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  • CLASSES

    Aldosterone Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Potassium-sparing diuretic; used for edema, ascites, HTN, hypokalemia, acne vulgaris, polycystic ovary syndrome, female hirsutism, and to diagnose primary hyperaldosteronism; also improves survival and NYHA functional class, and reduces hospitalizations in NYHA Class IV heart failure.

    COMMON BRAND NAMES

    Aldactone, CAROSPIR

    HOW SUPPLIED

    Aldactone/Spironolactone Oral Tab: 25mg, 50mg, 100mg
    CAROSPIR Oral Susp: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage (tablets or extemporaneous suspension)
    Adults

    25 to 100 mg/day PO in single or divided doses. Dosage may be titrated at 2-week intervals. Doses greater than 100 mg/day generally do not provide additional reductions in blood pressure.

    Neonates†, Infants†, Children†, and Adolescents†

    1 to 3.3 mg/kg/day PO given in 1 to 2 divided doses (Max: 100 mg/day) is recommended by clinical guidelines for the treatment of hypertension in pediatric patients. Doses up to 4 mg/kg/day PO given in 1 to 2 divided doses have been reported in an observational study of 100 patients (mean age 20.8 months, range 4 days to 21 years) with various indications, including co-administration with loop diuretics. The American Academy of Pediatrics (AAP) recommends that diuretics be used as add-on therapy in patients unresponsive to other antihypertensive drugs. Allow 72 hours between dosage adjustments due to the gradual onset of action.

    Oral dosage (CaroSpir suspension)
    Adults

    20 to 75 mg/day PO in single or divided doses. Titrate dosage as needed every 2 weeks. Doses more than 75 mg/day generally do not provide additional reductions in blood pressure.

    For the treatment of heart failure.
    Oral dosage (tablets or extemporaneous suspension)
    Adults

    Initially, 12.5 to 25 mg PO once daily. May reduce dosage to 25 mg PO every other day if hyperkalemia occurs with 25 mg PO once daily. May increase dosage to 50 mg/day, if clinically indicated and lower dose tolerated. Guidelines recommend an aldosterone antagonist, in select patients, in combination with an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI) and evidence-based beta blocker for patients with chronic reduced ejection fraction heart failure (HFrEF) to reduce morbidity and mortality. An aldosterone receptor antagonist is recommended in patients with HFrEF NYHA class II to IV with a GFR of more than 30 mL/minute and potassium less than 5 mEq/L. An aldosterone receptor antagonist may be considered to decrease hospitalizations in patients with preserved ejection fraction heart failure (HFpEF) with EF of 45% or more, elevated B-type natriuretic peptide (BNP) concentrations, or HF admission within 1 year, and estimated GFR of more than 30 mL/minute, creatinine less than 2.5 mg/dL, and potassium less than 5 mEq/L.

    Children† and Adolescents†

    1 to 4 mg/kg/day PO given in 1 to 4 divided doses (Max: 200 mg/day PO). Allow 72 hours between dosage adjustments due to the gradual onset of action.

    Neonates† and Infants†

    1 to 2 mg/kg/day PO given in 1 to 2 divided doses initially, and then titrate to effect (Max: 3 to 4 mg/kg/day). In 11 infants (1 to 12 months of age) with congestive heart failure secondary to congenital heart disease, 1 to 2 mg/kg/day PO divided every 12 hours was used in combination with digoxin and chlorothiazide. Significant reductions in liver size, weight, and respiratory rate were seen compared to baseline and no significant differences in electrolyte abnormalities were noted compared to a group of infants receiving therapy with potassium supplements, digoxin, and chlorothiazide. In an observational study, 1 to 4 mg/kg/day PO given in 1 to 2 divided doses was used in 100 patients (mean age 20.8 months, range 4 days to 21 years) with various indications. Allow 72 hours between dosage adjustments due to the gradual onset of action.

    Oral dosage (CaroSpir suspension)
    Adults

    20 mg PO once daily. May reduce dosage to 20 mg PO every other day if hyperkalemia (serum potassium above 5 mEq/L) occurs. May increase dosage to 37.5 mg PO once daily, if clinically indicated and lower dose tolerated. Guidelines recommend an aldosterone antagonist, in select patients, in combination with an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI) and evidence-based beta blocker for patients with chronic reduced ejection fraction heart failure (HFrEF) to reduce morbidity and mortality. An aldosterone receptor antagonist is recommended in patients with HFrEF NYHA class II to IV with a GFR of more than 30 mL/minute and potassium less than 5 mEq/L. An aldosterone receptor antagonist may be considered to decrease hospitalizations in patients with preserved ejection fraction heart failure (HFpEF) with EF of 45% or more, elevated B-type natriuretic peptide (BNP) concentrations, or HF admission within 1 year, and estimated GFR of more than 30 mL/minute, creatinine less than 2.5 mg/dL, and potassium less than 5 mEq/L.

    For the treatment of edema (e.g., due to nephrotic syndrome, congestive heart failure, or hepatic cirrhosis).
    Oral dosage (tablets or extemporaneous suspension)
    Adults

    Initially, 100 mg/day PO in single or divided doses. If used alone, continue at the initial dosage for at least 5 days, after which may adjust to optimize therapeutic response. The usual dosage range is 25 to 200 mg/day. If, after 5 days, an adequate diuretic response is not obtained, may add a second diuretic which acts more proximally in the renal tubule.

    Children† and Adolescents†

    1 to 4 mg/kg/day PO given in 1 to 4 divided doses (Max: 200 mg/day PO). Allow 72 hours between dosage adjustments due to the gradual onset of action.

    Neonates† and Infants†

    1 to 2 mg/kg/day PO given in 1 to 2 divided doses initially, and then titrate to effect (Max: 3 to 4 mg/kg/day). In 11 infants (1 to 12 months of age) with congestive heart failure secondary to congenital heart disease, 1 to 2 mg/kg/day PO divided every 12 hours was used in combination with digoxin and chlorothiazide. Significant reductions in liver size, weight, and respiratory rate were seen compared to baseline and no significant differences in electrolyte abnormalities were noted compared to a group of infants receiving therapy with potassium supplements, digoxin, and chlorothiazide. In an observational study, 1 to 4 mg/kg/day PO given in 1 to 2 divided doses was used in 100 patients (mean age 20.8 months, range 4 days to 21 years) with various indications. Allow 72 hours between dosage adjustments due to the gradual onset of action.

