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Interactions with Furosemide

Contents
Guanethidine, Nortriptyline, Amitriptyline, Diazepam, Lorazepam, Alprazolam, Bupropion (oral), Buspirone, Chlordiazepoxide, Clonazepam, Clorazepate, Diphenhydramine, Doxepin, Fentanyl topical, Flurazepam, Hydromorphone (oral), Morphine, Nitroglycerin (oral/buccal/sublingual/spray), Nitroglycerin topical (patches and ointment), Oxycodone, Phenobarbital, Propoxyphene, Secobarbital, Temazepam, Trazodone, Promethazine (oral), Trimipramine, Amoxapine, Clomipramine, Loxapine, Hydroxyzine, Zolpidem, Carisoprodol, Methocarbamol, Orphenadrine, Baclofen, Venlafaxine (oral), Diazepam rectal, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Maprotiline, Mirtazapine, Cabergoline, Citalopram (oral), Zaleplon, Escitalopram

If you are currently being treated with any of the following medications, you should not use Furosemide without reading these interactions.

Tizanidine

ADJUST DOSE: Tizanidine may potentiate the hypotensive effect of some medications secondary to its alpha-2 adrenergic activity. Pharmacologic studies have found tizanidine to possess between 1/10 to 1/50 of the potency of clonidine, a structurally similar agent, in lowering blood pressure. In a single-dose study where blood pressure was monitored closely after dosing, two-thirds of patients treated with an 8 mg dose had a 20% reduction in either the diastolic or systolic blood pressure. The reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing, and was associated at times with bradycardia, orthostatic hypotension, lightheadedness, dizziness, and rarely, syncope. The hypotensive effect of tizanidine is dose-related and has been measured following single doses of 2 mg or more. In clinical trials, the addition of tizanidine to antihypertensive therapy was associated with a 20% to 30% increase in the incidence of clinically significant decreases in systolic or diastolic blood pressure compared with placebo plus antihypertensive therapy and tizanidine alone. The incidence of orthostatic hypotension was also increased.

MANAGEMENT: Lower initial dosages and cautious dosage titration should be considered when tizanidine is initiated in patients receiving antihypertensive therapy or if antihypertensive therapy is initiated in patients receiving tizanidine. Although single doses of less than 8 mg of tizanidine have not been shown effective for spasticity in controlled clinical studies, it may be prudent to initiate treatment with 4 mg doses and gradually increase in 2 to 4 mg increments until optimum effect is achieved. The dose can be repeated at 6 to 8 hour intervals as needed, up to a maximum of three doses in 24 hours and a total daily dosage of 36 mg. However, experience with single doses exceeding 8 mg and daily doses exceeding 24 mg is limited. Close monitoring for development of hypotension is recommended. 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.

Cholestyramine, Colestipol

ADJUST DOSING INTERVAL: Limited data have shown that the bioavailability of orally administered furosemide is reduced by 95% during concurrent administration of cholestyramine and by 80% during concurrent administration of colestipol. (These figures are based on data from the area under the plasma concentration-time curve and total urinary elimination data.) These decreases in bioavailability were associated with 77% and 58% reductions in the diuretic response to furosemide. No data are available for bumetanide, torsemide, or ethacrynic acid, but a similar interaction is suspected.

MANAGEMENT: Diuretics should be administered at least 2 to 3 hours before cholestyramine or colestipol. If alternating dosage schedules is ineffective, it may be necessary to increase diuretic dosage during coadministration. Patients should be monitored for altered diuretic efficacy.

Sucralfate (oral)

ADJUST DOSING INTERVAL: Sucralfate may reduce the absorption and therapeutic effects of oral furosemide. The clinical significance is unknown.

MANAGEMENT: Oral furosemide and sucralfate doses should be separated by at least 2 hours.

