Hydrochlorothiazide / spironolactone Side Effects
Some side effects of hydrochlorothiazide / spironolactone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.
For the Consumer
Applies to hydrochlorothiazide / spironolactone: oral tablet
Get emergency medical help if you have any of these signs of an allergic reaction while taking hydrochlorothiazide / spironolactone: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Stop using this medication and call your doctor at once if you have a serious side effect such as:
eye pain, vision problems;
numbness or tingly feeling;
muscle pain or weakness;
slow, fast, or uneven heartbeat;
feeling drowsy, restless, or light-headed;
urinating less than usual or not at all;
nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.
Less serious side effects of hydrochlorothiazide / spironolactone may include:
mild nausea or vomiting;
gas, stomach pain; or
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.
For Healthcare Professionals
Applies to hydrochlorothiazide / spironolactone: oral tablet
Metabolic side effects of HCTZ are common, especially when doses greater than 50 mg per day are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50% of patients, and may predispose patients to cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, and elevated serum uric acid levels are also relatively common. Hydrochlorothiazide (HCTZ) may increase serum cholesterol.
Metabolic abnormalities are the most common side effects of spironolactone. Hyperkalemia is reported in approximately 10% of patients, which has caused intermittent muscle paralysis and death in rare cases. Hyponatremia is reported in 12% of patients. Hyponatremia may be more likely in patients with severe liver disease due to the nonosmotic release of antidiuretic hormone (ADH).
Since HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, and VLDL lipoprotein cholesterol levels by 50%, and may reduce insulin secretion, it should be used with caution in diabetic patients and in those with hypercholesterolemia. True glucose intolerance may develop in approximately 3% of patients. It is typically reversible within six months after discontinuation of therapy.
Hyperuricemia may be an important consideration in patients with a history of gout. Hypophosphatemia and low serum magnesium concentrations may occur, but are usually clinically insignificant except in malnourished patients.
A prospective study of 34 patients who received oral thiazide diuretics for 14 years without interruption revealed an increased mean fasting blood glucose level after treatment. Withdrawal of thiazide therapy for seven months in 10 of the patients resulted in mean reductions of 10% in fasting blood glucose and 25% in the 2-hour glucose tolerance test value. A control group was not reported.
Spironolactone interferes with 17-hydroxylase activity, which causes a decrease in testosterone synthesis. It also inhibits the intracellular binding of dihydrotestosterone to its receptor.
Rare cases of young women with liver disease who developed menarche only after spironolactone was discontinued are reported. Since estradiol synthesis is partially dependent on testosterone synthesis, spironolactone may cause primary or secondary amenorrhea in adolescents.
Endocrinologic problems associated with thiazide diuretics include glucose intolerance and a potentially deleterious effect on the lipid profile. This may be important in some patients with or who are at risk for diabetes or coronary artery disease. A single case of recurrent parathyroid adenoma is reported, although the association is probably coincidental.
Endocrinologic side effects of spironolactone are due to its antiandrogenic properties. Five percent to 30% of male patients complain of gynecomastia, impotence or diminished libido. Gynecomastia may be more likely in some male patients with liver disease due to the increased conversion of androgens to estrogens in severe liver disease. Female patients report hirsutism, oligomenorrhea, amenorrhea, menorrhagia, and breast tenderness. These side effects appear to be dose-related, and are more likely during long-term therapy.
Although hydrochlorothiazide has been used to treat nephrogenic diabetes insipidus, a case report in which the drug was believed to have caused this condition has been reported.
Renal insufficiency, manifested as an increase in serum creatinine and BUN may occur due to intravascular volume depletion induced by HCTZ-spironolactone. Rare cases of interstitial nephritis with HCTZ have been reported.
Hypersensitivity to HCTZ (usually nausea, vomiting, diarrhea, and rash) has been reported in less than 1% of patients. Rare cases of acute pulmonary edema, interstitial cystitis, and interstitial nephritis, and anaphylaxis have been reported.
Hypersensitivity to spironolactone is rare. Rashes occur in about 1% of patients. Rare cases of eosinophilia, contact dermatitis and anaphylaxis are reported.
There have been approximately 34 known cases of thiazide-induced pulmonary edema, encompassing 52 episodes of pulmonary edema, as of 1991 (per a 1996 review). In some cases, doses as small as 12.5 mg were associated with the development of pulmonary edema. The average time to onset of this adverse reaction is 44 minutes, women carry a relative risk of 9:1, and the average age is 56 years. The mortality rate is 6%. Some experts consider this side effect grossly underreported. One reported case involved a 44-year-old woman who developed acute pulmonary edema, disseminated intravascular coagulation, and a generalized rash within 30 minutes of ingesting a single spironolactone-hydrochlorothiazide tablet. An inadvertent rechallenge resulted in the same sequelae.
Dermatologic reactions of HCTZ include case reports of erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus is associated with HCTZ.
Dermatologic side effects of spironolactone occur in less than 5% of patients, and include rare cases of lichen planus and a lupus-like syndrome.
Postmarketing dermatologic side effects have included Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS).
