Furosemide (furosemide)

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

Furosemide/Ethacrynic Acid

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

MECHANISM OF ACTION: The exact mechanism of the interaction is not well understood.

CLINICAL EFFECTS: Concurrent use of furosemide and ethacrynic acid may increase the risk of ototoxicity.(1)

PREDISPOSING FACTORS: Rapid intravenous injection, severe renal impairment, high doses exceeding the usual recommended dose, concomitant therapy with other drugs known to ototoxic.

PATIENT MANAGEMENT: The US manufacturer of furosemide states that furosemide should not be used concurrently with ethacrynic acid.(1)

DISCUSSION: Furosemide and ethacrynic acid have the potential to cause ototoxicity.(1,2) Deafness, tinnitus, and vertigo with a sense of fullness have occurred, most frequently in patients with severe renal impairment. The deafness usually has been reported as being transient in nature and of short duration (one to 24 hours) but in some patients the hearing loss has been permanent.(2)

Loop Diuretics/Desmopressin

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

MECHANISM OF ACTION: Loop diuretics increase the risk of hyponatremia.(1-4)

CLINICAL EFFECTS: Concurrent use of loop diuretics may increase the risk of hyponatremia with desmopressin.(1-4)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants).

PATIENT MANAGEMENT: The concurrent use of loop diuretics with desmopressin is contraindicated.(1-4) If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Potassium Wasting Diuretics/Cisapride

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

MECHANISM OF ACTION: Concurrent administration may result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QT interval, which may result in potentially life-threatening arrhythmias.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of cisapride states that cisapride should not be used in patients with uncorrected hypokalemia or who might experience a rapid reduction of plasma potassium, such as those patients taking potassium-wasting diuretics in the acute setting.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The manufacturer of cisapride states that QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest, and sudden death have been reported in patients who were not taking agents known to increase cisapride levels. Some of these patients had uncorrected electrolyte disorders such as hypokalemia. Therefore, the manufacturer of cisapride states that cisapride should not be used in patients with uncorrected hypokalemia or who might experience a rapid reduction of plasma potassium, such as those patients taking potassium-wasting diuretics in the acute setting.(1) There is no published documentation to support this interaction.

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

Diuretics/Sodium Phosphate Bowel Cleanser

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

MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1)

CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on diuretics may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of oral sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3)

PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2)

PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as diuretics. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5)

DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8)

Loop Diuretics/Lithium

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

MECHANISM OF ACTION: Lithium is eliminated unchanged by the kidney; diuretic induced sodium elimination may lead to decreased renal clearance of lithium.

CLINICAL EFFECTS: Lithium has a narrow therapeutic range; even modest, unintended increases in lithium concentration may result in lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: Monitor closely to decrease the risk for lithium toxicity. Evaluate renal function and most recent lithium levels. If renal function is not stable, it would be prudent to withhold combination therapy until renal function is stable. If a loop diuretic is started, or if the dose is increased in a patient stabilized on lithium therapy, consider empirically lowering the lithium dose, and recheck lithium levels 5 to 7 days after diuretic initiation. Adjust lithium or diuretic dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on a loop diuretic, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: The documentation for this interaction is conflicting. A large epidemiologic study in elderly bipolar patients and case reports describe interactions between lithium and furosemide or bumetanide which resulted in increased levels of lithium and lithium toxicity. Several studies in healthy subjects have found that furosemide had no effect on lithium clearance or lithium serum concentrations. Other studies performed to assess the accuracy of lithium clearance in assessing proximal tubular reabsorption found that furosemide and bumetanide increased lithium clearance.

Selected Oat1-Oat3 Substrates/Nitisinone

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

MECHANISM OF ACTION: Nitisinone is an inhibitor of organic anion transporter 1 and 3 (OAT1/OAT3) which may inhibit the renal excretion of substrates of OAT1/OAT3.(1)

CLINICAL EFFECTS: Administration of nitisinone with OAT1/OAT3 substrates may result in elevated levels of and toxicity of the substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of nitisinone states concurrent use with OAT1/OAT3 substrates should be avoided.(1)

DISCUSSION: Nitisinone increased the area-under-curve (AUC) and maximum concentration (Cmax) of furosemide, an OAT1/OAT3 substrate, by 72% and 12%, respectively.(1) OAT1/OAT3 substrates linked to this monograph include: adefovir, bumetanide, furosemide, tenofovir and vadadustat.(1-2)

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

Diuretics/Zoledronic Acid

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

MECHANISM OF ACTION: Concurrent use of zoledronic acid and a diuretic may have adverse effects on the renal system.(1,2)

CLINICAL EFFECTS: Concurrent use of zoledronic acid and a diuretic may result in renal dysfunction. Deterioration in renal function, acute renal failure requiring dialysis, and death have been reported.(1)