Tadalafil

Based on their pharmacology, phosphodiesterase-5 (PDE5) inhibitors may conceivably potentiate the hypotensive effect of antihypertensive medications. These agents inhibit PDE5-mediated degradation of cyclic guanosine monophosphate (cGMP), which in vascular smooth muscles can cause peripheral vasodilation. However, clinical pharmacology studies of tadalafil (administered as a 10 mg dose except in studies with angiotensin II receptor (AR) blockers and amlodipine, which used a dose of 20 mg) have demonstrated no clinically significant interaction with various antihypertensive drugs from major classes including calcium channel blockers, ACE inhibitors, beta blockers, thiazide diuretics, and AR blockers. Tadalafil 10 mg and 20 mg also had no clinically significant effect on blood pressure changes due to tamsulosin, an alpha-1a blocker. In addition, analysis of data from Phase 3 clinical trials showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications. In patients receiving concomitant antihypertensive medications, tadalafil 20 mg may induce a blood pressure decrease that is, in general, minor and not likely to be clinically relevant. Nevertheless, patients should be advised of the potential for interaction and to contact their physician if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting.

Clofibrate

Clofibrate may increase the diuretic effect of furosemide by displacing it from its protein-binding sites. A reduction in furosemide dosage may be required, especially in patients with the nephrotic syndrome who have reduced albumin levels. If clofibrate and furosemide are used together, the patient should be monitored more closely for electrolyte imbalances.

Cisapride (oral)

CONTRAINDICATED: Some diuretics may produce hypokalemia and hypomagnesemia which could potentiate the risk of cisapride-induced arrhythmias in patients receiving both drugs concomitantly. Prolonged QT interval, torsades de pointes, and death have been reported.

MANAGEMENT: Cisapride is contraindicated in patients with uncorrected hypokalemia and hypomagnesemia, such as those taking potassium-wasting diuretics.

Theophylline, Aminophylline

Furosemide has reportedly increased, decreased, or not affected serum theophylline levels. The mechanism and clinical significance is unknown. Dosage adjustments may be required if an interaction is suspected.

Charcoal

GENERALLY AVOID: Charcoal may reduce the absorption of many drugs and can absorb enterohepatically circulated drugs. Clinical utility may be the reduction either of the effects or of the toxicity of many drugs. Activated charcoal may absorb any therapeutic agents administered while it is in the gastrointestinal tract.

MANAGEMENT: The regular ingestion of charcoal should be avoided by patients requiring maintenance medications. If concomitant use is necessary, the dosage or route of administration may need to be altered.

Licorice

GENERALLY AVOID: Chronic use of licorice may potentiate the hypokalemic effects of some diuretics and other drugs that deplete potassium (e.g., amphotericin B, cation exchange resins). Glycyrrhizic acid, a component of licorice, possesses mineralocorticoid activity and can induce hypokalemia. Severe hypokalemia can lead to muscle paralysis, rhabdomyolysis, metabolic alkalosis, cardiac arrhythmias, and respiratory arrest.

MANAGEMENT: Patients should consult a healthcare provider before taking any herbal or alternative medicine. In general, chronic use of licorice and licorice-containing products should be avoided in patients treated with potassium-depleting drugs. During concomitant use, patients should be advised to contact their physician if they experience signs and symptoms of hypokalemia such as fatigue, myalgia, muscle weakness, abdominal pain, hypoventilation, and irregular heartbeat.

Amikacin, Neomycin

GENERALLY AVOID: Coadministration of parenteral aminoglycoside antibiotics or oral neomycin in combination with loop diuretics may potentiate the risk of oto- and nephrotoxicity due to additive or synergistic pharmacologic effects of these drugs. The risk may be greater with high dosages of either drug, preexisting renal insufficiency, advanced age, dehydration, or the presence of other oto- or nephrotoxic drugs. The onset of ototoxicity may be greatly delayed, and cochlear damage may initially be asymptomatic. Reversible and irreversible hearing losses have been reported.

MANAGEMENT: The use of aminoglycoside antibiotics in combination with loop diuretics should generally be avoided. Serial, vestibular, audiometric, and renal function tests should be performed before and during therapy if coadministration is necessary.

Disopyramide

GENERALLY AVOID: Disopyramide can cause dose-related prolongation of the QT interval. Theoretically, coadministration with agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, because of additive arrhythmogenic potential.

