Spironolactone (spironolactone)

In patients with cirrhosis, spironolactone should be initiated with the lowest dose and titrated slowly; patients with cirrhosis and ascites should have therapy initiated in the hospital. (See Cautions: Precautions and Contraindications.)

The manufacturer states, for the treatment of heart failure in patients with an eGFR of 30-50 mL/minute per 1.73 m2, initiation of spironolactone at a dosage of 25 mg every other day (as oral tablets) should be considered because of the risk of hyperkalemia. Alternatively, ACCF and AHA state that the dosage of spironolactone should be reduced in heart failure patients with marginal renal function (eGFR 30-49 mL/minute per 1.73 m2); an initial dosage of 12.5 mg once daily or every other day and a maintenance dosage of 12.5-25 mg once daily as tablets (after 4 weeks of therapy and if serum potassium is 5 mEq/L or less) has been recommended. The manufacturer of the commercially available spironolactone oral suspension (CaroSpir(R)) states in patients with heart failure and an eGFR of 30-50 mL/minute per 1.73 m2, a reduced initial dosage of 10 mg once daily (as the oral suspension) should be considered because of the risk of hyperkalemia. The use of an aldosterone antagonist may be harmful in patients with an eGFR less than 30 mL/minute per 1.73 m2 because of potentially life-threatening hyperkalemia or renal insufficiency. (See Cautions: Electrolyte and Metabolic Effects.)

Spironolactone is administered orally.

Administration of spironolactone with food increases the bioavailability of the drug by approximately 90-100%. The manufacturers state that patients should establish a routine time for taking the drug with regard to meals.

Spironolactone tablets should be stored in tight, light-resistant containers at a temperature less than 25degreesC.

The commercially available oral suspension (CaroSpir(R)) is not therapeutically equivalent to spironolactone oral tablets (e.g., Aldactone(R)). In patients who require a dose exceeding 100 mg, tablets should be used; doses of CaroSpir(R) suspension exceeding 100 mg may result in higher than expected serum spironolactone concentrations. The oral suspension (CaroSpir(R)) should be stored at a controlled room temperature of 20-25degreesC but may be exposed to temperatures ranging from 15-30degreesC.

Although it has frequently been recommended that spironolactone tablets be administered in 3 or 4 doses daily, more recent information suggests that 1 or 2 doses daily may be adequate.

There is no enhanced messaging for this drug.

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

Agents Affecting Plasma Cortisol Levels/Cosyntropin

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: Agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cosyntropin states accuracy of diagnosis using the cosyntropin diagnostic test may be complicated by concomitant medications affecting plasma cortisol levels.(1) Agents affecting plasma cortisol levels and recommendation to stop prior to cosyntropin diagnostic test include: - Glucocorticoids: May elevate plasma cortisol levels. Stop these drugs on the day of testing. Long-acting glucocorticoids may need to be stopped for a longer period before testing. - Spironolactone: May elevate plasma cortisol levels. Stop spironolactone on the day of testing. - Estrogen: May elevate plasma total cortisol levels. Discontinue estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.(1)

DISCUSSION: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

Spironolactone/Mitotane

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

MECHANISM OF ACTION: The mechanism of this interaction has not been established. Spironolactone may block the action or increase the elimination of mitotane.(1)

CLINICAL EFFECTS: The levels and effectiveness of mitotane may be reduced.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of mitotane states that concomitant use with spironolactone should be avoided.(1) The Canadian and UK manufacturers of mitotane states that concomitant use with spironolactone is contraindicated.(3-4)

DISCUSSION: There are no pharmacokinetic studies on the concomitant use of mitotane and spironolactone. In a retrospective review of 54 patients on mitotane, 14 patients who received concomitant spironolactone had significantly lower mitotane levels despite higher doses than patients on mitotane alone.(1-2) In a case report, following addition of mitotane to the treatment schedule of a patient receiving spironolactone, the expected effects of mitotane did not occur. When spironolactone was stopped, the effects of mitotane were observed.(5)

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

Aldosterone Receptor Antagonists/Potassium Sparing Diuretics

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

MECHANISM OF ACTION: Aldosterone receptor antagonists increase serum potassium levels, as do potassium-sparing diuretics.(1-3)

CLINICAL EFFECTS: Concurrent use of aldosterone receptor antagonists with a potassium sparing diuretic may result in hyperkalemia.(1-3)

PREDISPOSING FACTORS: Renal impairment

PATIENT MANAGEMENT: The manufacturer of eplerenone states that the use of eplerenone for the treatment of hypertension in patients receiving potassium-sparing diuretics is contraindicated.(1) The US manufacturer of spironolactone states that spironolactone should not be used with potassium-sparing diuretics.(2) The US manufacturer of finerenone states that more frequent monitoring of potassium may be necessary in patients on concomitant medications that impair potassium excretion or increase serum potassium levels.(3)

