SPIRONOLACTONE- spironolactone tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
SPIRONOLACTONE (UNII: 27O7W4T232) (SPIRONOLACTONE - UNII:27O7W4T232)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Spironolactone tablets are indicated for treatment of NYHA Class III–IV heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure. Spironolactone tablets are usually administered in conjunction with other heart failure therapies. Spironolactone tablets are indicated as add-on therapy for the treatment of hypertension, to lower blood pressure in patients who are not adequately controlled on other agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one dru
Product summary:
Product: 63629-8132 NDC: 63629-8132-1 30 TABLET, FILM COATED in a BOTTLE Product: 63629-8133 NDC: 63629-8133-1 30 TABLET, FILM COATED in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8132-1, 63629-8133-1

SPIRONOLACTONE- spironolactone tablet, film coated

Bryant Ranch Prepack

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use SPIRONOLACTONE TABLETS safely and

effectively. See full prescribing information for SPIRONOLACTONE TABLETS.

SPIRONOLACTONE (spironolactone) tablets for oral use

Initial U.S. Approval: 1960

INDICATIONS AND USAGE

Spironolactone is an aldosterone antagonist indicated for:

The treatment of NYHA Class III–IV heart failure and reduced ejection fraction to increase survival, manage edema,

and to reduce the need for hospitalization for heart failure ( 1.1)

Use as an add-on therapy for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces

the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.2)

The management of edema in adult patients who are cirrhotic when edema is not responsive to fluid and sodium

restrictions and in the setting of nephrotic syndrome when treatment of the underlying disease, restriction of fluid and

sodium intake, and the use of other diuretics produce an inadequate response ( 1.3).

Treatment of primary hyperaldosternism for: ( 1.4)

Short-term preoperative treatment

Long-term maintenance for patients with discrete aldosterone-producing adrenal adenomas who are not candidates

for surgery and patients with bilateral micro or macronodular adrenal hyperplasia

DOSAGE AND ADMINISTRATION

Heart Failure: Initiate treatment at 25 mg once daily ( 2.2).

Hypertension: Initiate treatment at 25 to 100 mg daily in either single or divided doses ( 2.3).

Edema: Initiate therapy in a hospital setting and titrate slowly. The recommended initial daily dose is 100 mg in single

or divided doses ( 2.4).

Primary hyperaldosteronism: Initiate treatment at 100 to 400 mg in preparation for surgery. In patients unsuitable for

surgery use the lowest effective dosage determined for the individual patient ( 2.5).

DOSAGE FORMS AND STRENGTHS

Tablets: 25 mg, 50 mg, and 100 mg ( 3)

CONTRAINDICATIONS

Spironolactone tablets are contraindicated in patients with ( 4):

Hype rkale mia

Addison's disease

Concomitant use of eplerenone

WARNINGS AND PRECAUTIONS

Hyperkalemia: Monitor serum potassium within one week of initiation and regularly thereafter ( 5.1).

Hypotension and Worsening Renal Function: Monitor volume status and renal function periodically ( 5.2).

Electrolyte and Metabolic Abnormalities: Monitor serum electrolytes, uric acid and blood glucose periodically ( 5.3).

Gynecomastia: Spironolactone can cause gynecomastia ( 5.4).

ADVERSE REACTIONS

The most common adverse reaction with spironolactone treatment is gynecomastia ( 5.4, 6).

To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare, Inc. at 1866-941-7875 or

www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Agents increasing serum potassium: Concomitant administration can lead to hyperkalemia ( 5.1, 7.1).

Lithium: Increased risk of lithium toxicity ( 7.2).

NSAIDs: May reduce the diuretic, natriuretic and antihypertensive effect of spironolactone ( 7.3).

Digoxin: spironolactone can interfere with radioimmunologic assays of digoxin exposure ( 7.4).

Cholestyramine: Hyperkalemic metabolic acidosis has been reported with concomitant use ( 7.5).

Acetylsalicylic Acid (ASA): ASA may reduce the efficacy of spironolactone ( 7.6).