MANAGEMENT: Coadministration of disopyramide with medications that can cause potassium and/or magnesium disturbances should generally be avoided. Serum electrolytes should be evaluated and any abnormalities corrected prior to initiating therapy with disopyramide. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

Ginseng

GENERALLY AVOID: Ginseng has been reported to induce diuretic resistance in a patient treated with furosemide and cyclosporine. The patient was hospitalized for edema and hypertension approximately 10 days after initiating self-therapy with herbal supplements that included a fairly large quantity of ginseng. While in the hospital, all herbal products were withheld and the patient responded to intravenous furosemide. Following discharge, the patient resumed his herbal regimen and again experienced an episode of edema and hypertension shortly thereafter that was refractory to increases in the furosemide dosage. The patient was readmitted to the hospital, upon which herbal products were discontinued and the patient responded to intravenous furosemide over the next 48 hours. The temporal association of these events strongly suggests a potential drug interaction, however, the exact mechanism is unknown.

MANAGEMENT: Until further data are available, patients treated with furosemide or other loop diuretics should preferably avoid the use of ginseng supplements. The possibility of diuretic resistance should be considered and appropriately monitored if concomitant use is necessary.

Irinotecan

GENERALLY AVOID: Irinotecan-induced vomiting and/or diarrhea may increase the risk of dehydration.

MANAGEMENT: The use of diuretics during irinotecan administration or during periods of vomiting and diarrhea which may follow is not recommended.

Cisplatin

GENERALLY AVOID: The possible ototoxicity associated with loop diuretics and cisplatin may be additive. Bumetanide and furosemide may be less ototoxic than ethacrynic acid.

MANAGEMENT: This combination should be avoided unless the potential benefit outweighs the risk. Audiometric testing is recommended if these drugs are given concurrently.

Hydralazine

Hydralazine causes a significant increase in the plasma clearance of furosemide. A decrease in the elimination half-life of furosemide results. The mechanism is believed to be a hydralazine-induced increase in renal blood flow, which increases the plasma clearance (and diuretic effect) of furosemide. No special precautions appear to be necessary.

Digoxin (oral)

MONITOR: Although diuretics and digitalis glycosides are frequently and appropriately used together, diuretic-induced hypokalemia and hypomagnesemia may predispose patients on digitalis to arrhythmias.

MANAGEMENT: Digoxin, potassium and magnesium levels should be followed closely. Hypokalemia and hypomagnesemia should be treated appropriately. Digitalis dose adjustments may be required. Patients should be advised to notify their physicians if they experience signs of possible digoxin toxicity or electrolyte disturbances, such as weakness, lethargy, muscle pains or cramps, nausea, anorexia, visual disturbances, or irregular heartbeats.

Fosinopril, Quinapril, Ramipril, Benazepril, Lisinopril, Moexipril, Trandolapril, Perindopril

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.

Acebutolol, Metoprolol, Pindolol, Timolol, Metipranolol ophthalmic, Carteolol, Bisoprolol, Levobunolol ophthalmic, Carvedilol, Timolol ophthalmic, Betaxolol ophthalmic, Carteolol ophthalmic, Betaxolol, Esmolol, Penbutolol, Sotalol, Sotalol AF, Levobetaxolol ophthalmic

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.

Apomorphine

MONITOR: Antihypertensive agents and vasodilators may increase the hypotensive effect of apomorphine due to additive effects. Apomorphine alone has been associated with orthostatic hypotension, hypotension, syncope. and dose dependent decreases in systolic blood pressure. In clinical trials, an increased incidence of myocardial infarction, serious pneumonia, serious falls, and bone and joint injuries were reported in patients receiving concomitant therapy. The cause is unknown, but may be due to increased hypotension.

MANAGEMENT: Caution and close monitoring for altered efficacy and safety are recommended if patients receive apomorphine with an antihypertensive agent or vasodilator. Patients should be made aware of the possible side effects (e.g., dizziness, lightheadedness, orthostasis) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. They should also be advised to notify their physician if they experience dizziness or fainting.