PREDISPOSING FACTORS: The interaction may be more likely in elderly patients, patients who are taking other drugs that impact renal function, patients with pre-existing renal compromise, and patients who are dehydrated.(1)

PATIENT MANAGEMENT: Patients should be adequately hydrated with 500 ml (2 glasses of water) before and after zoledronic acid administration.(1) Creatinine clearance should be monitored before and after therapy and zoledronic acid should not be administered in patients with a creatinine clearance less than 35 ml/min.(1,3)

DISCUSSION: Zoledronic acid has been associated with renal dysfunction, including deterioration in renal function, acute renal failure requiring dialysis, and death. Risk factors include advanced age, concomitant nephrotoxic agents, and dehydration.(1) The FDA has received 16 reports of fatal acute renal failure and 9 reports of renal injury requiring dialysis following the administration of Reclast (zoledronic acid).(3)

Furosemide (Intravenous)/Chloral Hydrate

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

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve displacement of trichloracetic acid (a metabolite of chloral hydrate) from protein binding sites, which in turn results in increased free levothyroxine through pH changes or displacement.(1)

CLINICAL EFFECTS: Use of intravenous furosemide within 24 hours of chloral hydrate may result in agitation, flushing, hot flashes, tachycardia, and hypertension.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of intravenous furosemide in patients requiring chloral hydrate. Oral furosemide is not expected to interact.(1-3)

DISCUSSION: The use of intravenous furosemide within 24 hours of chloral hydrate has resulted in flushing, hot flashes, tachycardia, and hypertension.(1-3)

Furosemide/Aliskiren

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

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of aliskiren may decrease levels and effectiveness of furosemide.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent aliskiren and furosemide for decreased furosemide effects. The dose of furosemide may need to be adjusted if aliskiren is initiated or discontinued, or furosemide may need to be replaced with an alternative diuretic agent.

DISCUSSION: Concurrent aliskiren decreased furosemide maximum concentration (Cmax) and area-under-curve (AUC) by 50% and 30%, respectively. There were no significant effects on aliskiren levels.(1) Concurrent aliskiren decreased furosemide Cmax and AUC by 27% and 17%, respectively and 24-hour urinary furosemide excretion was reduced by 29%. There were no significant effects on aliskiren levels.(2)

Kaluretics/Digitalis Glycosides

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

MECHANISM OF ACTION: Potassium-losing diuretics may result in potassium depletion which can predispose patients to digitalis toxicity.

CLINICAL EFFECTS: May observe increased arrhythmias, resulting from an increase in the cardiac response to digitalis. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor serum potassium status and give potassium replacements as needed.

DISCUSSION: This interaction is well documented. Most patients taking diuretics do not develop significant potassium depletion if they are on low doses of diuretics and have adequate potassium intake.

Loop Diuretics/Ace Inhibitors; Arbs

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

MECHANISM OF ACTION: The exact mechanism is unknown. The initial hypotensive effect of the ACE inhibitors is mainly the result of suppression of the renin-angiotensin-aldosterone system. The ACE inhibitors inhibit the formation of angiotensin II and angiotensin II receptor antagonists block the action of angiotensin II, thereby lowering aldosterone levels with subsequent sodium and water depletion. Agents such as the loop diuretics that cause sodium and water loss may exaggerate the hypotensive state.

CLINICAL EFFECTS: The addition of an ACE inhibitor to a patient receiving a loop diuretic may result in severe postural hypotension. This effect is transient and is not expected to occur during long-term dosing. Symptomatic hypotension may result in patients treated with loop diuretics who are started on an angiotensin II receptor antagonist. Concurrent use of a renin-angiotensin system (RAS) inhibitor with diuretics and NSAIDs may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Addition of an ACE inhibitor or an angiotensin II receptor antagonist to a patient already receiving a diuretic or who is sodium depleted. Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individual's susceptibility to AKI.

PATIENT MANAGEMENT: In patients without heart failure, it may be advisable to discontinue the diuretic, reduce the dose of the diuretic, or increase salt intake prior to the initiation of the ACE inhibitor. If hypotension occurs, place the patient in a supine position. Hypotension is most likely when the ACE inhibitor is initiated. However, if subsequent hypotension occurs, a dosage adjustment or discontinuation of one agent may be required. Intravascular volume depletion should be corrected in patients prior to the initiation of an angiotensin II receptor antagonist. Concurrent use of a RAS inhibitor with loop diuretics and NSAIDs should be used with caution and monitored closely for signs of AKI.

DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(4,5) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (6) Severe postural hypotension(1,2) and transient postural hypotension(3) has been reported in patients receiving concurrent captopril and furosemide. The effect is transient and may be more prevalent in patients who are sodium depleted.(8) Reversible renal failure(9) and decreased renal function(10) have been reported in patients receiving concurrent administration with enalapril and furosemide. In a study in which electrolytes were replaced with saline or Ringer's solution, no postural hypotension was noted; however, significant decreases in diastolic blood pressure occurred at three, four, and six hours after concurrent administration.(11)

Loop Diuretics/Aminoglycosides

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

MECHANISM OF ACTION: The coadministration of aminoglycosides and loop diuretics may result in additive or synergistic ototoxicity and/or nephrotoxicity.

CLINICAL EFFECTS: The combination of an aminoglycoside and a loop diuretic may increase risk for serious nephrotoxicity or ototoxicity.(1,2) Vestibular or auditory ototoxicity may be permanent.(1,3)

PREDISPOSING FACTORS: Preexisting renal impairment, extended duration of aminoglycoside therapy, greater than one aminoglycoside dose per day, rapid injection or high doses of loop diuretics, concomitant use of additional nephrotoxic agents such as iodinated contrast media or vancomycin, or sepsis appear to increase the risk for nephrotoxicity and ototoxicity.(1-6). Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G, m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity. An additional risk factor includes patients with a maternal relative known to have a clinically relevant MT-RNR1 variant. The risk of ototoxicity can occur at standard recommended doses of aminoglycosides.(7)

PATIENT MANAGEMENT: Administer aminoglycoside dosage every 24 to > 48 hours based upon renal function and continue therapy for less than 4 to 7 days, whenever possible.(4,5) The recommended maximal infusion rate for high dose furosemide therapy is 4 mg/minute.(2) When concurrent therapy is necessary monitor renal, hearing, and vestibular function. Signs of vestibular dysfunction include loss of balance and/or the visual sensation that stationary objects are moving (oscillopsia). In hospitalized or bedbound patients these symptoms may not be noticed or may be ascribed to other etiologies.(3)

DISCUSSION: Several studies and case reports have documented altered aminoglycoside levels, nephrotoxicity, and ototoxicity with concurrent therapy.(8-14) Otic aminoglycosides are included in this interaction because high aminoglycoside concentrations in the ear have been associated with an increased risk for hearing loss.

Loop Diuretics/Nsaids; Salicylates

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

MECHANISM OF ACTION: During concurrent administration of a loop diuretic and a nonsteroidal anti-inflammatory drug (NSAID), patients may retain sodium as a result of NSAID-induced prostaglandin inhibition.

CLINICAL EFFECTS: The pharmacological effects of loop diuretics may be decreased due to reduced antihypertensive and diuretic actions. Concurrent use of NSAIDs with loop diuretics and renin-angiotensin system (RAS) inhibitors may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI.

PATIENT MANAGEMENT: Monitor patients for a decrease in the effects of the loop diuretic. It may be necessary to administer a higher dose of the diuretic or an alternative anti-inflammatory agent. Concurrent use of NSAIDs with loop diuretics and RAS inhibitors should be used with caution and monitored closely for signs of AKI.

DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, RAS inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(19,20) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (21) Administration of indomethacin alone has been reported to decrease sodium excretion and increase blood pressure. In patients receiving a loop diuretic (e.g., bumetanide, furosemide), these effects interfere with clinical management. Several NSAIDs have been shown to interact with loop diuretics interfering with the pharmacological effects of the diuretic. In volunteers on sodium restricted diets, ibuprofen and indomethacin inhibited furosemide diuresis.

Loop Diuretics/Sglt2 Inhibitors

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

MECHANISM OF ACTION: SGLT2 inhibitors cause intravascular volume contraction through osmotic diuresis, which can result in hypotension in patients who are volume depleted from loop diuretic use.(1-7)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors with loop diuretics may result in dehydration, hypotension, and acute renal failure.(1-8)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or ARBs and/or NSAIDs, are on a low sodium diet, have low systolic blood pressure prior to initiating SGLT2 inhibitors, and/or are 65 years of age or older.(1-7)

PATIENT MANAGEMENT: Before initiating SGLT2 inhibitors in patients maintained on loop diuretics, assess volume status and correct if needed and also assess renal function. Patients receiving concurrent therapy should be monitored for hypotension and acute renal failure.(1-8)