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, spironolactone may affect sex differentiation of the male during embryogenesis ( 8.1)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Heart Failure

1.2 Hypertension

1.3 Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome

1.4 Primary Hyperaldosteronism

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

2.2 Treatment of Heart Failure

2.3 Treatment of Essential Hypertension

2.4 Treatment of Edema

2.5 Treatment of Primary Hyperaldosteronism

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hyperkalemia

5.2 Hypotension and Worsening Renal Function

5.3 Electrolyte and Metabolic Abnormalities

5.4 Gynecomastia

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

7.1 Drugs and Supplements Increasing Serum Potassium

7.2 Lithium

7.3 Nonsteroidal anti-inflammatory drugs (NSAIDs)

7.4 Digoxin

7.5 Cholestyramine

7.6 Acetylsalicylic Acid

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Use in Renal Impairment

8.7 Use in Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Heart Failure

14.2 Hypertension

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Heart Failure

Spironolactone tablets are indicated for treatment of NYHA Class III–IV heart failure and reduced

ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart

failure.

Spironolactone tablets are usually administered in conjunction with other heart failure therapies.

1.2 Hypertension

Spironolactone tablets are indicated as add-on therapy for the treatment of hypertension, to lower blood

pressure in patients who are not adequately controlled on other agents. Lowering blood pressure

reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial

infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide

variety of pharmacologic classes.

Control of high blood pressure should be part of comprehensive cardiovascular risk management,

including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,

exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood

pressure goals. For specific advice on goals and management, see published guidelines, such as those

of the National High Blood Pressure Education Program's Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different

mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular

morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other

pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and

most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions

in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk

increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe

hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is

similar across populations with varying absolute risk, so the absolute benefit is greater in patients who

are at higher risk independent of their hypertension (for example, patients with diabetes or

hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a

lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and

many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart

failure, or diabetic kidney disease). These considerations may guide selection of therapy.

1.3 Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome

Sections or subsections omitted from the full prescribing information are not listed.

Spironolactone tablets are indicated for the management of edema in the following settings:

Cirrhosis of the liver when edema is not responsive to fluid and sodium restriction.

Nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake,

and the use of other diuretics produce an inadequate response.

Because it increases serum potassium, spironolactone tablets may be useful for treating edema when

administration of other diuretics has caused hypokalemia.

1.4 Primary Hyperaldosteronism

Spironolactone tablets are indicated in the following settings:

Short-term preoperative treatment of patients with primary hyperaldosteronism.

Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas

who are not candidates for surgery.

Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia

(idiopathic hyperaldosteronism).

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

Spironolactone tablets can be taken with or without food, but should be taken consistently with respect

to food [see Clinical Pharmacology (12.3)] .

2.2 Treatment of Heart Failure

In patients with serum potassium ≤5.0 mEq/L and eGFR >50 mL/min/1.73 m

, initiate treatment at 25 mg

once daily. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily

as clinically indicated. Patients who develop hyperkalemia on 25 mg once daily may have their dosage

reduced to 25 mg every other day [see Warnings and Precautions (5.1)] . In patients with an eGFR

between 30 and 50 mL/min/1.73 m

, consider initiating therapy at 25 mg every other day because of the

risk of hyperkalemia [see Use in Specific Populations (8.6)].

2.3 Treatment of Essential Hypertension

The recommended initial daily dose is 25 to 100 mg of spironolactone tablets administered in either

single or divided doses is recommended. Dosage can be titrated at two-week intervals. Doses greater

than 100 mg/day generally do not provide additional reductions in blood pressure.

2.4 Treatment of Edema

In patients with cirrhosis, initiate therapy in a hospital setting and titrate slowly [see Use in Specific

Populations (8.7)] . The recommended initial daily dosage is 100 mg of spironolactone tablets

administered in either single or divided doses, but may range from 25 to 200 mg daily. When given as

the sole agent for diuresis, administer for at least five days before increasing dose to obtain desired

effect.

2.5 Treatment of Primary Hyperaldosteronism

Administer spironolactone tablets in doses of 100 to 400 mg daily in preparation for surgery. For

patients who are considered unsuitable for surgery, spironolactone tablets can be used as long-term

maintenance therapy at the lowest effective dosage determined for the individual patient.

3 DOSAGE FORMS AND STRENGTHS

Spironolactone tablets USP 25 mg are light yellow to yellow colored, round, biconvex, film coated

tablets with inscription “AD” on one side and plain on the other side having faint odour of peppermint.