Albuterol inhalation, Metaproterenol, Isoetharine inhalation, Terbutaline inhalation, Bitolterol inhalation, Pirbuterol inhalation, Salmeterol (inhalation), Albuterol, Terbutaline (oral), Levalbuterol, Formoterol, Arformoterol inhalation

MONITOR: Beta-2 adrenergic agonist bronchodilators may cause hypokalemia and/or prolongation of the QT interval. The coadministration of potassium-wasting diuretics may exacerbate hypokalemia, potentially increasing the risk of ventricular arrhythmias including ventricular tachycardia and torsade de pointes. Patients who are taking systemic or nebulized beta agonists, high doses of beta agonists, or concomitant theophylline or corticosteroids may be at a greater risk of developing hypokalemia.

MANAGEMENT: Caution is advised when beta-2 agonists must be used concomitantly with diuretics. Close clinical and laboratory monitoring of potassium status is recommended. Patients should be advised to notify their physician if they experience weakness, lethargy, irregular heartbeats, muscle pain or cramps, dizziness, lightheadedness, syncope, irregular heartbeats, or tachycardia.

Arsenic trioxide

MONITOR CLOSELY: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. Theoretically, coadministration with agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential.

MANAGEMENT: Caution is advised if arsenic trioxide must be used concomitantly with medications that can cause potassium and/or magnesium disturbances. Serum electrolytes should be evaluated and any abnormalities corrected prior to initiating therapy with arsenic trioxide. During therapy, potassium concentrations should be kept above 4 mEq/dL and magnesium concentrations above 1.8 mg/dL. Patients should also have frequent ECGs and be monitored for serious arrhythmias when QT intervals are prolonged. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Dofetilide

MONITOR CLOSELY: Dofetilide can cause dose- and concentration-related QT interval prolongation. Theoretically, coadministration with agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential.

MANAGEMENT: Caution is advised if dofetilide must be used concomitantly with medications that can cause potassium and/or magnesium disturbances. Serum electrolytes should be evaluated and any abnormalities corrected prior to initiating therapy with dofetilide. During therapy, potassium concentrations should be kept above 4 mEq/dL and magnesium concentrations above 1.8 mg/dL. Patients should also have frequent ECGs and be monitored for serious arrhythmias when QT intervals are prolonged. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Pimozide (oral)

MONITOR CLOSELY: Pimozide can cause dose-related prolongation of the QT interval. While clinical data are lacking, the coadministration of pimozide and agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential.

MANAGEMENT: Caution is advised when pimozide must be used concomitantly with medications that can cause potassium and/or magnesium disturbances. Serum electrolytes should be monitored and any abnormalities corrected prior to initiating therapy with pimozide.

Dolasetron

MONITOR CLOSELY: The risk of arrhythmia may be increased in patients taking dolasetron and diuretics. Dolasetron induced ECG changes (PR and QTc prolongation; QRS widening) have been observed in healthy volunteers and in controlled clinical trials. Diuretics may further predispose the patient to arrhythmia by inducing electrolyte abnormalities.

MANAGEMENT: Close clinical and laboratory monitoring for cardiac rhythm and electrolyte disturbances is recommended if this combination is used.

Ziprasidone

MONITOR CLOSELY: Ziprasidone can cause dose-related prolongation of the QT interval. While clinical data are lacking, the coadministration of ziprasidone and agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential.

MANAGEMENT: Caution is advised when ziprasidone must be used concomitantly with medications that can cause potassium and/or magnesium disturbances. Serum electrolytes should be monitored and any abnormalities corrected prior to initiating therapy with ziprasidone. Patients should be advised to notify their physician if they experience possible signs of an electrolyte imbalance, such as weakness, lethargy, drowsiness, confusion, muscle pains or cramps, dizziness, nausea, vomiting, tachycardia, or an irregular heartbeat.

Aliskiren

MONITOR: Coadministration with aliskiren may decrease the blood concentrations of furosemide. The mechanism of interaction has not been described. According to the product labeling for aliskiren, peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of furosemide were reduced by approximately 50% and 30%, respectively, during concomitant administration. Furosemide had no significant effect on the systemic exposure of aliskiren.

