Spironolactone Information
Spironolactone ()
Spironolactone ()
Spironolactone () Description
Spironolactone () Tablets USP, for oral administration contain 25 mg, 50 mg or 100 mg of the aldosterone antagonist Spironolactone () , 17-hydroxy-7α - mercapto-3-oxo-17α -pregn-4-ene-21-carboxylic acid γ-lactone acetate. The molecular formula is CH0S and is represented by the following structural formula:
Spironolactone () is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Inactive ingredients include calcium sulfate, corn starch, crospovidone, dextrose, hypromellose, magnesium stearate, maltodextrin, natural peppermint flavor, polydextrose, polyethylene glycol, povidone, silicon dioxide, titanium dioxide, triacetin.
Spironolactone () Clinical Pharmacology
Spironolactone () is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension.
Through its action in antagonizing the effect of aldosterone, Spironolactone () inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.
Spironolactone () has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism.
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 1.10, 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 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 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized Spironolactone () by almost 100%. The clinical importance of this finding is not known.
Spironolactone () Clinical Studies
Patients were randomized 1:1 to Spironolactone () 25 mg orally once daily or matching placebo. Follow-up visits and laboratory measurements (including serum potassium and creatinine) were performed every four weeks for the first 12 weeks, then every 3 months for the first year, and then every 6 months thereafter. Dosing could be withheld for serious hyperkalemia or if the serum creatinine increased to >4.0 mg/dL. Patients who were intolerant of the initial dosage regimen had their dose decreased to one tablet every other day at one to four weeks. Patients who were tolerant of one tablet daily at 8 weeks may have had their dose increased to two tablets daily at the discretion of the investigator.
The Randomized Spironolactone () Evaluation Study enrolled 1,663 patients (3% U.S.) at 195 centers in 15 countries between March 24, 1995, and December 31, 1996. The study population was primarily white (87%, with 7% black, 2% Asian, and 4% other), male (73%), and elderly (median age 67). The median ejection fraction was 0.26. Seventy percent were NYHA class III and 29% class IV. The presumed etiology of heart failure was ischemic in 55%, and non-ischemic in 45%. There was a history of myocardial infarction in 28%, of hypertension in 24%, and of diabetes in 22%. The median baseline serum creatinine was 1.2 mg/dL and the median baseline creatinine clearance was 57 mL/min. The mean daily dose at study end for the patients randomized to Spironolactone () was 26 mg.
Concomitant medications included a loop diuretic in 100% of patients and an ACE inhibitor in 97%. Other medications used at any time during the study included digoxin (78%), anticoagulants (58%), aspirin (43%), and beta-blockers (15%).
The primary endpoint for The Randomized Spironolactone () Evaluation Study was time to all-cause mortality. The Randomized Spironolactone () Evaluation Study was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. The survival curves by treatment group are shown in Figure 1.
Figure 1. Survival by Treatment Group in The Randomized Spironolactone () Evaluation Study
Spironolactone () reduced the risk of death by 30% compared to placebo (p
Spironolactone () also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias or myocardial infarction) by 30% (p
Mortality hazard ratios for some subgroups are shown in Figure 2. The favorable effect of Spironolactone () on mortality appeared similar for both genders and all age groups except patients younger than 55; there were too few non-whites in The Randomized Spironolactone () Evaluation Study to draw any conclusions about differential effects by race. Spironolactone () ’s benefit appeared greater in patients with low baseline serum potassium levels and less in patients with ejection fractions
Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup in The Randomized Spironolactone () Evaluation Study
Figure 2: The size of each box is proportional to the sample size as well as the event rate. ACEI denotes angiotensin-converting enzyme inhibitor, LVEF denotes left ventricular ejection fraction, Cr Clearance denotes creatinine clearance and Ser Creatinine denotes serum creatinine.
Spironolactone () Indications And Usage
Spironolactone () tablets are indicated in the management of:
Primary hyperaldosteronism
Short-term preoperative treatment of patients with primary hyperaldosteronism.
Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery.
Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).
Essential hypertension
Hypokalemia
Severe heart failure (NYHA class III - IV)
Usage In Pregnancy:
Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy.
Spironolactone () tablets are indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see ). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary.
There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
Spironolactone () Contraindications
Spironolactone () is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalemia.
Spironolactone () Warnings
Excessive potassium intake may cause hyperkalemia in patients receiving Spironolactone () (see ). Spironolactone () should not be administered concurrently with other potassium-sparing diuretics. Spironolactone () , when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when Spironolactone () is given concomitantly with these drugs.
Spironolactone () should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Lithium generally should not be given with diuretics (see ).
Spironolactone () Precautions
All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, eg, hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hyperkalemia.
Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with Spironolactone () .
Concomitant administration of potassium-sparing diuretics and ACE inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs), eg, indomethacin, has been associated with severe hyperkalemia.
If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.
If hyperkalemia is present, Spironolactone () 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 polysterene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.
Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.
Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be caused or aggravated, especially when Spironolactone () is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening.
Spironolactone () therapy may cause a transient elevation of BUN, especially in patients with preexisting renal impairment. Spironolactone () may cause mild acidosis.
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 () is discontinued. In rare instances some breast enlargement may persist when Spironolactone () is discontinued.
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, 100 and 150 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 20 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 the presence of metabolic activation, Spironolactone () has been reported to be negative in some mammalian mutagenicity tests and inconclusive (but slightly positive) for mutagenicity in other mammalian tests . In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests , inconclusive in others, and negative in still others.
In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg Spironolactone () /kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 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 two-week pos-treatment observation period. These effects were associated with retarted 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 two-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.
Spironolactone () Adverse Reactions
The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity.
Spironolactone () Overdosage
The oral LD of Spironolactone () is greater than 1,000 mg/kg in mice, rats, and rabbits.
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, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function.
Patients who have renal impairment may develop Spironolactone () -induced hyperkalemia. In such cases, Spironolactone () 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.
Spironolactone () Dosage And Administration
After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, Spironolactone () may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Spironolactone () may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.
Spironolactone () How Supplied
Spironolactone () Tablets, USP are available as follows:
25 mg ― Each white to off-white, round, film coated tablet, imprinted with on one side and 803 on the other side contains 25 mg of Spironolactone () , USP. (NDC 50268-726-15) 10 tablets per card, 5 cards per carton
50 mg — Each white to off-white, oval, film coated tablet, imprinted with and 672 on one side and partial bisect on the other side contains 50 mg of Spironolactone () , USP.
100 mg — Each white to off-white, round, film coated tablet, imprinted with and 673 on one side and bisect on the other side contains 100 mg of Spironolactone () , USP. Protect from light.
Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].
Manufactured by:Actavis Elizabeth LLC200 Elmora AvenueElizabeth, NJ 07207 USA
Distributed by:AvPAK615 North First StreetPulaski, TN 38478
Revised — May 2009AP05-11
Spironolactone () Package Label.principal Display Panel
NDC 50268-726-15 50 TABLETS (5 X 10)
NDC 50268-726-15 50 TABLETS (5 X 10)
EACH TABLET CONTAINS:Spironolactone () , USP....................25mg
USUAL ADULT DOSAGE: Four tablets daily or as recommended in attached literature.
Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].
Manufactured by: Actavis Elizabeth, LLCElizabeth, NJ 07207 USADistributed by: AvPAKPulaski, TN 38478