DISCUSSION: The one of the main risks of aldosterone receptor antagonist therapy is hyperkalemia. The risk of hyperkalemia can be reduced by avoiding potassium sparing diuretics during therapy.(1-3)

Aldosterone Receptor Antagonists/Trimethoprim

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

MECHANISM OF ACTION: Eplerenone, finerenone, spironolactone, and trimethoprim have all been proven to increase serum potassium levels.(1-7) The increase is achieved by reduction in potassium elimination by trimethoprim(4,5) and inhibition of aldosterone by eplerenone, finerenone, and spironolactone.(2,3,8) The use of these medications in combination can have an additive effect on serum potassium resulting in potentially dangerous levels.(9)

CLINICAL EFFECTS: Concurrent use of trimethoprim and aldosterone antagonists may result in increased serum potassium levels(9) and risk of sudden death.(10)

PREDISPOSING FACTORS: Interaction risk appears to be greater in patients with renal insufficiency, heart failure, when receiving other drugs associated with hyperkalemia risk (e.g. ACE Inhibitors, non-steroidal antiinflammatory agents(NSAIDs), angiotensin II receptor antagonists), and/or in older patients.(1,2,3,6,9,10)

PATIENT MANAGEMENT: Alternative antibiotic therapy should be considered for patients who have renal impairment, heart failure, or take other meds associated with hyperkalemia risk.(1,2,9,10) Patients using trimethoprim and an aldosterone antagonist concurrently should have their serum potassium monitored at baseline and during treatment. Peak potassium increase is delayed and generally occurs after 4 or more days of therapy.(6)

DISCUSSION: A nested case-control study of elderly patients chronically treated with spironolactone evaluated hospital admissions due to hyperkalemia within 14 days of receiving a prescription for SMX-TMP, amoxicillin, norfloxacin, or nitrofurantion. 248 patients were identified. Two thirds of the patients with hyperkalemia on admission had received SMX-TMP, a 12-fold increased risk compared to patients receiving amoxicillin or norfloxacin.(9) A nested case-control study of elderly patients chronically treated with spironolactone evaluated sudden death within 14 days of receiving a prescription for SMX-TMP, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantion. 328 patients were identified and matched to up to 4 case controls. Compared with amoxicillin, use of SMX-TMP was associated with a more than 2-fold (2.46 adjusted OR) increased risk of death.(10)

Baxdrostat; Potassium-Spar Diuretics/Cyclosporine;Tacrolimus

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

MECHANISM OF ACTION: Concurrent use of cyclosporine(1) or tacrolimus(2) with baxdrostat(3) or a potassium-sparing diuretic may result in additive or synergistic effects on potassium levels.

CLINICAL EFFECTS: Concurrent use of cyclosporine(1) or tacrolimus(2) with baxdrostat(3) or a potassium-sparing diuretic may result in severe hyperkalemia.

PREDISPOSING FACTORS: Renal impairment increases the risk for hyperkalemia.

PATIENT MANAGEMENT: The US manufacturers of cyclosporine(1) and tacrolimus(2) state that potassium-sparing diuretics should not be used during therapy with these agents.

DISCUSSION: Hyperkalemia has been reported with cyclosporine, therefore, the US manufacturer states that potassium-sparing diuretics should not be used with cyclosporine.(1) In tacrolimus clinical trials, mild to severe hyperkalemia was reported in 31% of kidney transplant patients, 45% of US liver transplant patients, and 13% of European liver transplant patients. The manufacturer of tacrolimus states that potassium levels should be closely monitored in all patients maintained on tacrolimus and that potassium-sparing diuretics should be avoided during tacrolimus therapy.(2)

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)

Potassium Sparing Diuretics/Potassium Supplements

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

MECHANISM OF ACTION: Decreased renal excretion of potassium, resulting from administration of a potassium sparing diuretic.

CLINICAL EFFECTS: May observe hyperkalemia which may be severe or even fatal.

PREDISPOSING FACTORS: Renal function impairment.

PATIENT MANAGEMENT: If both drugs are administered, monitor potassium levels. Adjust the dose of the drugs accordingly. This combination should probably be avoided if possible.

DISCUSSION: The interaction is well documented. Patients with decreased renal function are especially at risk of developing hyperkalemia from this drug combination. A commonly held belief is that a potassium sparing diuretic formulated in combination with a thiazide diuretic, such as Dyazide, will not exhibit this interaction. Although the likelihood of hyperkalemia occurring may be reduced somewhat, a danger still exists.