MANAGEMENT: The potential for diminished pharmacologic effects of furosemide should be considered during coadministration with aliskiren.

Flurbiprofen, Ketorolac, Mefenamic acid, Nabumetone, Piroxicam, Diclofenac, Etodolac, Oxaprozin, Diflunisal, Meclofenamate, Celecoxib (oral), Rofecoxib (oral), Meloxicam, Valdecoxib

MONITOR: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics may adversely affect renal function due to NSAID inhibition of the renal synthesis of prostaglandins that help maintain renal perfusion in dehydrated states. The risk may be increased in patients on dietary sodium restriction. At the same time, hypotensive effect of the diuretics may be reduced because inhibition of prostaglandins can lead to unopposed pressor activity and, consequently, elevation in blood pressure. Natriuretic and diuretic effects may also be reduced, as NSAIDs have been reported to cause sodium and water retention, which may account for the increased risk of congestive heart failure associated with the combination. One study showed an increase in the incidence density of congestive heart failure (in patients over 55 years of age) from 9.3 per 1,000 person-years in patients on diuretics to 23.3 per 1,000 person-years in patients on both diuretic and NSAID therapy. NSAIDs may also increase the risk of hyperkalemia associated with potassium-sparing diuretics.

MANAGEMENT: In patients receiving both diuretic and NSAID therapy, management consists of avoiding dehydration and carefully monitoring the patient's renal function and blood pressure. If renal insufficiency or hyperkalemia develops, both drugs should be discontinued until the condition is corrected.

Epoprostenol

MONITOR: Epoprostenol and diuretics have been given concurrently in clinical trials. While some data have shown epoprostenol to have little or no significant clinical effect on furosemide kinetics and pharmacologic effect, coadministration may produce additional reductions in blood pressure.

MANAGEMENT: If these drugs are used together, it is generally recommended that blood pressure be measured more frequently until a stable blood pressure pattern is observed.

Vancomycin

MONITOR: Increased adverse effects are possible when glycopeptide antibiotics are administered concomitantly with other potentially nephrotoxic and neurotoxic drugs.

MANAGEMENT: If these drugs must be used together, renal function, auditory and vestibular function, and serum drug concentrations should be monitored.

Cefixime, Cefprozil, Cefadroxil, Cefaclor, Cefpodoxime, Cephalexin, Loracarbef, Ceftibuten, Cefoxitin, Cefepime

MONITOR: Limited data suggest that some loop diuretics enhance the nephrotoxicity of some cephalosporins by an unknown mechanism. Data are available for cephaloridine and cephalothin only. Other cephalosporins are much less nephrotoxic.

MANAGEMENT: During concomitant therapy, it is advisable to obtain a serum creatinine level within 48 hours and periodically during therapy.

Clozapine, Olanzapine, Quetiapine, Aripiprazole

MONITOR: Neuroleptic agents may potentiate the hypotensive effect of some medications secondary to their peripheral alpha-1 adrenergic blocking activity. Orthostatic hypotension and syncope associated with vasodilation may occur, particularly during the initial dose titration period of neuroleptic therapy.

MANAGEMENT: Close clinical monitoring for development of hypotension is recommended if neuroleptic agents are prescribed with antihypertensive medications or vasodilators. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. A lower starting dosage and slower titration of the neuroleptic agent may be appropriate in patients receiving antihypertensive therapy, especially if they are elderly.

Metformin

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.

Chloral hydrate, Chloral hydrate rectal

MONITOR: Rare cases of flushing, hot flashes, tachycardia, and labile blood pressure have been reported after administration of intravenous furosemide within 24 hours of chloral hydrate. The proposed mechanism is displacement of chloral hydrate's metabolite, trichloroacetic acid, from protein binding sites which either produces serum pH changes or displaces levothyroxine from its protein binding sites, resulting in increased levels of free levothyroxine. Chloral hydrate derivatives may also interact. Oral furosemide is not expected to interact.

MANAGEMENT: Caution and monitoring for adverse effects are advisable if intravenous furosemide is administered to a patient who has taken chloral hydrate or a derivative.