DISCUSSION: In clinical trials of canagliflozin, volume depletion-related adverse effects were associated with the use of loop diuretics, moderate renal impairment (eGFR 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2), and age 75 years and older. In a pool of eight Phase 3 clinical trials, 2.3% of all patients taking 100 mg of canagliflozin experienced at least one volume depletion-related event, compared to 3.2% of patients taking 100 mg of canagliflozin with a loop diuretic. 3.4% of all patients taking 300 mg of canagliflozin experienced at least one volume depletion-related event, compared to 8.8% of patients taking 300 mg of canagliflozin with a loop diuretic.(1,2) Cases of acute renal failure, most requiring hospitalization, have been reported in patients receiving canagliflozin and dapagliflozin. Twenty-six of 101 cases involved concurrent use of diuretics.(7) In a post-hoc analysis of the EMPEROR-Preserve trial, the combination of empagliflozin and diuretics was associated with a higher incidence of volume depletion events (HR 1.34; 95% CI, 1.13-1.59). The most commonly reported events were hypotension, syncope, and dehydration. Coadministration of diuretics and empagliflozin did not result in a difference in the incidence of acute renal failure, hyperkalemia, or adverse events leading to trial discontinuation (including fatal events) compared to empagliflozin alone. There was also no change in the benefit of empagliflozin for the primary end point of first hospitalization for heart failure or cardiovascular death.(8)

Selected Antihypertensives And Vasodilators/Apomorphine

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

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

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

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

Selected Diuretics/Tobramycin Inhalation

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

MECHANISM OF ACTION: The combination may have additive or synergistic risks for ototoxicity and/or nephrotoxicity.(1,2)

CLINICAL EFFECTS: Concurrent use may result in an increased risk of aminoglycoside toxicity.(1)

PREDISPOSING FACTORS: Severe renal impairment, sepsis, or concomitant use of additional ototoxic or nephrotoxic agents may further increase the risk for toxicity. Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G, m.1095T>C, and m.1494C>T) are at greatly increased risk of developing ototoxicity. An additional risk factor includes patients with a maternal relative known to have a clinically relevant MT-RNR1 variant. The risk of ototoxicity can occur at standard recommended doses of aminoglycosides.(3)

PATIENT MANAGEMENT: Instruct patients to contact their provider for new onset or worsening tinnitus. Tinnitus may be a sentinel symptom of ototoxicity. In clinical trials of tobramycin inhalation 8 patients (3%) receiving tobramycin reported tinnitus while no patients in the placebo group reported this symptom.(1) For renally impaired patients receiving long term tobramycin inhalation therapy, consider measurement of serum tobramycin to assure low systemic levels. The manufacturer of tobramycin for inhalation states that the product should not be administered concurrently with ethacrynic acid, furosemide, intravenous mannitol, or urea.(1)

DISCUSSION: Although systemic absorption of inhaled tobramycin is limited, the manufacturer states that because these diuretics may enhance the risk for aminoglycoside toxicity, they should not be administered concurrently with inhaled tobramycin.(1)

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

• Anuria
• Azotemia
• Hypocalcemia
• Hypochloremia
• Hypokalemia
• Hypomagnesemia
• Hyponatremia
• Hypoproteinemia
• Hypotension
• Hypovolemia
• Metabolic alkalosis
• Pancreatitis

• Acute myocardial infarction
• Benign prostatic hyperplasia
• Bladder outflow obstruction
• Cardiogenic shock
• Diabetes mellitus
• Gout
• Hearing loss
• Hyperuricemia
• Orthostatic hypotension
• Systemic lupus erythematosus

There is no enhanced messaging for this drug.

Less Frequent

• Hypocalcemia
• Hypokalemia
• Hypomagnesemia
• Hyponatremia

Rare or Very Rare

• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Acute pancreatitis
• Agranulocytosis
• Allergic dermatitis
• Anaphylaxis
• Anemia
• Aplastic anemia
• Bullous pemphigoid
• Dehydration
• DRESS syndrome
• Eosinophilia
• Erythema multiforme
• Exfoliative dermatitis
• Hearing loss
• Hemolytic anemia
• Hypersensitivity angiitis
• Hypochloremic alkalosis
• Interstitial nephritis
• Jaundice
• Leukopenia
• Obstructive hyperbilirubinemia
• Ototoxicity
• Purpura
• Skin rash
• Stevens-johnson syndrome
• Systemic lupus erythematosus
• Thrombocytopenic disorder
• Thrombophlebitis
• Toxic epidermal necrolysis
• Urticaria
• Vasculitis
• Xanthopsia

More Frequent

• Orthostatic hypotension

Less Frequent

• Abdominal pain with cramps
• Anorexia
• Blurred vision
• Cramps
• Diarrhea
• Dizziness
• Drowsy
• Edema
• Headache disorder
• Injection site pain
• Muscle spasm
• Skin photosensitivity
• Xerostomia

Rare or Very Rare

• Accidental fall
• Constipation
• Fever
• Gastrointestinal irritation
• General weakness
• Glycosuria
• Hypercholesterolemia
• Hyperglycemia
• Hypertriglyceridemia
• Hyperuricemia
• Mouth irritation
• Muscle weakness
• Nausea
• Nervousness
• Paresthesia
• Pruritus of skin
• Tinnitus
• Ureteral spasm
• Vertigo
• Vomiting

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