Spironolactone/Abiraterone

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

MECHANISM OF ACTION: When used in an androgen-deprived environment created by abiraterone, spironolactone binds to the androgen receptor and acts as an androgen agonist.

CLINICAL EFFECTS: Spironolactone may increase prostate-specific antigen (PSA) levels in metastatic prostate cancer patients on abiraterone.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of spironolactone and abiraterone is not recommended.

DISCUSSION: In a case report, a 67-year-old man with metastatic castration-resistant prostate cancer (mCRPC) on abiraterone for 6 months with good response started spironolactone for heart failure. His PSA rose from 0.004 ng/mL prior to starting spironolactone to 0.93 ng/mL. After spironolactone discontinuation, PSA dropped to 0.38 ng/mL, but subsequently rose again due to disease progression.(3) A 67-year-old man on spironolactone 25 mg daily and a history of prostate cancer experienced bone progression and a rise in PSA. He was started on abiraterone 1,000 mg daily and prednisone 5 mg twice daily, but PSA continued to rise 5 months after starting abiraterone.(3) In a case report, an 86-year-old man on abiraterone for mCRPC started spironolactone and experienced biochemical and radiologic disease progression with PSA rising from 278.7 ng/mL to 792.7 ng/mL. After spironolactone was discontinued, PSA dropped to 334.2 ng/mL.(4) A 57-year-old man with mCRPC on spironolactone failed to respond to abiraterone and prednisone, with PSA rising from 5.97 ng/mL to 8.08 ng/mL. Spironolactone was discontinued and PSA dropped to 2.8 ng/mL after 2 weeks and 0.45 ng/mL after 2 months. After 10 months on abiraterone, the patient experienced disease progression and was switched to enzalutamide. Eight months later, his PSA rose slightly to 0.2 ng/mL. He revealed that he had been taking spironolactone for 3 weeks. Spironolactone was stopped and PSA dropped to 0.14 ng/mL.(5)

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

Agents That Increase Potassium/Baxdrostat

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

MECHANISM OF ACTION: The combination of baxdrostat and agents that increase potassium such as aldosterone receptor antagonists, potassium-sparing diuretics, and potassium supplements can have an additive effect on serum potassium levels.

CLINICAL EFFECTS: Concurrent use of baxdrostat and agents that increase potassium may result in hyperkalemia, which may be severe.

PREDISPOSING FACTORS: More frequent monitoring is recommended for patients at increased risk of hyperkalemia (e.g., patients greater than or equal to 65 years or age, those with diabetes mellitus or chronic kidney disease).(1)

PATIENT MANAGEMENT: The manufacturer of baxdrostat states concurrent use with medications that may increase potassium warrants more frequent monitoring of serum potassium.(1) Assess serum potassium prior to initiation of baxdrostat and monitor periodically during treatment. Correct serum potassium abnormalities prior to initiation of baxdrostat.(1) If hyperkalemia occurs, treat hyperkalemia and consider interrupting or discontinuing baxdrostat. Consider more frequent monitoring of serum potassium in patients who restart baxdrostat after experiencing hyperkalemia. Permanently discontinue baxdrostat if clinically significant hyperkalemia recurs.(1)

DISCUSSION: Baxdrostat may increase potassium. Concurrent use with aldosterone receptor antagonists, potassium-sparing diuretics, and potassium supplements may have additive effects on serum potassium levels, resulting in hyperkalemia. The risk of hyperkalemia can be reduced by monitoring serum potassium more frequently when baxdrostat is administered concomitantly with these agents.

Aldosterone Receptor Antag; Baxdrostat/Nsaids; Salicylates

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

MECHANISM OF ACTION: The exact mechanism is unknown; however, nonsteroidal anti-inflammatory (NSAID) inhibition of prostaglandins may allow baxdrostat, eplerenone, finerenone, or spironolactone-induced nephrotoxicity or hyperkalemia to occur in some patients.(1-4) In some patients, NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of baxdrostat, eplerenone, finerenone, or spironolactone.(1-4)

CLINICAL EFFECTS: Concurrent use of baxdrostat, eplerenone, finerenone, or spironolactone with NSAIDs may result in renal failure or hyperkalemia. The effects of the diuretic, natriuretic, or antihypertensive effects of baxdrostat, eplerenone, finerenone, or spironolactone may be decreased.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid concurrent therapy with baxdrostat, eplerenone, finerenone, or spironolactone with NSAIDs. If these agents are used concurrently, monitor renal function and serum electrolytes. If decreased renal function or hyperkalemia develops, discontinue both agents. The manufacturer of eplerenone recommends checking serum potassium and serum creatinine within 3-7 days of concurrent therapy with NSAIDs.(1) The manufacturer of spironolactone states concurrent use with NSAIDs may lead to severe hyperkalemia and extreme caution should be used during concurrent therapy.(2)

DISCUSSION: Although acute renal failure and hyperkalemia have only been reported in studies and case reports involving indomethacin, diclofenac, flurbiprofen, and ibuprofen with either triamterene or amiloride, the proposed mechanism suggests that all nonsteroidal anti-inflammatory agents may be capable of this interaction with all potassium-sparing diuretics. Patients receiving diuretics are at an increased risk of NSAID-induced renal failure.

