Spironolactone and Hydrochlorothiazide

Spironolactone and hydrochlorothiazide is a prescription medication used to treat high blood pressure and fluid retention caused by various conditions. Spironolactone and hydrochlorothiazide is a single product containing 2 medications: spironolactone and hydrochlorothiazide. Spironolactone belongs to a group of drugs called diuretics ("water pills"). Specifically, it is a "potassium-sparing" diuretic known as an "aldosterone antagonist". By blocking aldosterone, spironolactone helps the body get rid of excess fluid  by increasing the amount of salt and water the kidneys remove from the blood, while still keeping potassium in the body. Hydrochlorothiazide belongs to a group of drugs called thiazide diuretics, which work by stopping reabsorption of salt into your body. This prevents fluid from building up in the body.

This medication comes in tablet form. It is typically given once daily with or without food.

Common side effects include nausea, vomiting, and headache.

Spironolactone and hydrochlorothiazide can cause dizziness and weakness. Do not drive or operate heavy machinery until you know how this medication affects you. 

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• ACE inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), quinapril (Accupril), and ramipril (Altace)
• angiotensin receptor II blockers such as azilsartan (Edarbi), candesartan (Atacand), irbesartan (Avapro), losartan (Cozaar), olmesartan (Benicar), telmisartan (Micardis, Twynsta), and valsartan (Diovan)
• medicines that block a substance in the body called aldosterone such as eplerenone (Inspra) and spironolactone (Aldactone)
• heparin (Hemochron, Hep-Lock)
• nonsteroidal anti-inflammatory medications such as ibuprofen (Motrin, Nuprin) or naproxen (Aleve) and salicylates
• corticosteroids such as prednisone, hydrocortisone (Cortef), and dexamethasone (Decadron, Dexone, Hexadrol)
• lithium (Eskalith, Lithobid)
• potassium products including potassium chloride (K-Dur, Klor-Con, Micro-K), potassium citrate (Urocit-K, Polycitra-K), potassium gluconate, potassium phosphate (Neutra-Phos-K, K-Phos)
• salt substitutes that contain potassium
• alcohol
• a group of pain medicines called narcotics such as oxycodone (Roxicodone, Oxycontin, Oxecta)
• barbiturates such as amobarbital (Amytal), butalbital (Fioricet, Fiorinal), phenobarbital (Luminal) and others
• digoxin (Digox, Lanoxin)
• substances that raise blood pressure (pressor amines) such as norepinephrine (Levophed)
• medicines that relax skeletal muscles such as cyclobenzaprine (Flexeril) and carisoprodol (Soma)
• cholestyramine (Questran)

This is not a complete list of spironolactone and hydrochlorothiazide drug interactions. Ask your doctor or pharmacist for more information.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of spironolactone and hydrochlorothiazide, salt substitutes containing potassium should be avoided. 

Tell your doctor is you are breastfeeding or plan to breastfeed. 

Spironolactone and hydrochlorothiazide has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from spironolactone and hydrochlorothiazide, a choice should be made whether to stop nursing or to stop use of this medication. The importance of the drug to the mother should be considered. 

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For spironolactone and hydrochlorothiazide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to spironolactone and hydrochlorothiazide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of spironolactone and hydrochlorothiazide combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of spironolactone and hydrochlorothiazide combination in geriatric patients.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking spironolactone and hydrochlorothiazide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using spironolactone and hydrochlorothiazide with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Dofetilide
• Eplerenone
• Triamterene