Fluphenazine, Prochlorperazine, Thioridazine (oral), Perphenazine, Mesoridazine, Trifluoperazine, Risperidone (oral), Paliperidone

MONITOR: Some neuroleptic agents may cause prolongation of the QT interval. While clinical data are lacking, the coadministration of other agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes. In addition, neuroleptic agents may potentiate the hypotensive effect of diuretics secondary to their peripheral alpha-1 adrenergic blocking activity. Orthostatic hypotension and syncope associated with vasodilation may occur, particularly during the initial dose titration period of neuroleptic therapy.

MANAGEMENT: Caution is advised when neuroleptics must be used concomitantly with medications that can cause potassium and/or magnesium disturbances. Serum electrolytes should be monitored and any abnormalities corrected prior to initiating therapy with a neuroleptic. Close clinical monitoring for development of hypotension is recommended if neuroleptic agents are prescribed with a diuretic medication. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. A lower starting dosage and slower titration of the neuroleptic agent may be appropriate in patients receiving antihypertensive therapy, especially if they are elderly.

Magnesium sulfate, Magnesium sulfate injection, Magnesium hydroxide, Magnesium citrate, Senna, Bisacodyl, Lactulose, Polyethylene glycol 3350

MONITOR: The chronic use or abuse of laxatives may potentiate the pharmacologic effects of diuretics. Laxatives can cause significant losses of fluid and electrolytes, including sodium, potassium, magnesium and zinc, and these effects may be additive to those of diuretics.

MANAGEMENT: In general, laxatives should only be used on a short-term, intermittent basis in recommended dosages. During concomitant use with diuretics, 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. If maintenance of bowel regularity is required, patients should be advised to exercise and increase fiber in the diet and/or consider the use of bulk-forming laxatives.

Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone

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.

Guanethidine, Nortriptyline, Amitriptyline, Diazepam, Lorazepam, Alprazolam, Bupropion (oral), Buspirone, Chlordiazepoxide, Clonazepam, Clorazepate, Diphenhydramine, Doxepin, Fentanyl topical, Flurazepam, Hydromorphone (oral), Morphine, Nitroglycerin (oral/buccal/sublingual/spray), Nitroglycerin topical (patches and ointment), Oxycodone, Phenobarbital, Propoxyphene, Secobarbital, Temazepam, Trazodone, Promethazine (oral), Trimipramine, Amoxapine, Clomipramine, Loxapine, Hydroxyzine, Zolpidem, Carisoprodol, Methocarbamol, Orphenadrine, Baclofen, Venlafaxine (oral), Diazepam rectal, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Maprotiline, Mirtazapine, Cabergoline, Citalopram (oral), Zaleplon, Escitalopram

MONITOR: The concomitant administration of agents with hypotensive effects and psychotherapeutic agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics), narcotic analgesics, alcohol, or muscle relaxants may additively increase hypotensive and/or central nervous system depressant effects.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for hypotension and excessive or prolonged CNS depression. Ambulatory patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness, confusion, orthostasis, fainting) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. Patients should also be advised to notify their doctor if they experience excessive side effects that interfere with their normal activities, or dizziness and fainting.

Aldesleukin

MONITOR: The concomitant administration of antihypertensive agents may potentiate the hypotensive effects of aldesleukin. Life-threatening (grade 4) hypotension has been reported with aldesleukin alone.

MANAGEMENT: Blood pressure should be monitored during concomitant administration. Aldesleukin doses should be held if systolic blood pressure falls to less than 90 mmHg.

Amphotericin B, Amphotericin B liposomal

MONITOR: The concomitant use of amphotericin and potassium-wasting diuretics may result in increased risk of hypokalemia due to additive effects.

MANAGEMENT: Patients receiving diuretics with amphotericin should be monitored closely for development of hypokalemia. Potassium supplementation may be necessary. Patients should be advised to notify their physician if they experience signs of electrolyte disturbances such as weakness, lethargy, and muscle pains or cramps.