    Oral dosage (CaroSpir suspension)
    Adults

    75 mg/day PO in single or divided doses for patients with cirrhosis. Initiate therapy in a hospital setting and titrate slowly. If used alone, continue at the initial dosage for at least 5 days, after which may adjust to optimize therapeutic response. If patients require dosages more than 100 mg/day, use another formulation.

    For the treatment of primary hyperaldosteronism.
    Oral dosage (tablets)
    Adults

    100 to 400 mg/day PO in preparation for surgery. May use at lowest effective dosage for long-term maintenance therapy in patients unsuitable for surgery.

    For the treatment of pulmonary edema† due to chronic lung disease (CLD)†.
    Oral dosage (tablets or extemporaneous suspension)
    Infants and Neonates

    3 to 4 mg/kg/day PO divided twice daily has been used in combination with chlorothiazide or hydrochlorothiazide. Because of the potential effects on electrolytes, it may be prudent to begin with a lower dose and titrate as tolerated in patients at risk for electrolyte imbalance.

    For the treatment of symptoms of bloating and weight gain associated with premenstrual syndrome (PMS)†.
    Oral dosage (tablets)
    Adult females

    Initially, 25 mg PO 2 to 4 times daily. Alternatively, 100 mg PO once daily from day 12 of the cycle until menstruation was found to be statistically superior to placebo in relieving the feeling of bloatedness. Diuretic use should be limited to patients who demonstrate a premenstrual weight gain of more than 1.4 kg. Individualize dosage to achieve desired diuresis and minimize weight gain.

    For the treatment of polycystic ovary syndrome†.
    Oral dosage (tablets)
    Adult females

    50 to 200 mg/day PO in 1 or 2 divided doses.

    For the treatment of female hirsutism†.
    Oral dosage (tablets)
    Adult females

    50 to 200 mg/day PO in 1 or 2 divided doses.

    For the treatment of acne vulgaris†.
    Oral dosage (tablets)
    Adults

    50 to 200 mg/day PO. Clinical response may be dose-dependent as doses of 150 to 200 mg/day PO appear to be more effective. Trials of spironolactone for treatment of acne include small numbers of patients and vary in dosage studied, outcome parameters, and reporting methodology.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    400 mg/day PO for tablets; 100 mg/day PO for oral suspension.

    Geriatric

    400 mg/day PO for tablets; 100 mg/day PO for oral suspension.

    Adolescents

    Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO (Max: 200 mg/day PO) have been used off-label for edema due to nephrotic syndrome.

    Children

    Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO (Max: 200 mg/day PO) have been used off-label for edema due to nephrotic syndrome.

    Infants

    Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO have been used off-label.

    Neonates

    Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In patients with cirrhosis, start with the lowest initial dose and titrate slowly. Use with caution in patients with hepatic disease; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

    Renal Impairment

    Tablets or Extemporaneous Suspension
    CrCl 10 mL/minute/1.73 m2 or more: No dosage adjustment needed; however, monitor renal function closely as hyperkalemia is more likely to occur in patients with renal impairment. For heart failure patients with CrCl 30 to 49 mL/minute, clinical practice guidelines recommend 12.5 mg PO once daily or every other day for the first 4 weeks followed by 12.5 to 25 mg PO once daily.
    CrCl less than 10 mL/minute/1.73 m2: Avoid use.
     
    Suspension (CaroSpir)
    CrCl more than 50 mL/minute/1.73 m2: No dosage adjustment needed.
    CrCl 30 to 50 mL/minute/1.73 m2: Consider initial dosage of 10 mg PO once daily due to the risk of hyperkalemia.

    ADMINISTRATION

    Oral Administration

    May be taken without regard to meals; however, should be taken consistently with respect to food.

    Oral Liquid Formulations

    The commercially available spironolactone oral suspension is not therapeutically equivalent to the tablets. In patients requiring a dose more than 100 mg, another formulation should be used.
    Shake well before use.
    Measure with a calibrated oral device to ensure accurate dosing.

    Extemporaneous Compounding-Oral

    Extemporaneous Formulas for Oral Suspension
    NOTE: The extemporaneous preparation of spironolactone is not FDA-approved.
    Several recipes resulting in DIFFERENT final concentrations have been described.
    Adherence to stated techniques for preparation is recommended to obtain uniform suspensions and to avoid problems in formulation (e.g., excessively thick suspensions) during compounding.
     
    - Method 1 (1 mg/mL suspension)
    Pulverize ten (10) spironolactone 25 mg tablets.
    Add a small amount of Purified Water, USP and allow to dissolve for 5 minutes.
    Add 50 mL of 1.5% Carboxymethylcellulose and 100 mL of Simple Syrup NF and mix.
    Use a sufficient quantity of purified water to produce a total volume of 250 mL.
    Transfer to a glass bottle.
    Shake well.
    Storage: The resulting suspension is stable for 3 months at room temperature or refrigerated.
     
    - Method 2 (2.5, 5, or 10 mg/mL suspension)
    Add two hundred (200) spironolactone 25 mg (for 2.5 mg/mL concentration), 50 mg (for 5 mg/mL concentration), or 100 mg (for 10 mg/mL concentration) tablets to a large glass mortar.
    Break with the pestle, and grind tablets until they and their film coats are a fine powder.
    Slowly add 100 mL of Purified Water USP, and triturate to form a fine paste; any film coat particles should dissolve at this phase.
    Gradually add 1900 mL of Cherry Syrup, NF in 3 steps as follows: 1) add about one-third of the cherry syrup to the paste, triturate well, and transfer the mortar contents to a large stainless steel container. 2) Rinse mortar with about one-third of cherry syrup and transfer contents to the stainless steel container. 3) Repeat step 2 with the remaining one-third cherry syrup.
    Homogenize for 10 minutes at high speed using a laboratory model homogenizer.
    Transfer the resulting suspension to amber glass bottles with constant stirring.
    Shake well.
    Storage: The resulting suspension is reported stable for 4 weeks at 5 and 30 degrees C.
     
    - Method 3 (25 mg/mL suspension)
    Add one hundred twenty (120) spironolactone 25 mg tablets to a large glass mortar.
    Break with the pestle, and grind tablets into a fine powder.
    Add approximately 40 mL of the chosen vehicle and mix to a uniform paste. Vehicle choices include: 1) a 1:1 mixture of Ora-Sweet and Ora-Plus 2) a 1:1 mixture of Ora-Sweet SF and Ora-Plus 3) cherry syrup.
    Add geometric portions of the vehicle almost to volume and mix thoroughly after each addition.
    Transfer the contents to a calibrated bottle and add enough vehicle to bring to a total volume of 120 mL.
    Storage: The resulting suspension is reported stable for 60 days at 5 and 25 degrees C when protected from light.