A 67-year-old woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion and personality changes associated with a new positive ANA and anti-nRNP, and a skin biopsy consistent with lupus erythematosus while taking hydrochlorothiazide (HCTZ), levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.
In a patient receiving spironolactone, histology of an associated lupoid eruption was consistent with lupus erythematosus, including immune deposits at the dermal-epidermal junction was observed. There was a striking absence of serologic signs of lupus, however, and the rash resolved after spironolactone was discontinued.
The incidence of premature ventricular contractions with HCTZ as measured by 48-hour ambulatory ECG monitoring is the same in both patients with and without left ventricular hypertrophy despite a similar fall in serum potassium concentrations.
Cases of hyperkalemia associated with fatal and refractory ventricular fibrillation are reported during spironolactone therapy.
Cardiac arrhythmias, including ventricular ectopy and complete AV heart block, are associated with hypokalemia and hyponatremia due to HCTZ. However, the addition of the potassium-sparing agent spironolactone to HCTZ may reduce the incidence of hypokalemia associated adverse cardiac effects. Hypotension has been reported in association with HCTZ-induced pulmonary edema. Orthostatic hypotension may occur and may rarely be associated with syncope, particularly in the elderly.
Cardiovascular side effects of spironolactone are limited mainly to hypovolemia, although the risk of hyperkalemia associated spironolactone may be important, especially in some patients with heart disease. However, with the combination product of HCTZ-spironolactone a more normalized potassium concentration may be maintained.
Thiazide diuretics may increase serum cholesterol and triglycerides, resulting in increased risk of cholesterol gallstone formation. Reports of bowel strictures associated with thiazide ingestion have been reported in the 1960's although these patients were on a combination hydrochlorothiazide-potassium product.
Gastrointestinal side effects of HCTZ are unusual, and include case reports of pancreatitis and acute cholecystitis.
Gastrointestinal complaints of spironolactone are usually minor. General abdominal discomfort, diarrhea, and vomiting are reported in less than 5% of patients.
Respiratory side effects of HCTZ are rare, and include approximately 30 case reports of acute noncardiogenic pulmonary edema. These cases are thought to be due to idiosyncrasy or a hypersensitivity mechanism.
There are rare case reports of hydrochlorothiazide-induced immune hemolytic anemia. The following illustrates a fatal case:
A 53-year-old man with hypertension developed nausea, vomiting, diarrhea, and progressive anorexia and weakness associated with scleral icterus, anemia with spherocytosis, dark red urine with proteinuria, bilirubinuria, hemoglobinuria, and elevated lactic dehydrogenase levels 18 months after beginning hydrochlorothiazide and methyldopa. Haptoglobin was less than 50 mg per dl. Direct and indirect Coombs tests were positive. The patient died suddenly; autopsy revealed no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.
Immunologic side effects of HCTZ are rare, and include case reports of allergic vasculitis and hemolytic anemia. There are numerous case reports of patients developing a rash histologically identical to subacute cutaneous lupus following HCTZ administration.
Hematologic side effects of HCTZ are rare. Cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been reported.
Hematologic problems of spironolactone are also rare, and include case reports of reversible leukopenia and agranulocytosis.
Some cases of agranulocytosis reported in patients receiving spironolactone are associated with a normal bone marrow, suggesting peripheral destruction of white blood cells, while some cases of agranulocytosis have been associated with bone marrow hypocellularity of the myelocytic cell lines.
Musculoskeletal side effects of HCTZ are unusual, and include case reports of myalgias and chills.
Hepatic toxicity associated with spironolactone is extremely rare. Two cases of hepatitis with a strong association to spironolactone use have been reported.
A 53-year-old woman with aldosteronism secondary to an adrenal adenoma developed reversible hepatitis during spironolactone therapy. The syndrome resolved upon drug discontinuation, and was reproducible on rechallenge. The authors did not find signs or symptoms of hypersensitivity to the drug.
A 74-year-old man with edema, minimal alcohol consumption (less than 30 g/day), and no history of liver or biliary disease became icteric 7 weeks after beginning spironolactone therapy. Liver biopsy revealed cholestatic lesions with many biliary thrombi and overloaded centrolobular cells, damaged hepatocytes, and focal necrosis. Infectious hepatitis was serologically excluded. All liver function abnormalities normalized 3 months after discontinuing spironolactone. The authors of this case report point out the structural similarity between spironolactone and steroids, drugs which are associated with cholestatic liver injury.
Nervous system side effects including cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction.
Oncologic side effects of spironolactone probably do not exist. Isolated case reports of tumorogenesis associated with spironolactone have not been substantiated in large studies.
Animal studies have suggested an association between spironolactone with benign adenomas of the thyroid and testes, malignant breast tumors, proliferative changes in the liver, including hepatocellular carcinoma, and leukemia. Dosages used in these studies were 25 to 250 times the maximum recommended human dosage (on a per kg basis).
Ocular side effects have included idiosyncratic reactions to the hydrochlorothiazide component resulting in acute transient myopia and acute angle-closure glaucoma.
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