Aldosterone Receptor Antagonists; Baxdrostat/Lithium

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

MECHANISM OF ACTION: Aldosterone receptor antagonists, including eplerenone, finerenone and spironolactone, bind to mineralocorticoid receptors, blocking the action of aldosterone. Baxdrostat inhibits aldosterone synthesis. The subsequent increase in sodium and water excretion may lead to reduced renal clearance of lithium.(1-4)

CLINICAL EFFECTS: Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to 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.(5)

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).(5) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: Evaluate renal function and most recent lithium levels. If renal function is not stable or if the lithium level is in the high therapeutic range, then consider lowering the lithium dose when an aldosterone antagonist is started, or consider withholding the aldosterone antagonist until renal function is stable. If renal function is stable and baseline lithium concentrations are in the therapeutic range, recheck lithium levels 5 to 7 days after initiation of baxdrostat, eplerenone, finerenone, or spironolactone. Adjust the lithium dose as necessary based on lithium serum levels and patient response. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(5) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: Although the magnitude and frequency of this specific diuretic interaction is not clear, manufacturer product information for spironolactone and lithium state that lithium patients should generally not receive diuretics.(2,3) The manufacturer of eplerenone recommends frequent monitoring of lithium levels in patients who receive concomitant therapy.(1)

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)

K+ Sparing Diuretics/Angiotensin Ii Receptor Blocker (ARB)

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

MECHANISM OF ACTION: Angiotensin II receptor blockers (ARBs) may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ARB may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ARB. In all patients taking eplerenone who start taking an an ARB, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.

DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) In a systemic literature review and meta-analysis of 20 randomized controlled studies, it was found that treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L).(21) A retrospective cohort study in patients with hypertension, diabetes, and albuminuria between 2008 and 2018 examined the efficacy and safety of mineralocorticoid receptor antagonists eplerenone and spironolactone in combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more frequent in combination therapy patients (n=1,282) versus monotherapy (n=5,484) (22.3 vs 10.9 per 100 person-years for combination and monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant ARBs with potassium sparing diuretics.

Potassium Sparing Diuretics/Aliskiren

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

MECHANISM OF ACTION: Aliskiren may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with aliskiren may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and aliskiren. In all patients taking eplerenone who start taking aliskiren, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.

DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant aliskiren with potassium sparing diuretics.

Potassium Sparing Diuretics/Drospirenone

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

MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. Potassium sparing diuretics may also increase potassium levels.(1)

CLINICAL EFFECTS: Concurrent use of drospirenone and potassium sparing diuretics may result in hyperkalemia.(1)

PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, heparin, and NSAIDs may increase potassium levels.(1)

PATIENT MANAGEMENT: Patients receiving drospirenone with a potassium sparing diuretic should have their serum potassium level checked during the first treatment cycle.(1)

DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of potassium sparing diuretics may also increase potassium levels.(1)

Potassium Sparing Diuretics/Selected Ace Inhibitors

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

MECHANISM OF ACTION: ACE inhibitors decrease the renal excretion of potassium. MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ACE inhibitor may result in hyperkalemia. CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ACE inhibitor may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus. PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ACE inhibitor. In all patients taking eplerenone who start taking an ACE inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy. PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ACE inhibitors. In all patients taking eplerenone who start taking an ACE inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.

DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) In a systemic literature review and meta-analysis of 20 randomized controlled studies, it was found that treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L).(21) A retrospective cohort study in patients with hypertension, diabetes, and albuminuria between 2008 and 2018 examined the efficacy and safety of mineralocorticoid receptor antagonists eplerenone and spironolactone in combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more frequent in combination therapy patients (n=1,282) versus monotherapy (n=5,484) (22.3 vs 10.9 per 100 person-years for combination and monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant ACE inhibitors with potassium sparing diuretics. Selected ACE inhibitors linked to this monograph include: alacepril, cilazapril, delapril, imidapril, spirapril, temocapril, and zofenopril. DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with concomitant spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) In a systemic literature review and meta-analysis of 20 randomized controlled studies, it was found that treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L).(21) A retrospective cohort study in patients with hypertension, diabetes, and albuminuria between 2008 and 2018 examined the efficacy and safety of mineralocorticoid receptor antagonists eplerenone and spironolactone in combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more frequent in combination therapy patients (n=1,282) versus monotherapy (n=5,484) (22.3 vs 10.9 per 100 person-years for combination and monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant ACE inhibitors with potassium sparing diuretics. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

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 Potassium Sparing Diuretics/Moexipril

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

MECHANISM OF ACTION: ACE inhibitors such as moexipril may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ACE inhibitor such as moexipril may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ACE inhibitor such as moexipril.

DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant moexipril with potassium sparing diuretics.

Spironolactone/Digoxin

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

MECHANISM OF ACTION: Spironolactone may decrease the renal clearance of digoxin. Spironolactone may also interfere with some digoxin assays.

CLINICAL EFFECTS: Concurrent spironolactone may result in elevated levels of and toxicity from digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. Spironolactone may also interfere with some digoxin assays, resulting in falsely elevated levels.

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

PATIENT MANAGEMENT: Concurrent administration of spironolactone and digoxin should be closely monitored, and potassium and digoxin concentrations should be measured frequently. Patients should be monitored for changes in therapeutic effects. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced.(8)

DISCUSSION: Simultaneous administration of spironolactone and digoxin has been shown to decrease in digoxin's volume of distribution, plasma clearance, and renal clearance, with corresponding increases in the plasma digoxin concentration. Although the influence of spironolactone on digoxin's pharmacodynamic effects has not been as extensively evaluated as its pharmacokinetic effects, in two studies the inotropic action of digoxin was reduced during spironolactone administration as measured by preejection period index. However, one study reported that in patients for whom potassium depletion may lead to digoxin toxicity, a potassium-sparing diuretic may safely be used to reduce potassium excretion and thereby reduce the risk of arrhythmias. Spironolactone has been reported to interfere with some digoxin assays. Concomitant administration of spironolactone and digoxin increased the digoxin serum concentration 25%. (8)

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• Primary adrenocortical insufficiency

• Hyperkalemia
• Pregnancy

• Hyperglycemia
• Hyperuricemia
• Hypocalcemia
• Hypochloremic alkalosis
• Hypomagnesemia
• Hyponatremia
• Hypovolemia
• Kidney disease with reduction in glomerular filtration rate (GFr)

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More Frequent

• Hyperkalemia

Less Frequent

• Hypomagnesemia
• Hyponatremia

Rare or Very Rare

• Agranulocytosis
• Anaphylaxis
• Cholestatic hepatitis
• Dehydration
• DRESS syndrome
• Dyspnea
• Eosinophilia
• Gastric ulcer
• Gastrointestinal hemorrhage
• Hyperglycemia
• Hypersensitivity angiitis
• Hyperuricemia
• Hypocalcemia
• Hypochloremic alkalosis
• Hypotension
• Hypovolemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Vasculitis

More Frequent

• Gastrointestinal irritation

Less Frequent

• Abnormal sexual function
• Dizziness
• Erectile dysfunction
• Gynecomastia
• Headache disorder

Rare or Very Rare

• Abdominal pain with cramps
• Acute cognitive impairment
• Allergic dermatitis
• Alopecia
• Amenorrhea
• Ataxia
• Cramps in legs
• Diarrhea
• Drowsy
• Fever
• Gastritis
• Irregular menstrual periods
• Lethargy
• Libido changes
• Maculopapular rash
• Mastalgia
• Menstrual disorder
• Nausea
• Postmenopausal bleeding
• Pruritus of skin
• Skin rash
• Urticaria
• Vomiting

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The use of spironolactone during pregnancy may affect the sex differentiation of a male fetus during embryogenesis. Studies in rats indicate that spironolactone may cause feminization of male fetuses and endocrine dysfunction in female fetuses exposed to the drug in utero. Data from published case reports and case series have not demonstrated an association of major malformations or other adverse pregnancy outcomes with spironolactone use. Because of the potential risk to the male fetus due to the antiandrogenic properties of spironolactone, the drug should be avoided during pregnancy; pregnant women who receive spironolactone should be advised of the potential risk to a male fetus.

Spironolactone is not distributed into milk; however, the active metabolite, canrenone, is distributed into milk in low amounts that are expected to be clinically inconsequential. The developmental and health benefits of breastfeeding along with the mother's clinical need for spironolactone and any potential adverse effects on the breastfed child from spironolactone or from the underlying maternal condition should be considered.

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