Prednisolone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisone, Cortisone, Triamcinolone (oral and injectable), Triamcinolone inhalation, Betamethasone, Fludrocortisone, Triamcinolone acetonide injection

MONITOR: The concomitant use of corticosteroids and agents that deplete potassium (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins) may result in increased risk of hypokalemia. Corticosteroids can produce hypokalemia and other electrolyte disturbances via mineralocorticoid effects, the degree of which varies with the agent (from most to least potent: fludrocortisone - cortisone/hydrocortisone - prednisolone/prednisone - other glucocorticoids) and route of administration (i.e. systemic vs. local). However, large systemic doses of any corticosteroid can demonstrate these effects, particularly if given for longer than brief periods. When used pharmacologically, adrenocorticotropic agents such as corticotropin have similar mineralocorticoid activities as cortisone and hydrocortisone.

MANAGEMENT: Patients receiving potassium-depleting agents with corticosteroids should be monitored closely for development of hypokalemia, particularly if fludrocortisone or large doses of another corticosteroid or adrenocorticotropic agent is given. Potassium supplementation may be necessary. Patients should be advised to notify their physician if they experience signs of electrolyte disturbances such as weakness, lethargy, and muscle pains or cramps.

Cyclosporine, Nimodipine

MONITOR: The concurrent or sequential use of two or more potentially nephrotoxic or neurotoxic drugs may increase the risk of toxicity. Patients who are elderly, debilitated, dehydrated, or who have pre-existing renal dysfunction may have a higher risk of developing adverse reactions.

MANAGEMENT: Close clinical and laboratory monitoring of renal and neurologic function and drug serum concentrations (if clinically appropriate) is recommended.

Treprostinil

MONITOR: The concurrent use of treprostinil and agents with hypotensive or vasodilator effects may have additive blood pressure lowering effects. Treprostinil has been used concurrently with diuretics and calcium channel blockers in clinical trials.

MANAGEMENT: If these drugs are used together, it is generally recommended that blood pressure be measured more frequently until a stable blood pressure pattern is observed. Patients should be advised to notify their physician if they experience dizziness or syncope.

Acetohexamide, Glipizide, Glyburide, Tolazamide, Tolbutamide, Acarbose, Glimepiride, Miglitol, Repaglinide (oral), Insulin regular, Insulin isophane, Insulin zinc, Insulin zinc extended, Insulin lispro, Insulin glargine, Insulin aspart, Nateglinide (oral), Insulin glulisine, Insulin detemir, Insulin inhalation

MONITOR: The efficacy of oral hypoglycemic agents and insulin may be diminished by certain drugs, including thiazides and other diuretics, corticosteroids, estrogens, progestins, thyroid hormones, human growth hormone, phenothiazines, atypical antipsychotics, sympathomimetic amines, protease inhibitors, phenytoin, clozapine, megestrol, danazol, isoniazid, asparaginase, pegaspargase, diazoxide, 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: Close clinical monitoring of glycemic control is recommended if these drugs are coadministered with antidiabetic agents. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen. Dose adjustments of the hypoglycemic agent may be required.

Levodopa

MONITOR: The hypotensive effects of levodopa and antihypertensive agents may be additive. Postural hypotension may occur.

MANAGEMENT: Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Dose adjustments of the antihypertensive agent may be required. Patients should be advised to notify their physician if they experience dizziness or syncope.

Nefazodone

MONITOR: The manufacturer reports that nefazodone may potentiate the hypotensive effects of many drugs. Orthostatic hypotension may occur. The mechanism may be related to additive hypotensive effects. In clinical studies, nefazodone was associated with potentially significant blood pressure decreases (SBP 90 mmHg or less and 20 mmHg or more decrease from baseline) in 5.1% of patients, postural hypotension in 2.8%, and syncope in 0.2% (vs 0.3% for placebo).

MANAGEMENT: The manufacturer recommends caution during concomitant use. Blood pressure monitoring may be advisable. Patients should be advised of the possibility of orthostatic hypotension and to notify their caregiver if they experience symptoms such as lightheadedness, dizziness or syncope.

