during concurrent administration with iron-containing products. The proposed mechanism is chelation of methyldopa by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. In one study, five hypertensive patients receiving chronic methyldopa therapy (250 mg to 1500 mg daily) all had elevated blood pressure following the addition of ferrous sulfate 325 mg three times daily for 2 weeks. The systolic pressure had increased by more than 15 mmHg in three of the patients and the diastolic pressure increased by more than 10 mmHg in two. Blood pressure returned to baseline within 7 days of discontinuing the iron. In 12 normal subjects, administration of methyldopa 500 mg with ferrous sulfate 325 mg or ferrous gluconate 600 mg resulted in an 88% and 79% reduction, respectively, in the renal excretion of unmetabolized, free methyldopa compared to administration of methyldopa alone. In another study, administration of ferrous sulfate simultaneously with methyldopa reduced the bioavailability of methyldopa by 83%, while administration one hour or two hours before methyldopa reduced its bioavailability by 55% and 42%, respectively.

MANAGEMENT: Until more information is available, patients receiving methyldopa in combination with iron-containing products should be advised to separate the times of administration by as much as possible. Patients should be monitored closely for altered hypertensive effect and methyldopa dosage increased as necessary. Selection of an alternative antihypertensive therapy may be necessary.

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MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

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ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

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MONITOR: Multivitamin preparations containing vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants in some patients. Vitamin K1 in its active, reduced form serves as a cofactor in the generation of functional clotting factors, during which it becomes oxidized. It is reactivated in a process that is inhibited by oral anticoagulants, thus intake of additional vitamin K through supplements or diet can reverse the action of oral anticoagulants. Although the amount of vitamin K in over-the-counter multivitamin preparations is generally well below the dose thought to affect anticoagulation, there have been isolated case reports of patients stabilized on warfarin whose INR decreased following initiation of a multivitamin supplement and returned to therapeutic levels upon cessation of the multivitamin. Increases in warfarin dosage were required in some cases when the multivitamin was continued. One patient whose warfarin dosage was increased developed a subcapsular hematoma in her right kidney two weeks after she discontinued the multivitamin without informing her physician. Her INR was 13.2 and she was treated with vitamin K and fresh frozen plasma. It is possible that patients with low vitamin K status may be particularly susceptible to the interaction. Investigators have shown that vitamin K deficiency can cause an oversensitivity to even small increases in vitamin K intake. In one study where warfarin-stabilized patients were given a multivitamin tablet containing 25 mcg of vitamin K1 daily for 4 weeks, subtherapeutic INRs occurred in 9 of 9 patients with low vitamin K1 levels (<1.5 mcg/L) and only 1 of 7 patients with normal vitamin K1 levels (>4.5 mcg/L). INR decreased by a median of 0.51 and warfarin dosage had to be increased by 5.3% in patients with low vitamin K1 levels, whereas INR and warfarin dosage did not change significantly in patients with normal vitamin K1 levels. The prevalence of vitamin K deficiency may be small, but significant in the anticoagulated population. In a survey of 179 consecutive ambulatory patients on stable warfarin therapy attending an anticoagulation clinic, 22 (12.3%) were found to have vitamin K1 deficiency (<0.1 ng/mL).

MANAGEMENT: The potential for multivitamin supplements containing even low levels of vitamin K to affect anticoagulation should be recognized. In particular, elderly and/or malnourished patients may require more frequent monitoring of INR following the initiation or discontinuation of a multivitamin supplement, and the anticoagulant dosage adjusted as necessary.

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ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

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MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.

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The consumption of grapefruit juice may slightly increase plasma concentrations of amlodipine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Data have been conflicting and the clinical significance is unknown. Monitoring for calcium channel blocker adverse effects (e.g., headache, hypotension, syncope, tachycardia, edema) is recommended.

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One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

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The recommended maximum number of medicines in the 'cardiovascular agents' category to be taken concurrently is usually four. Your list includes thirteen medicines belonging to the 'cardiovascular agents' category:

• amlodipine
• atenolol
• bisoprolol
• candesartan
• carvedilol
• enalapril
• furosemide
• gemfibrozil
• hydrochlorothiazide
• methyldopa
• propranolol
• simvastatin
• verapamil

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'blood modifiers' category to be taken concurrently is usually two. Your list includes three medicines belonging to the 'blood modifiers' category:

• aspirin
• clopidogrel
• warfarin

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'antidiabetic drugs' category to be taken concurrently is usually three. Your list includes four medicines belonging to the 'antidiabetic drugs' category:

• glyburide
• glimepiride
• GlipiZIDE XL (glipizide)
• metformin

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'antihypertensives' category to be taken concurrently is usually two. Your list includes nine medicines belonging to the 'antihypertensives' category:

• amlodipine
• atenolol
• bisoprolol
• candesartan
• carvedilol
• enalapril
• methyldopa
• propranolol
• verapamil

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'calcium channel blockers' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'calcium channel blockers' category:

• amlodipine
• verapamil

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'beta blockers' category to be taken concurrently is usually one. Your list includes four medicines belonging to the 'beta blockers' category:

• atenolol
• bisoprolol
• carvedilol
• propranolol

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'non-insulin antidiabetic agents' category to be taken concurrently is usually two. Your list includes four medicines belonging to the 'non-insulin antidiabetic agents' category:

• glyburide
• glimepiride
• GlipiZIDE XL (glipizide)
• metformin

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'insulin secretagogues' category to be taken concurrently is usually one. Your list includes three medicines belonging to the 'insulin secretagogues' category:

• glyburide
• glimepiride
• GlipiZIDE XL (glipizide)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'coagulation modifiers' category to be taken concurrently is usually two. Your list includes three medicines belonging to the 'coagulation modifiers' category:

• aspirin
• clopidogrel
• warfarin

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.