Spironolactone (Page 4 of 5)

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 Randomized Spironolactone Evaluation Study was time to all-cause mortality. 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 Randomized Spironolactone Evaluation Study

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

Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup in 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.

14.2 Hypertension

The dose response of spironolactone for hypertension has not been well characterized. In patients with hypertension, decreases in systolic blood pressure have been observed at doses ranging from 25 mg/day to 100 mg/day. Doses greater than 100 mg/day generally do not provide additional reductions in blood pressure [see Dosage and Administration (2.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING

Spironolactone Tablets USP, 25 mg are white to off-white, round, biconvex, film-coated tablets debossed with ‘660’ on one side and plain on the other side and are supplied as follows:
Unit dose packages of 100 (10 x 10) NDC 60687-465-01

Spironolactone Tablets USP, 50 mg are white to off-white, oval shaped, biconvex, film-coated tablets debossed with ‘661’ on the scored side and plain on the other side and are supplied as follows:
Unit dose packages of 100 (10 x 10) NDC 60687-476-01

Spironolactone Tablets USP, 100 mg are white to off-white, round, biconvex, film-coated tablets debossed with ‘662’ on one side and scored on the other side and are supplied as follows:
Unit dose packages of 100 (10 x 10) NDC 60687-487-01

Storage
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

17 PATIENT COUNSELING INFORMATION

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

PACKAGING INFORMATION

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Zydus Pharmaceuticals (USA) Inc. as follows:
(25 mg / 100 UD) NDC 60687-465-01 packaged from NDC 68382-660
(50 mg / 100 UD) NDC 60687-476-01 packaged from NDC 68382-661
(100 mg / 100 UD) NDC 60687-487-01 packaged from NDC 68382-662

Distributed by:
American Health Packaging Columbus, OH 43217

8446501/0623F

Package/Label Display Panel – Carton – 25 mg

25 mg Spironolactone Tablets 100UD Carton
(click image for full-size original)

NDC 60687- 465 -01

Spironolactone
Tablets, USP

25 mg

100 Tablets (10 x 10)                 Rx Only

Each Film Coated Tablet Contains:
Spironolactone, USP……………………………………………………….. 25 mg

Usual Dosage: See package insert for full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions permitted between
15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Protect from light.

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

The drug product contained in this package is from
NDC # 68382-660, Zydus Pharmaceuticals (USA) Inc.

Distributed by:
American Health Packaging
Columbus, Ohio 43217

746501 0446501/0222

Package/Label Display Panel – Blister – 25 mg

25 mg Spironolactone Tablet 100 Blister
(click image for full-size original)

Spironolactone Tablet, USP

25 mg

Package/Label Display Panel – Carton – 50 mg

50 mg Spironolactone Tablets 100UD Carton
(click image for full-size original)

NDC 60687- 476 -01

Spironolactone
Tablets, USP

50 mg

100 Tablets (10 x 10)                 Rx Only

Each Film Coated Tablet Contains:
Spironolactone, USP …………………………………………….50 mg

Usual Dosage: See package insert for full prescribing
information.

Store at 20° to 25°C (68° to 77°F); excursions permitted
between 15° to 30°C (59° to 86°F) [see USP Controlled
Room Temperature].
Protect from light.

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or
broken.

The drug product contained in this package is from
NDC # 68382-661, Zydus Pharmaceuticals (USA) Inc.

Distributed by:
American Health Packaging
Columbus, Ohio 43217

747601 0447601/0222

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