Spironolactone and hydrochlorothiazide

Drug interactions ACE inhibitors, Angiotensin II receptor antagonists, aldosterone blockers, potassium supplements, heparin, low molecular weight heparin, and other drugs known to cause hyperkalemia: Concomitant administration may lead to severe hyperkalemia. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (e.g., oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required (see Precautions ). Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur.

Pressor amines (e.g., norepinephrine): Both spironolactone and hydrochlorothiazide reduce the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with spironolactone and hydrochlorothiazide tablets. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result. Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when spironolactone and hydrochlorothiazide tablets and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Acetylsalicylic acid: Acetylsalicylic acid may reduce the efficacy of spironolactone.

Therefore, when spironolactone and hydrochlorothiazide and acetylsalicylic acid are used concomitantly, spironolactone and hydrochlorothiazide tablets may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained. Digoxin: Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. Monitor serum digoxin levels and adjust dose accordingly. Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (see Precautions ).

Cholestyramine: Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine. Abiraterone: Spironolactone binds to the androgen receptor and may increase prostate‑specific antigen (PSA) levels in abiraterone-treated prostate cancer patients. Concomitant use of spironolactone is not recommended. Mitotane: Avoid concomitant use of spironolactone and hydrochlorothiazide tablets and mitotane. Spironolactone reduces mitotane plasma levels.

The effect of concomitant spironolactone on the pharmacokinetics of mitotane has not been studied; however, patients exhibited significantly lower mitotane levels compared to those who did not receive concomitant spironolactone despite receiving higher mitotane doses.

Pregnancy Teratogenic effects Hydrochlorothiazide Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Spironolactone Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose.

No teratogenic or other embryo-toxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed.

Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone 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. There are no adequate and well-controlled studies with spironolactone and hydrochlorothiazide tablets in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia.

Therefore, the use of spironolactone and hydrochlorothiazide tablets in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus. Non-teratogenic effects Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier and appear in cord blood. Therefore, the use of spironolactone and hydrochlorothiazide tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. The hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Nursing mothers Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted. Thiazides are excreted in human milk in small amounts. Thiazides when given at high doses can cause intense diuresis which can in turn inhibit milk production. The use of spironolactone and hydrochlorothiazide tablets during breast feeding is not recommended.

If spironolactone and hydrochlorothiazide tablets are used during breast feeding, doses should be kept as low as possible.