    STORAGE

    Aldactone:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    CAROSPIR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Adrenal insufficiency, anuria, diabetes mellitus, hyperkalemia, renal disease, renal failure, renal impairment

    Spironolactone is contraindicated in patients with hyperkalemia, Addison's disease (chronic adrenal insufficiency), or other conditions associated with hyperkalemia and should not be administered to those who are receiving other potassium-sparing agents. The Endocrine Society guidelines on the diagnosis and treatment of primary adrenal insufficiency state that use of aldosterone antagonists, such as spironolactone, are contraindicated in patients with adrenal insufficiency (Addison's disease). Hyperkalemia stimulates aldosterone production and aldosterone, in turn, enhances sodium and water reabsorption in exchange for potassium excretion in the distal tubule and collecting duct of the kidney. In Addison's disease, aldosterone deficiency results in hyponatremia, hypovolemia, hypotension and hyperkalemia. Thus, spironolactone therapy will exacerbate the hyponatremia, hypovolemia, hypotension and hyperkalemia seen in adrenal insufficiency and worsen the signs and symptoms of the disease.   Spironolactone-induced hyperkalemia can cause life-threatening cardiac arrhythmias, and it is more likely to occur in patients with impaired renal function or diabetes mellitus. Excessive diuresis may cause symptomatic dehydration, hypotension, and worsening renal function. Spironolactone tablets are contraindicated in patients with anuria or any renal disease associated with severe renal impairment (CrCl less than 10 mL/minute) or acute renal failure. Monitor serum potassium and renal function 3 days and 1 week after initiation or dosage increase, monthly for 3 months, quarterly for a year, and every 6 months thereafter. Monitor volume status periodically. Patients receiving spironolactone should not receive potassium supplementation or increase their dietary intake of potassium unless they have refractory hypokalemia. In adults, the risk of hyperkalemia increases progressively when serum creatinine exceeds 1.6 mg/dL; the threshold for pediatric patients is unknown. In adults, spironolactone should be discontinued if the serum creatinine is greater than 4 mg/dL or serum potassium is greater than 5 mEq/L. Spironolactone may cause a transient elevation of BUN, especially in patients with preexisting renal impairment. The precaution for spironolactone in patients with diabetes mellitus is primarily due to the risk of hyperkalemia and not the risk of inducing hyperglycemia, which may occur with thiazide or loop diuretics.

    Acid/base imbalance, metabolic acidosis, metabolic alkalosis, respiratory acidosis

    Correct significant acid/base imbalance before spironolactone is initiated, as mild acidosis or hypochloremic metabolic alkalosis may occur with its use. Close monitoring of the acid-base status is required in debilitated patients or severely ill patients in whom respiratory acidosis or metabolic acidosis may occur (e.g., cardiopulmonary disease or uncontrolled diabetes). These patients are at a higher risk for developing sudden metabolic acidosis or respiratory acidosis, with resultant rapid increases in serum potassium concentrations that could be exacerbated by potassium-sparing diuretic therapy.

    Ascites, biliary cirrhosis, hepatic disease

    Spironolactone-induced fluctuations in serum electrolyte concentrations can occur rapidly and precipitate hepatic encephalopathy and hepatic coma in patients with hepatic disease with biliary cirrhosis and ascites. In these patients, initiate spironolactone in the hospital. Clearance of spironolactone and its metabolites is reduced in patients with cirrhosis; start with the lowest initial dose and titrate slowly in these patients. Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported in patients with decompensated hepatic cirrhosis, even with normal renal function.

    Menstrual irregularity

    Spironolactone can cause antiandrogenic and endocrine effects; use with caution in patients with menstrual irregularity or breast enlargement.

    New primary malignancy, tumorigenicity

    Spironolactone has been demonstrated to be tumorigenic in chronic toxicity studies in rats. Although human data are not available, the potential for tumorigenicity or development of a new primary malignancy are potential risks to consider during spironolactone therapy. FDA-approved labeling for the tablet product recommends that spironolactone only be used as indicated within the prescribing information; avoid unnecessary use.[45984]

    Prostate cancer

    Use spironolactone with caution in patients with prostate cancer. In addition to being an aldosterone antagonist, it has been shown to have some antiandrogenic activity. However, in vitro and in animal studies have confirmed that spironolactone is only a weak and partial androgen antagonist, and has intrinsic androgenic activity. One case report has been published regarding a patient with progression of heavily pretreated castration-refractory prostate cancer (CRPC) after the addition of spironolactone for heart failure to abiraterone therapy; this patient's PSA returned to its previous level 2 weeks after discontinuation of spironolactone. In another case, a patient with progressive metastatic CRPC on abiraterone and subsequent enzalutamide therapy twice had significant decreases in PSA and stabilization of visceral disease after discontinuation of spironolactone.

    Driving or operating machinery

    Somnolence and dizziness have been reported to occur in some patients. Therefore, caution is advised when driving or operating machinery until the response to treatment with spironolactone has been determined.

    Geriatric

    Periodic assessment of renal function, along with monitoring of serum electrolytes to detect possible electrolyte imbalances, especially hyperkalemia, should be done at appropriate intervals during spironolactone therapy, particularly in the geriatric patient. According to the Beers Criteria, diuretics are considered potentially inappropriate medications (PIMs) in geriatric patients; use with caution due to the potential for causing or exacerbating SIADH or hyponatremia. Sodium levels should be closely monitored when starting or changing dosages of diuretics in older adults. The Beers expert panel recommends avoiding spironolactone in geriatric patients with a creatinine clearance less than 30 mL/minute due to the potential for increased serum potassium. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. Diuretics may cause fluid and electrolyte imbalances and may precipitate or exacerbate urinary incontinence.

    Pregnancy

    Avoid spironolactone in pregnancy or advise pregnant women of the potential risk to a male fetus. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. Animal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero. Animal offspring exposed to spironolactone during late pregnancy exhibited changes in the reproductive tract, including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction that persisted into adulthood. Limited data from published case reports and case series did not demonstrate an association between major malformations or other adverse pregnancy outcomes with spironolactone use.