Using spironolactone and hydrochlorothiazide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aceclofenac
• Acemetacin
• Acetyldigoxin
• Alacepril
• Amphetamine
• Amtolmetin Guacil
• Arginine
• Arsenic Trioxide
• Aspirin
• Benazepril
• Benzphetamine
• Bromfenac
• Bufexamac
• Captopril
• Celecoxib
• Choline Salicylate
• Cilazapril
• Clonixin
• Cyclophosphamide
• Delapril
• Deslanoside
• Dexibuprofen
• Dexketoprofen
• Dextroamphetamine
• Diclofenac
• Diflunisal
• Digitalis
• Digitoxin
• Digoxin
• Dipyrone
• Droperidol
• Droxicam
• Enalaprilat
• Enalapril Maleate
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenoprofen
• Fepradinol
• Feprazone
• Flecainide
• Floctafenine
• Flufenamic Acid
• Flurbiprofen
• Fosinopril
• Ibuprofen
• Imidapril
• Indomethacin
• Ketanserin
• Ketoprofen
• Ketorolac
• Levomethadyl
• Lisdexamfetamine
• Lisinopril
• Lithium
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Methamphetamine
• Methotrexate
• Metildigoxin
• Moexipril
• Morniflumate
• Nabumetone
• Naproxen
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Ouabain
• Oxaprozin
• Oxyphenbutazone
• Parecoxib
• Pentopril
• Perindopril
• Phenylbutazone
• Piketoprofen
• Piroxicam
• Potassium
• Pranoprofen
• Proglumetacin
• Propyphenazone
• Proquazone
• Proscillaridin
• Quinapril
• Ramipril
• Rofecoxib
• Salicylic Acid
• Salsalate
• Sodium Salicylate
• Sotalol
• Spirapril
• Sulindac
• Temocapril
• Tenoxicam
• Tiaprofenic Acid
• Tolfenamic Acid
• Tolmetin
• Trandolapril
• Trimethoprim
• Valdecoxib
• Zofenopril

Using spironolactone and hydrochlorothiazide with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aminolevulinic Acid
• Bepridil
• Carbamazepine
• Cholestyramine
• Digitoxin
• Ginkgo
• Gossypol
• Licorice
• Topiramate

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of spironolactone and hydrochlorothiazide. Make sure you tell your doctor if you have any other medical problems, especially:

• Addison's disease (adrenal problem) or
• Anuria (not able to pass urine) or
• Hypercalcemia (high calcium in the blood) or
• Hyperkalemia (high potassium in the blood) or
• Kidney disease, severe or
• Liver disease, severe or
• Sulfa drug allergy, history of—Should not be used in patients with these conditions.

• Asthma, history of—May increase likelihood of having an allergic reaction.

• Diabetes or
• Electrolyte imbalances (eg, low chloride, magnesium, potassium, or sodium in the body) or
• Fluid imbalances (caused by dehydration, vomiting, or diarrhea) or
• Glaucoma, secondary angle-closure or
• Gout or
• Hyperlipidemia (high cholesterol or fats in the blood) or
• Kidney disease or
• Liver disease or
• Myopia (changes in the eyeball causing vision problems), acute or
• Systemic lupus erythematosus (SLE)—Use with caution. May make these conditions worse.

• Sympathectomy—Blood pressure–lowering effects of spironolactone and hydrochlorothiazide may be increased.

Mechanism of Action

Spironolactone and Hydrochlorothiazide is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component.

The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Hydrochlorothiazide promotes the excretion of sodium and water primarily by inhibiting their reabsorption in the cortical diluting segment of the distal renal tubule.

Spironolactone and Hydrochlorothiazide is effective in significantly lowering the systolic and diastolic blood pressure in many patients with essential hypertension, even when aldosterone secretion is within normal limits.

Both Spironolactone and Hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. The diuretic and antihypertensive effects of the individual components are potentiated when Spironolactone and Hydrochlorothiazide are given concurrently.

Pharmacokinetics

Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (as tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a low fat breakfast and blood was drawn thereafter.

The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.1, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively.

In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities.

Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile.

The effect of food on spironolactone absorption (two 100 mg spironolactone tablets) was assessed in a single-dose study of nine healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known.

Hydrochlorothiazide is rapidly absorbed following oral administration. Onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. Hydrochlorothiazide plasma concentrations attain peak levels at 1 to 2 hours and decline with a half-life of 4 to 5 hours. Hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. It is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney.

General

Spironolactone can cause hyperkalemia. The risk of hyperkalemia may be increased in patients with renal insufficiency, diabetes mellitus or with concomitant use of drugs that raise serum potassium (see Drug Interactions). Hydrochlorothiazide can cause hypokalemia and hyponatremia. The risk of hypokalemia may be increased in patients with cirrhosis, brisk diuresis, or with concomitant use of drugs that lower serum potassium. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Spironolactone and Hydrochlorothiazide.

Gynecomastia may develop in association with the use of spironolactone; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when Spironolactone and Hydrochlorothiazide is discontinued. In rare instances, some breast enlargement may persist when Spironolactone and Hydrochlorothiazide is discontinued.

Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

Information for Patients

Patients who receive Spironolactone and Hydrochlorothiazide should be advised to avoid potassium supplements and foods containing high levels of potassium including salt substitutes.

Laboratory Tests

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments.

Drug Interactions

Concomitant administration may lead to severe hyperkalemia.

Potentiation of orthostatic hypotension may occur.

(e.g., oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required (see PRECAUTIONS).

Intensified electrolyte depletion, particularly hypokalemia, may occur.

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.

Possible increased responsiveness to the muscle relaxant may result.

Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

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 and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

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).

Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine.

Drug/Laboratory Test Interactions

Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS: General). Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function.

Several reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay specific) has been fully established.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150, and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, and 100 mg spironolactone/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females.

A dose-related (above 30 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of one year. In two year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors.

Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others.

In a three-litter reproduction study in which female rats received dietary doses of 15 and 500 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 500 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a 2-week posttreatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility, and fecundity. Spironolactone (100 mg/kg/day), administered i.p. to female mice during a 2-week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating.

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Pregnancy

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 embryotoxic 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 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 in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus.

Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier and appear in cord blood. Therefore, the use of Spironolactone and Hydrochlorothiazide 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 during breast feeding is not recommended. If Spironolactone and Hydrochlorothiazide is used during breast feeding, doses should be kept as low as possible.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity.

Hydrochlorothiazide

Body as a whole: Weakness.

Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, or antihypertensive drugs).

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialoadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

Eye Disorders: acute myopia and acute angle-closure glaucoma (see WARNINGS).

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Anaphylactic reactions, necrotizing angitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.

Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal: Muscle spasm.

Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness.

Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS).

Skin: Erythema multiforme, pruritus.

Special Senses: Transient blurred vision, xanthopsia.

Spironolactone

Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.

Reproductive: Gynecomastia (see PRECAUTIONS), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. Carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established.

Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia.

Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis.

Metabolism:Hyperkalemia, electrolyte disturbances (see WARNINGS and PRECAUTIONS).

Musculoskeletal:Leg cramps.

Nervous System/Psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness.

Liver/Biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.

Renal: Renal dysfunction (including renal failure).

Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritus.  

The oral LD 50 of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia (less commonly seen with Spironolactone and Hydrochlorothiazide because the hydrochlorothiazide component tends to produce hypokalemia), or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage.

However, because Spironolactone and Hydrochlorothiazide tablets contain both Spironolactone and Hydrochlorothiazide, the toxic effects may be intensified, and signs of thiazide overdosage may be present. These include electrolyte imbalance such as hypokalemia and/or hyponatremia. The potassium-sparing action of spironolactone may predominate and hyperkalemia may occur, especially in patients with impaired renal function. BUN determinations have been reported to rise transiently with hydrochlorothiazide. There may be CNS depression with lethargy or even coma.

Treatment

Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions.

Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, Spironolactone and Hydrochlorothiazide should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

Optimal dosage should be established by individual titration of the components (see BOXED WARNING).

Edema in Adults (Congestive Heart Failure, Hepatic Cirrhosis or Nephrotic Syndrome)

The usual maintenance dose of Spironolactone and Hydrochlorothiazide tablets is 100 mg each of Spironolactone and Hydrochlorothiazide daily, administered in a single dose or in divided doses, but may range from 25 mg to 200 mg of each component daily depending on the response to the initial titration. In some instances it may be desirable to administer separate tablets of either spironolactone or hydrochlorothiazide in addition to Spironolactone and Hydrochlorothiazide tablets in order to provide optimal individual therapy.

The onset of diuresis with Spironolactone and Hydrochlorothiazide tablets occurs promptly and, due to prolonged effect of the spironolactone component, persists for 2 to 3 days after Spironolactone and Hydrochlorothiazide tablets are discontinued.

Essential Hypertension

Although the dosage will vary depending on the results of titration of the individual ingredients, many patients will be found to have an optimal response to 50 mg to 100 mg each of Spironolactone and Hydrochlorothiazide daily, given in a single dose or in divided doses.

Concurrent potassium supplementation is not recommended when Spironolactone and Hydrochlorothiazide tablets are used in the long-term management of hypertension or in the treatment of most edematous conditions, since the spironolactone content of Spironolactone and Hydrochlorothiazide tablets is usually sufficient to minimize loss induced by the hydrochlorothiazide component.