Spironolactone (Page 4 of 5)

Absorption

The mean time to reach peak plasma concentration of spironolactone and the active metabolite, canrenone, in healthy volunteers is 2.6 and 4.3 hours, respectively.

Effect of Food

Food increased the bioavailability of spironolactone (as measured by AUC) by approximately 95.4%. Patients should establish a routine pattern for taking spironolactone tablets with regard to meals [see Dosage and Administration (2.1)] .

Distribution

Spironolactone and its metabolites are more than 90% bound to plasma proteins.

Elimination

The mean half-life of spironolactone is 1.4 hour. The mean half-life values of its metabolites including canrenone, 7-α-(thiomethyl) spirolactone (TMS), and 6-ß-hydroxy-7-α-(thiomethyl) spirolactone (HTMS) are 16.5, 13.8, and 15 hours, respectively.

Metabolism

Spironolactone is rapidly and extensively metabolized. Metabolites can be divided into two main categories: those in which sulfur of the parent molecule is removed (e.g., canrenone) and those in which the sulfur is retained (e.g., TMS and HTMS). In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were approximately a third 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.

Excretion

The metabolites are excreted primarily in the urine and secondarily in bile.

Specific Populations

The impact of age, sex, race/ethnicity, and renal impairment on the pharmacokinetics of spironolactone have not been specifically studied.

Patients with Hepatic Impairment

The terminal half-life of spironolactone has been reported to be increased in patients with cirrhotic ascites [see Use in Specific Populations (8.7)] .

Drug Interaction Studies

Drugs and Supplements Increasing Serum Potassium

Concomitant administration of spironolactone tablets with potassium supplementation, salt substitutes containing potassium, a diet rich in potassium, or drugs that can increase potassium, including ACE inhibitors, angiotensin II antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparin and low molecular weight heparin, may lead to severe hyperkalemia [see Warnings and Precautions (5.1) and Drug Interactions (7.1)] .

Lithium

Spironolactone tablets reduce the renal clearance of lithium, inducing a high risk of lithium toxicity [see Warnings and Precautions (5.1) and Drug Interactions (7.2)] .

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing, and thiazide diuretics [see Drug Interactions (7.3)] .

Acetylsalicylic Acid

A single dose of 600 mg of acetylsalicylic acid inhibited the natriuretic effect of spironolactone, which was hypothesized be due to inhibition of tubular secretion of canrenone, causing decreased effectiveness of spironolactone [see Drug Interactions (7.6)] .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Orally administered spironolactone tablets have 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 tablets/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. No increased tumors were seen at doses of 100 mg/kg/day. This dose represents about 5X the human recommended daily dose of 200 mg/day, when based on body surface area.

Mutagenesis

Neither spironolactone tablets nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone tablets nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone tablets have 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.

Impairment of Fertility

In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg spironolactone tablets/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 tablets were found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two-week post-treatment 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 tablets (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.

14 CLINICAL STUDIES

14.1 Heart Failure

The Randomized Spironolactone Evaluation Study was a placebo controlled, double-blind study of the effect of spironolactone on mortality in patients with highly symptomatic heart failure and reduced ejection fraction. To be eligible to participate patients had to have an ejection fraction of ≤ 35%, NYHA class III-IV symptoms, and a history of NYHA class IV symptoms within the last 6 months before enrollment. Patients with a baseline serum creatinine of > 2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of > 5.0 mEq/L were excluded.

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.

The initial dose of spironolactone was 25 mg once daily. Patients who were intolerant of the initial dosage regimen had their dose decreased to one 25 mg 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 50 mg daily at the discretion of the investigator. The mean daily dose at study end for patients randomized to spironolactone was 26 mg.

1663 patients were randomized 1:1 to spironolactone or placebo. 87% of patients were white, 7% black, 2% Asian. 73% were male and median age was 67. The median ejection fraction was 26%. 70% were NYHA class III and 29% class IV. The 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.

At baseline 100% of patients were taking loop diuretic and 95% were taking an ACE inhibitor. 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 because of significant mortality benefit demonstrated during a planned interim analysis. Compared to placebo, spironolactone reduced the risk of death by 30% (p < 0.001; 95% confidence interval 18% to 40%). Spironolactone also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias, or myocardial infarction) by 30% (p < 0.001; 95% confidence interval 18% to 41%).

The survival curves by treatment group are shown in Figure 1.

Figure 1. Survival by Treatment Group in the Randomized Spironolactone Evaluation Study

Figure 1. Survival by Treatment Group in the Randomized Spironolactone Evaluation Study
(click image for full-size original)

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 evaluate if the effects differ by race. Spironolactone’s benefit appeared greater in patients with low baseline serum potassium levels and less in patients with ejection fractions < 0.2. These subgroup analyses must be interpreted cautiously.

Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup in the Randomized Spironolactone Evaluation Study

Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup in the Randomized Spironolactone Evaluation Study
(click image for full-size original)

Figure 2: The size of each box is proportional to the sample size as well as the event rate. LVEF denotes left ventricular ejection fraction, Ser Creatinine denotes serum creatinine, Cr Clearance denotes creatinine clearance, and ACEI denotes angiotensin-converting enzyme inhibitor.

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