    Breast-feeding

    Spironolactone is not present in breast-milk; however, canrenone, the major metabolite of spironolactone, does appear in breast-milk in low amounts that are not expected to be clinically relevant. Data from a breast-feeding woman at 17 days postpartum did not indicate any adverse effects on the breast-fed infant; long term effects on a breast-fed infant are unknown. There are no data on the effects of spironolactone on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for spironolactone and any potential adverse effects on the breast-fed child from spironolactone or from the underlying maternal condition. Previous American Academy of Pediatrics recommendations classified spironolactone as usually compatible with breast-feeding.

    Infertility

    In animal studies involving female rats, spironolactone was associated with a reduction in circulating estrogen levels and retarded ovarian follicle development. Inhibition of ovulation and reduction in number of implanted embryos were observed with spironolactone administration to female mice. The potential for infertility in humans is unknown.[45984]

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    gout / Delayed / 0-1.0
    hypomagnesemia / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    metabolic alkalosis / Delayed / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    postmenopausal bleeding / Delayed / Incidence not known
    tumorigenicity / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    dehydration / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypovolemia / Early / Incidence not known
    erythema / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known

    Mild

    paresthesias / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    weakness / Early / Incidence not known
    mastalgia / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    vomiting / Early / Incidence not known
    nausea / Early / Incidence not known
    diarrhea / Early / Incidence not known
    lethargy / Early / Incidence not known
    headache / Early / Incidence not known
    drowsiness / Early / Incidence not known
    dizziness / Early / Incidence not known
    polyuria / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    fever / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with spironolactone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Spironolactone is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with dihydrocodeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like spironolactone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If spironolactone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with oxycodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Acetaminophen; Pentazocine: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when potassium-sparring diuretics are administered with pentazocine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Acetaminophen; Propoxyphene: (Moderate) Opiate agonists may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetazolamide: (Moderate) Carbonic anhydrase inhibitors promote electrolyte excretion including hydrogen ions, sodium, and potassium. They can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Aldesleukin, IL-2: (Moderate) Potassium sparing diuretics may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If spironolactone is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with alfentanil. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Aliskiren: (Moderate) Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Aliskiren; Amlodipine: (Moderate) Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Aliskiren; Valsartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Alprazolam: (Major) Avoid coadministration of alprazolam and spironolactone due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with spironolactone, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as spironolactone or other potassium-sparing diuretics, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Long-term use of potassium-sparing diuretics has been found to increase renal tubular reabsorption of magnesium which may cause hypermagnesemia in patients also receiving magnesium supplements, especially in patients with renal insufficiency.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Long-term use of potassium-sparing diuretics has been found to increase renal tubular reabsorption of magnesium which may cause hypermagnesemia in patients also receiving magnesium supplements, especially in patients with renal insufficiency.
    Ambrisentan: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
    Amifostine: (Major) Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Amlodipine; Atorvastatin: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
    Amlodipine; Benazepril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Amlodipine; Olmesartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Amlodipine; Valsartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Amobarbital: (Moderate) Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.
    Amphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Amphetamine; Dextroamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Angiotensin II receptor antagonists: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Angiotensin-converting enzyme inhibitors: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Apomorphine: (Moderate) Use of potassium-sparing diuretics and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
    Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Ardeparin: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Aripiprazole: (Major) Monitor for aripiprazole-related adverse reactions during concurrent use of spironolactone. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP2D6 inhibitor. Adults receiving a combination of a CYP2D6 inhibitor and spironolactone for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor alone. Aripiprazole is a substrate for CYP2D6 and CYP3A4; spironolactone is a weak CYP3A4 inhibitor. Additionally, monitor blood pressure and adjust spironolactone dose accordingly as aripiprazole may enhance the hypotensive effects of antihypertensive agents.
    Arsenic Trioxide: (Moderate) Use caution when using arsenic trioxide with potassium-sparing diuretics. Electrolyte abnormalities, such as increased potassium, may increase the risk for QT prolongation and torsade de pointes.
    Articaine; Epinephrine: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Aspirin, ASA: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Barbiturates, such as butalbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone. (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Barbiturates, such as butalbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone. (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia. (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Aspirin, ASA; Caffeine: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia. (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with spironolactone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Spironolactone is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with dihydrocodeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Carisoprodol: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia. (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Dipyridamole: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Omeprazole: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like spironolactone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If spironolactone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with oxycodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Aspirin, ASA; Pravastatin: (Moderate) Concomitant use of aspirin and spironolactone may decrease the efficacy of spironolactone due to possible inhibition of tubular secretion of canrenone. Monitor patient closely during coadministration for desired effect; a higher maintenance dose may be necessary. In drug interaction studies, a single dose of 600 mg of aspirin inhibited the natriuretic effect of spironolactone. Salicylates can also increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. This combination may cause hyperkalemia.
    Atorvastatin: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
    Atorvastatin; Ezetimibe: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Azelastine; Fluticasone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Azilsartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Azilsartan; Chlorthalidone: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Beclomethasone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Barbiturates, such as phenobarbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Belladonna; Opium: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Benazepril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with benzhydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Benzphetamine: (Minor) Benzphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Betamethasone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Bismuth Subsalicylate: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: (Moderate) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with diuretics.
    Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Brompheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Budesonide: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Budesonide; Formoterol: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Budesonide; Glycopyrrolate; Formoterol: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Bupivacaine; Epinephrine: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with spironolactone is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine and spironolactone can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when spironolactone is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping spironolactone, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If spironolactone is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and spironolactone is a CYP3A4 inhibitor. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and spironolactone can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when spironolactone is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping spironolactone, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If spironolactone is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and spironolactone is a CYP3A4 inhibitor. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Butabarbital: (Moderate) Barbiturates, such as butalbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Butalbital; Acetaminophen: (Moderate) Barbiturates, such as butalbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Barbiturates, such as butalbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Barbiturates, such as butalbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone. (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including potassium-sparing diuretics. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.
    Calcium Phosphate, Supersaturated: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as diuretics may increase the risk of acute phosphate nephropathy in patients receiving sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Canagliflozin: (Major) When canagliflozin is initiated in patients already receiving diuretics, symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, canagliflozin can lead to hyperkalemia. Patients treated with canagliflozin 300 mg/day were more likely to experience increases in potassium. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating canagliflozin in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
    Canagliflozin; Metformin: (Major) When canagliflozin is initiated in patients already receiving diuretics, symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, canagliflozin can lead to hyperkalemia. Patients treated with canagliflozin 300 mg/day were more likely to experience increases in potassium. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating canagliflozin in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
    Candesartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Captopril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of spironolactone; carbamazepine dose adjustments may be needed. Concomitant use may increase carbamazepine concentrations. Carbamazepine is a CYP3A substrate and spironolactone is a CYP3A inhibitor.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbinoxamine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbonic anhydrase inhibitors: (Moderate) Carbonic anhydrase inhibitors promote electrolyte excretion including hydrogen ions, sodium, and potassium. They can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Cardiac glycosides: (Moderate) Monitor for an increase in digoxin-related adverse effects and consider empirically decreasing the digoxin dose by approximately 15 to 30% or modifying digoxin dosing frequency. It is unknown to what extent, if any, spironolactone may increase actual digoxin exposure. Spironolactone and its metabolites interfere with some radioimmunoassays for digoxin. Spironolactone may be falsely detected as digoxin at levels up to 0.5 ng/mL. Although less common, digoxin results may also appear to be falsely reduced. Digoxin assays that use an LC/MS/MS method may be less likely to interact with spironolactone.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with spironolactone is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of spironolactone, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with tramadol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with spironolactone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Spironolactone is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with dihydrocodeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with spironolactone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Spironolactone is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with dihydrocodeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Cholestyramine: (Moderate) Use caution if spironolactone is administered concurrently with cholestyramine. Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Ciclesonide: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Cidofovir: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as diuretics, is contraindicated. Diuretics should be discontinued at least 7 days prior to beginning cidofovir.
    Citalopram: (Moderate) Citalopram causes dose-dependent QT interval prolongation. Concurrent use of citalopram and medications known to cause electrolyte imbalance may increase the risk of developing QT prolongation. Therefore, caution is advisable during concurrent use of citalopram and diuretics. In addition, patients receiving a diuretic during treatment with citalopram may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of citalopram should be considered in patients who develop symptomatic hyponatremia.
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with spironolactone and monitor for adverse reactions. If spironolactone is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Spironolactone is a weak CYP3A inhibitor. Additionally, monitor blood pressure and adjust spironolactone dose accordingly as clozapine may enhance the hypotensive effects of antihypertensive agents.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Codeine: (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with spironolactone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of spironolactone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. spironolactone is a weak inhibitor of CYP3A4. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with codeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Corticosteroids: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Cortisone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Cosyntropin: (Major) Patients receiving spironolactone should omit their pre-test doses on the day selected for testing. Patients taking inadvertent doses of spironolactone may exhibit abnormally high basal plasma cortisol concentrations and a decreased response to the test.
    Cyclosporine: (Major) Avoid concomitant use of cyclosporine and potassium-sparing diuretics, such as spironolactone, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations. Additionally, closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions as concurrent use may increase cyclosporine exposure. The dose of cyclosporine may need to be adjusted. Cyclosporine is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor.
    Dalteparin: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Darifenacin: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Deflazacort: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Desvenlafaxine: (Moderate) Patients receiving a diuretic during treatment with a Serotonin norepinephrine reuptake inhibitor (SNRI) may be at greater risk of developing hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs. Cases involving serum sodium levels lower than 110 mmol/L have been reported. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Dexamethasone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextroamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with spironolactone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and spironolactone is a CYP3A inhibitor.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and spironolactone together with caution. Metabolic acidosis is associated with the use of dichlorphenamide and has been reported with spironolactone in patients with decompensated hepatic cirrhosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Digitoxin: (Moderate) Monitor for an increase in digoxin-related adverse effects and consider empirically decreasing the digoxin dose by approximately 15 to 30% or modifying digoxin dosing frequency. It is unknown to what extent, if any, spironolactone may increase actual digoxin exposure. Spironolactone and its metabolites interfere with some radioimmunoassays for digoxin. Spironolactone may be falsely detected as digoxin at levels up to 0.5 ng/mL. Although less common, digoxin results may also appear to be falsely reduced. Digoxin assays that use an LC/MS/MS method may be less likely to interact with spironolactone.
    Digoxin: (Moderate) Monitor for an increase in digoxin-related adverse effects and consider empirically decreasing the digoxin dose by approximately 15 to 30% or modifying digoxin dosing frequency. It is unknown to what extent, if any, spironolactone may increase actual digoxin exposure. Spironolactone and its metabolites interfere with some radioimmunoassays for digoxin. Spironolactone may be falsely detected as digoxin at levels up to 0.5 ng/mL. Although less common, digoxin results may also appear to be falsely reduced. Digoxin assays that use an LC/MS/MS method may be less likely to interact with spironolactone.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with spironolactone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If spironolactone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Spironolactone is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with dihydrocodeine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with spironolactone is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
    Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with spironolactone is necessary as concurrent use may increase dofetilide exposure. Spironolactone is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of potassium-sparing diuretics may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if potassium-sparing diuretics are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Estetrol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of potassium-sparing diuretics may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if potassium-sparing diuretics are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of potassium-sparing diuretics may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if potassium-sparing diuretics are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of potassium-sparing diuretics may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if potassium-sparing diuretics are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of potassium-sparing diuretics may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if potassium-sparing diuretics are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Duloxetine: (Moderate) Patients receiving a diuretic during treatment with a Serotonin norepinephrine reuptake inhibitor (SNRI) may be at greater risk of developing hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs. Cases involving serum sodium levels lower than 110 mmol/L have been reported. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Eliglustat: (Major) Coadministration of eliglustat and spironolactone is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Spironolactone is a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Empagliflozin: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Empagliflozin; Linagliptin: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Empagliflozin; Metformin: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Enalapril, Enalaprilat: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Enalapril; Felodipine: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations. (Moderate) Concurrent use of felodipine and spironolactone should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Enoxaparin: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Ephedrine: (Major) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by potassium-sparing diuretics. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Ephedrine; Guaifenesin: (Major) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by potassium-sparing diuretics. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Epinephrine: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Eplerenone: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    Epoprostenol: (Moderate) Epoprostenol can have additive effects when administered with other antihypertensive agents. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Eprosartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Escitalopram: (Moderate) Patients receiving a diuretic during treatment with escitalopram may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of escitalopram should be considered in patients who develop symptomatic hyponatremia.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Ethanol: (Moderate) Patients should be cautioned that ingesting alcohol can increase the chance of low blood pressure and dizziness when taking spironolactone. Patients may wish to limit alcohol ingestion while taking this drug and should be monitored for signs or symptoms of hypotension, including postural hypotension and dizziness.
    Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Felodipine: (Moderate) Concurrent use of felodipine and spironolactone should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like spironolactone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If spironolactone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with fentanyl. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or spironolactone; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including spironolactone, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fludrocortisone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Flunisolide: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Fluoxetine: (Moderate) Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Fluticasone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Fluticasone; Salmeterol: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Fluticasone; Vilanterol: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Fluvoxamine: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
    Food: (Major) Licorice extract, which contains glycyrrhizic acid, possesses aldosterone-like properties. Thus, licorice candy and foods containing licorice extract should be avoided by patients taking spironolactone in order to not antagonize the drug's therapeutic actions.
    Formoterol; Mometasone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Fosinopril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Gallium Ga 68 Dotatate: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Glimepiride; Rosiglitazone: (Moderate) Monitor for an increase in rosiglitazone-related adverse effects during concomitant use with spironolactone; adjust the dose of rosiglitazone based on clinical response. Coadministration may increase the exposure of rosiglitazone. Rosiglitazone is a CYP2C8 substrate and spironolactone is a CYP2C8 inhibitor.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Haloperidol: (Moderate) In general, haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.
    Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like spironolactone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If spironolactone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Hydrocortisone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Hydromorphone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with hydromorphone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Ibritumomab Tiuxetan: (Major) Avoid coadministration of potassium phosphate and potassium-sparing diuretics as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
    Ibuprofen lysine: (Moderate) Ibuprofen lysine may reduce the effect of diuretics; diuretics can increase the risk of nephrotoxicity of NSAIDs in dehydrated patients. During coadministration of NSAIDs and diuretic therapy, patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like spironolactone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If spironolactone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with oxycodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Amiloride can have additive effects when administered with other antihypertensive agents. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Inamrinone: (Moderate) Hypokalemia may occur due to excessive diuresis during inamrinone therapy. Fluid and electrolyte changes and renal function should be carefully monitored during inamrinone therapy.
    Indapamide: (Moderate) The effects of indapamide may be additive when administered with other antihypertensive agents or diuretics. This may be desirable, but occasionally orthostatic hypotension may occur. Dosages should be adjusted based on clinical response.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Irbesartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
    Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with spironolactone is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with spironolactone is necessary; consider the use of an alternative agent to spironolactone that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor. The effect of weak CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with spironolactone as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; spironolactone is a weak CYP3A4 inhibitor. Coadministration with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomilnacipran: (Moderate) Patients receiving a diuretic during treatment with a Serotonin norepinephrine reuptake inhibitor (SNRI) may be at greater risk of developing hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs. Cases involving serum sodium levels lower than 110 mmol/L have been reported. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Levorphanol: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with levorphanol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with spironolactone is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
    Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with spironolactone is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor. (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with spironolactone is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
    Lisdexamfetamine: (Minor) Lisedexamfetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Lisinopril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Lithium: (Minor) The risk of lithium toxicity may be increased in patients receiving medications that affect kidney function and sodium excretion, such as diuretics. However, concurrent use of potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) with lithium is generally regarded as safe. Lithium is primarily reabsorbed from the proximal tubules whereas potassium-sparing diuretics inhibit the endothelial sodium channel in the renal collecting duct thereby inhibiting reabsorption of sodium and lithium. In one small study evaluating concurrent use of lithium and spironolactone, lithium clearance was increased by 16%, which was not considered clinically significant. Amiloride has been safely used as a reversal agent for lithium-induced nephrogenic diabetes insipidus. There is a lack of evidence to evaluate the effect of lithium and triamterene co-administration, however, a significant interaction would not be expected due to the pharmacologic similarities with other potassium-sparing diuretics.
    Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with spironolactone is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Spironolactone is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lonafarnib: (Major) Avoid coadministration of lonafarnib and spironolactone; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing spironolactone. Lonafarnib is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
    Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Losartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Losartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Low Molecular Weight Heparins: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Magnesium Citrate: (Moderate) The use of saline laxatives (e.g., magnesium citrate) with potassium-sparing diuretics may interfere with the potassium-sparing effect of such diuretics due to excess fluid and electrolyte loss. In addition, potassium-sparing diuretics may interfere with the kidneys ability to regulate magnesium concentrations; long-term use of potassium-sparing diuretics has been found to increase renal tubular reabsorption of magnesium which may cause hypermagnesemia, especially in patients with renal insufficiency.
    Magnesium Hydroxide: (Moderate) Long-term use of potassium-sparing diuretics has been found to increase renal tubular reabsorption of magnesium which may cause hypermagnesemia in patients also receiving magnesium supplements, especially in patients with renal insufficiency.
    Magnesium Salicylate: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Magnesium Salts: (Moderate) Long-term use of potassium-sparing diuretics has been found to increase renal tubular reabsorption of magnesium which may cause hypermagnesemia in patients also receiving magnesium supplements, especially in patients with renal insufficiency. (Moderate) Long-term use of potassium-sparing diuretics has been found to increase renal tubular reabsorption of magnesium which may cause hypermagnesemia in patients also receiving magnesium supplements, especially in patients with renal insufficiency. In addition, use caution when prescribing sulfate salt bowel preps in patients taking medications that may affect renal function such as diuretics.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as diuretics.
    Mannitol: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with spironolactone is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A4 and spironolactone is a weak CYP3A4 inhibitor.
    Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A4 and spironolactone is a weak CYP3A4 inhibitor. Concomitant use with spironolactone can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with meperidine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Meperidine; Promethazine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A4 and spironolactone is a weak CYP3A4 inhibitor. Concomitant use with spironolactone can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with meperidine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Mephobarbital: (Moderate) Barbiturates, such as mephobarbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with spironolactone is necessary. Repaglinide is a CYP2C8 substrate and spironolactone is a CYP2C8 inhibitor.
    Metformin; Rosiglitazone: (Moderate) Monitor for an increase in rosiglitazone-related adverse effects during concomitant use with spironolactone; adjust the dose of rosiglitazone based on clinical response. Coadministration may increase the exposure of rosiglitazone. Rosiglitazone is a CYP2C8 substrate and spironolactone is a CYP2C8 inhibitor.
    Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; spironolactone is a weak CYP3A inhibitor. Concomitant use with spironolactone can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with methadone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Methamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Methazolamide: (Moderate) Carbonic anhydrase inhibitors promote electrolyte excretion including hydrogen ions, sodium, and potassium. They can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension.
    Methylphenidate Derivatives: (Moderate) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate derivatives and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives. Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics.
    Methylprednisolone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Midazolam: (Moderate) Use caution when midazolam is coadministered with spironolactone. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
    Milnacipran: (Moderate) Patients receiving a diuretic during treatment with a Serotonin norepinephrine reuptake inhibitor (SNRI) may be at greater risk of developing hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs. Cases involving serum sodium levels lower than 110 mmol/L have been reported. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mirtazapine: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Mitotane: (Moderate) An isolated case report indicated that mitotane activity might be antagonized by the concurrent administration of spironolactone. Until more data are available to confirm an interaction, the use of spironolactone with mitotane should be approached with caution.
    Moexipril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Mometasone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Morphine: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when a potassium-sparing diuretic is administered with morphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction.
    Morphine; Naltrexone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when a potassium-sparing diuretic is administered with morphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with spironolactone is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and spironolactone is a strong/moderate/weak CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with spironolactone is necessary. The dose of sirolimus may also need to be reduced with coadministration of spironolactone. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of spironolactone. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; spironolactone is a weak CYP3A inhibitor.
    Naproxen; Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Nebivolol; Valsartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Nefazodone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with spironolactone is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with spironolactone due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and spironolactone is a CYP3A4 inhibitor. Coadministration with another CYP3A4 inhibitor increased the AUC of nisoldipine by 30% to 45%.
    Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Non-Ionic Contrast Media: (Major) Do not use diuretics before non-ionic contrast media administration. Concomitant use of diuretics and non-ionic contrast media may increase the risk for acute kidney injury, including renal failure.
    Nonsteroidal antiinflammatory drugs: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Norepinephrine: (Moderate) Spironolactone may reduce the vascular responsiveness to norepinephrine. Caution should be exercised with coadministration of spironolactone and norepinephrine.
    Octreotide: (Moderate) Patients receiving diuretics or other agents to control fluid and electrolyte balance may require dosage adjustments while receiving octreotide due to additive effects.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Moderate) Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Oliceridine: (Moderate) Monitor patients for signs of diminished diuresis and/or effects on blood pressure if diuretics are used concomitantly with oliceridine; increase the dosage of the diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
    Olmesartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Oxybutynin: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like spironolactone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If spironolactone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with oxycodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by diuretics. If these drugs are used together, closely monitor for changes in blood pressure.
    Oxymorphone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when potassium-sparring diuretics are administered with oxymorphone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of paclitaxel with spironolactone is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP2C8 substrate and spironolactone is a CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and potassium-sparing diuretics who are susceptible to hypotension.
    Paroxetine: (Moderate) Patients receiving a diuretic during treatment with paroxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of paroxetine should be considered in patients who develop symptomatic hyponatremia.
    Penicillin G: (Major) Concomitant use of high doses of parenteral penicillin G potassium with potassium-sparing diuretics can cause hyperkalemia.
    Pentazocine: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when potassium-sparring diuretics are administered with pentazocine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Pentazocine; Naloxone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when potassium-sparring diuretics are administered with pentazocine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Pentobarbital: (Moderate) Barbiturates may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perindopril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Perindopril; Amlodipine: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenobarbital: (Moderate) Barbiturates, such as phenobarbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Barbiturates, such as phenobarbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Pimozide: (Major) Avoid concomitant use of pimozide and spironolactone. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate, and spironolactone is a weak CYP3A inhibitor.
    Polyethylene Glycol; Electrolytes: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as diuretics.
    Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as diuretics.
    Potassium Phosphate: (Major) Avoid coadministration of potassium phosphate and potassium-sparing diuretics as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
    Potassium Phosphate; Sodium Phosphate: (Major) Avoid coadministration of potassium phosphate and potassium-sparing diuretics as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
    Potassium: (Major) The use of potassium supplements in patients receiving spironolactone may increase the risk for hyperkalemia. Potassium supplements should generally be avoided in heart failure patients receiving spironolactone. Monitor serum potassium concentrations closely if concomitant use is necessary.
    Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.
    Prednisolone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Prednisone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Prilocaine; Epinephrine: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Primidone: (Moderate) Barbiturates, such as primidone, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Promethazine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with spironolactone; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and spironolactone with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; spironolactone is a weak CYP3A4 inhibitor.
    Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Propoxyphene: (Moderate) Opiate agonists may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Pseudoephedrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Pseudoephedrine; Triprolidine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving pseudoephedrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Quinapril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Quinapril; Hydrochlorothiazide, HCTZ: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Ramipril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Remifentanil: (Moderate) Opiate agonists like remifentanil may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with spironolactone is necessary. Repaglinide is a CYP2C8 substrate and spironolactone is a CYP2C8 inhibitor.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Rosiglitazone: (Moderate) Monitor for an increase in rosiglitazone-related adverse effects during concomitant use with spironolactone; adjust the dose of rosiglitazone based on clinical response. Coadministration may increase the exposure of rosiglitazone. Rosiglitazone is a CYP2C8 substrate and spironolactone is a CYP2C8 inhibitor.
    Sacubitril; Valsartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Salsalate: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
    Secobarbital: (Moderate) Barbiturates, such as secobarbital, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Patients receiving a diuretic during treatment with a Serotonin norepinephrine reuptake inhibitor (SNRI) may be at greater risk of developing hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs. Cases involving serum sodium levels lower than 110 mmol/L have been reported. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Sertraline: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
    Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with spironolactone is necessary. The dose of sirolimus may also need to be reduced with coadministration of spironolactone. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of spironolactone. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; spironolactone is a weak CYP3A inhibitor.
    Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as diuretics may increase the risk of acute phosphate nephropathy in patients receiving sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that may affect renal function such as diuretics. In addition, use caution in patients receiving drugs where hypokalemia is a particular risk.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Long-term use of potassium-sparing diuretics has been found to increase renal tubular reabsorption of magnesium which may cause hypermagnesemia in patients also receiving magnesium supplements, especially in patients with renal insufficiency. In addition, use caution when prescribing sulfate salt bowel preps in patients taking medications that may affect renal function such as diuretics.
    Solifenacin: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms. Risk versus benefit should be addressed in patients receiving diuretics and solifenacin.
    Streptozocin: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if spironolactone must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like spironolactone can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If spironolactone is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with sufentanil. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor serum potassium concentrations if trimethoprim and a potassium-sparing diuretic are used together. Concomitant use may increase the risk of hyperkalemia. The risk for trimethoprim-associated hyperkalemia is greatest in patients with additional risk factors for hyperkalemia such as age greater than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim.
    Tacrolimus: (Major) Avoid concomitant use of tacrolimus and potassium-sparing diuretics, such as spironolactone, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations. Additionally, monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with spironolactone is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; spironolactone is a weak CYP3A inhibitor.
    Tapentadol: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when potassium-sparing diuretics are administered with tapentadol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Telmisartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Telmisartan; Amlodipine: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thiopental: (Moderate) Concurrent use of thiopental and alpha-blockers or antihypertensive agents increases the risk of developing hypotension.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Tinzaparin: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tolterodine: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Tolvaptan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with spironolactone is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of spironolactone, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with tramadol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with spironolactone is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of spironolactone, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with tramadol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Trandolapril: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Trandolapril; Verapamil: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Tranylcypromine: (Contraindicated) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Triamcinolone: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics.
    Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with spironolactone and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and spironolactone is a weak CYP3A inhibitor.
    Trimethoprim: (Moderate) Monitor serum potassium concentrations if trimethoprim and a potassium-sparing diuretic are used together. Concomitant use may increase the risk of hyperkalemia. The risk for trimethoprim-associated hyperkalemia is greatest in patients with additional risk factors for hyperkalemia such as age greater than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim.
    Tubocurarine: (Moderate) Coadministration of spironolactone and nondepolarizing skeletal muscle relaxants (e.g., tubocurarine) may result in increased responsiveness to the muscle relaxant; use caution with concomitant administration of these agents.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with spironolactone. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; spironolactone is a weak CYP3A4 inhibitor.
    Valsartan: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Valsartan; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as spironolactone, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Venlafaxine: (Moderate) Patients receiving a diuretic during treatment with a Serotonin norepinephrine reuptake inhibitor (SNRI) may be at greater risk of developing hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs. Cases involving serum sodium levels lower than 110 mmol/L have been reported. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Vilazodone: (Moderate) Patients receiving vilazodone with medications known to cause hyponatremia, such as diuretics, may be at increased risk of developing hyponatremia. Hyponatremia has occurred in association with the use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of vilazodone, as well as implementation of the appropriate medical interventions.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with spironolactone is necessary. Vinorelbine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
    Vortioxetine: (Moderate) Patients receiving a diuretic during treatment with vortioxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Clinically significant hyponatremia has been reported during therapy with vortioxetine. One case involving serum sodium levels lower than 110 mmol/l has occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of vortioxetine should be considered in patients who develop symptomatic hyponatremia.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with spironolactone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Spironolactone is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled BP.
    Ziconotide: (Moderate) Patients taking diuretics with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of diuretic cessation is warranted in addition to ziconotide discontinuation.
    Ziprasidone: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope.