Iloprost

MONITOR: Theoretically, iloprost may potentiate the hypotensive effect of vasodilators and antihypertensive agents. Iloprost is a synthetic analogue of prostacyclin PGI2 and can dilate both systemic and pulmonary arterial vascular beds.

MANAGEMENT: 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. Vital signs and blood pressure should be monitored regularly.

Aminolevulinic acid

MONITOR: Theoretically, photosensitivity reactions of actinic keratoses may be additively or synergistically increased in patients taking photosensitizing drugs during aminolevulinic acid therapy.

MANAGEMENT: The patient's response to photodynamic therapy should be monitored. Patients should be advised to avoid exposure to sunlight or bright indoor light during the period between application of aminolevulinic acid and photoactivation.

Fluoxetine, Sertraline, Paroxetine, Fluvoxamine

MONITOR: Two cases of fatal hyponatremia have been reported in women receiving both furosemide and fluoxetine. However, causality was not clearly established due to the presence of other drugs and the serious conditions of both patients. Each of these drugs is known to cause hyponatremia--furosemide by renal sodium losses and fluoxetine, like other selective serotonin uptake inhibitors (SSRIs), by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Data for this interaction are not available for other loop diuretics or SSRIs.

MANAGEMENT: Until more information is available, serum sodium be closely monitored in patients who are taking SSRIs while undergoing vigorous diuresis with loop diuretics.

Phenelzine, Tranylcypromine, Selegiline (oral), Procarbazine, Isocarboxazid, Selegiline (transdermal), Linezolid, Rasagiline

Monoamine oxidase inhibitors (MAOIs) may theoretically potentiate the hypotensive effect of some medications. This effect may stem from a gradual MAOI-induced accumulation of false neurotransmitters in peripheral adrenergic neurons that have minimal activity at alpha- and beta-adrenergic receptors, resulting in a functional block of sympathetic neurotransmission. Indeed, MAOIs alone quite commonly produce orthostatic hypotension. In addition, bradycardia has been reported with the concomitant use of beta blockers and MAOIs. The clinical significance of these effects is unknown. If these drugs are coadministered, patients should be monitored for evidence of an interaction (e.g., hypotension, orthostasis, bradycardia, tachycardia, dizziness, or syncope).

Aspirin (oral), Salsalate, Magnesium salicylate, Aspirin (rectal)

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.

Phenytoin (oral), Mephenytoin, Ethotoin

Some hydantoins may reduce the gastrointestinal absorption of some loop diuretics. Serum diuretic concentrations and diuretic effects after oral dosing may be decreased. Data are available for furosemide and phenytoin only. Increases in diuretic dosage may be necessary.

Minocycline, Demeclocycline

The coadministration of diuretics and tetracyclines may result in decreased renal function manifested by increases in serum creatinine and blood urea nitrogen (BUN). Usually, no clinical intervention is necessary, unless decreases in renal function occur. If renal function deteriorates, discontinuation of one or both agents may be necessary.

Teriparatide

The concomitant administration of intravenous furosemide 20 mg to 100 mg and teriparatide did not significantly affect calcium response in normal subjects or patients with mild to severe renal insufficiency. Serum calcium increased by 2% and urinary excretion of calcium by 37% (clinically insignificant). No action is necessary.

Apraclonidine ophthalmic

The manufacturer reports that apraclonidine ophthalmic may cause additive or synergistic effects on heart rate and blood pressure if used concomitantly with other medications that affect these parameters, including ophthalmic and systemic beta blockers, cardiac glycosides, and antihypertensive agents. Caution and particular attention to the possibility of more pronounced cardiac effects is recommended when using this combination. Patients should be advised to notify their physician if they experience a slow pulse, irregular heartbeats, dizziness, or syncope.

Enoxacin, Lomefloxacin, Norfloxacin, Ofloxacin

The plasma concentration of lomefloxacin following administration of furosemide has been reported to be higher than after lomefloxacin alone. The area under the curve of lomefloxacin was increased and the total and renal clearances of lomefloxacin were decreased. A similar interaction may occur if other quinolones are administered with other loop diuretics. The loop diuretic may decrease the renal clearance of the quinolone by competing for tubular secretion. The clinical significance is unknown.

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