    PREGNANCY AND LACTATION

    Pregnancy

    Avoid spironolactone in pregnancy or advise pregnant women of the potential risk to a male fetus. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. Animal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero. Animal offspring exposed to spironolactone during late pregnancy exhibited changes in the reproductive tract, including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction that persisted into adulthood. Limited data from published case reports and case series did not demonstrate an association between major malformations or other adverse pregnancy outcomes with spironolactone use.

    Spironolactone is not present in breast-milk; however, canrenone, the major metabolite of spironolactone, does appear in breast-milk in low amounts that are not expected to be clinically relevant. Data from a breast-feeding woman at 17 days postpartum did not indicate any adverse effects on the breast-fed infant; long term effects on a breast-fed infant are unknown. There are no data on the effects of spironolactone on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for spironolactone and any potential adverse effects on the breast-fed child from spironolactone or from the underlying maternal condition. Previous American Academy of Pediatrics recommendations classified spironolactone as usually compatible with breast-feeding.

    MECHANISM OF ACTION

    Mechanism of Action: Spironolactone inhibits the effects of aldosterone on the distal renal tubules. Unlike amiloride and triamterene, spironolactone exhibits its diuretic effect only in the presence of aldosterone, and these effects are enhanced in patients with hyperaldosteronism. Aldosterone antagonism enhances sodium, chloride, and water excretion, and reduces the excretion of potassium, ammonium, and phosphate. Spironolactone does not inhibit renal transport mechanisms or carbonic anhydrase activity. In addition, spironolactone acts as an androgen receptor blocker by competitively inhibiting dihydrotestosterone at its receptor sites, and at high doses, spironolactone interferes with steroid synthesis in the adrenal glands and gonads. Sebum excretion rates also are reduced in a dose-dependent manner with spironolactone.
     
    Spironolactone is a poor antihypertensive, but it does have modest hypotensive effects. The hypotensive mechanism of spironolactone is unknown. It is possibly due to the ability of the drug to inhibit aldosterone's effect on arteriole smooth muscle. Spironolactone also can alter the extracellular-intracellular sodium gradient across the membrane. In general, diuretics lower blood pressure by initially decreasing cardiac output and reducing plasma and extracellular fluid volume. Cardiac output and extracellular fluid volume eventually return to normal, but peripheral resistance is reduced, resulting in lower blood pressure. In general, diuretics worsen glucose tolerance and exert detrimental effects on the lipid profile.

    PHARMACOKINETICS

    Spironolactone is administered orally. Spironolactone is extensively metabolized, via hepatic pathways, to active metabolites. The clinical effects of spironolactone are partially due to canrenone, a metabolite. The parent drug and canrenone are greater than 90% plasma protein-bound. The duration of action after multiple doses of spironolactone is 2 to 3 days. Both unchanged drug (less than 10%) and its metabolites are excreted primarily in the urine. The remainder of a dose is excreted in the feces via biliary elimination. The half-life of spironolactone after a single dose is 1 to 2 hours. The half-life of canrenone ranges from 10 to 35 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5, CYP2C8
    Spironolactone is rapidly and extensively metabolized primarily by CYP3A4/5, and to a lesser extent by CYP2C8. In vitro studies also show that spironolactone is an irreversible inhibitor of CYP3A4/5 and CYP2C8.

    Oral Route

    Approximately 60% to 90% of a dose of spironolactone is absorbed from the GI tract after oral administration. The peak plasma concentration of spironolactone occurs 0.5 to 1.5 hours after administration; the Cmax of the active metabolite canrenone occurs 2.5 to 5 hours after dosing. For an equivalent dose, the oral suspension results in 15% to 37% higher serum concentrations compared to the tablets; information about dose proportionality is limited, and based on comparative studies, doses of oral suspension higher than 100 mg may result in higher than expected plasma concentrations. Food will enhance absorption when given concurrently. A high fat and high calorie meal increases bioavailability of the oral suspension by about 90%. There is considerable first-pass elimination and significant enterohepatic recirculation. The onset of diuresis is gradual, with peak effects occurring on the third day after administration.