Spironolactone tablets USP 50 mg are light orange to orange colored, oval, biconvex, film coated

tablets with inscription “AE” on one side and breakline on the other side having faint odour of

peppermint.

Spironolactone tablets USP 100 mg are light peach to peach colored, round, biconvex, film coated

tablets with inscription “AF” on one side and breakline on the other side having faint odour of

peppermint.

4 CONTRAINDICATIONS

Spironolactone tablets are contraindicated in the patients with:

Hyperkalemia

Addison's disease

Concomitant use of eplerenone

5 WARNINGS AND PRECAUTIONS

5.1 Hyperkalemia

Spironolactone can cause hyperkalemia. This risk is increased by impaired renal function or

concomitant potassium supplementation, potassium-containing salt substitutes or drugs that increase

potassium, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers [see

Drug Interactions (7.1)] .

Monitor serum potassium within 1 week of initiation or titration of spironolactone and regularly

thereafter. More frequent monitoring may be needed when spironolactone is given with other drugs that

cause hyperkalemia or in patients with impaired renal function.

If hyperkalemia occurs, decrease the dose or discontinue spironolactone and treat hyperkalemia.

5.2 Hypotension and Worsening Renal Function

Excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function,

particularly in salt-depleted patients or those taking angiotensin converting enzyme inhibitors and

angiotensin II receptor blockers. Worsening of renal function can also occur with concomitant use of

nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal

function periodically.

5.3 Electrolyte and Metabolic Abnormalities

In addition to causing hyperkalemia, spironolactone can cause hyponatremia, hypomagnesemia,

hypocalcemia, hypochloremic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can occur

and rarely gout is precipitated. Monitor serum electrolytes, uric acid and blood glucose periodically.

5.4 Gynecomastia

Spironolactone can cause gynecomastia. In The Randomized Spironolactone Evaluation Study, patients

with heart failure treated with a mean dose of 26 mg of spironolactone once daily, about 9% of the male

subjects developed gynecomastia. The risk of gynecomastia increases in a dose-dependent manner with

an onset that varies widely from 1 to 2 months to over a year. Gynecomastia is usually reversible.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hyperkalemia [see Warnings and Precautions (5.1)]

Hypotension and Worsening Renal Function [see Warnings and Precautions (5.2)]

Electrolyte and Metabolic Abnormalities [see Warnings and Precautions (5.3)]

Gynecomastia [see Warnings and Precautions (5.4]

Impaired neurological function/ coma in patients with hepatic impairment, cirrhosis and ascites [see

Use in Specific Populations (8.7)]

The following adverse reactions associated with the use of spironolactone were identified in clinical

trials or postmarketing reports. Because these reactions were reported voluntarily from a population of

uncertain size, it is not always possible to estimate their frequency, reliably, or to establish a causal

relationship to drug exposure.

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

Reproductive: Decreased libido, inability to achieve or maintain erection, irregular menses or

amenorrhea, postmenopausal bleeding, breast and nipple pain.

Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia.

Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic

reactions, vasculitis.

Metabolism: Hyperkalemia, electrolyte disturbances [see Warnings and Precautions (5.1, 5.3)] ,

hyponatremia, hypovolemia.

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, pruritis.

7 DRUG INTERACTIONS

7.1 Drugs and Supplements Increasing Serum Potassium

Concomitant administration of spironolactone with potassium supplementation or drugs that can increase

potassium may lead to severe hyperkalemia. In general, discontinue potassium supplementation in heart

failure patients who start spironolactone [see Warnings and Precautions (5.1) and Clinical Pharmacology

(12.3)] . Check serum potassium levels when ACE inhibitor or ARB therapy is altered in patients

receiving spironolactone.

Examples of drugs that can increase potassium include:

ACE inhibitors

angiotensin receptor blockers

non-steroidal anti-inflammatory drugs (NSAIDs)

heparin and low molecular weight heparin

trimethoprim

7.2 Lithium

Like other diuretics, spironolactone reduces the renal clearance of lithium, thus increasing the risk of

lithium toxicity. Monitor lithium levels periodically when spironolactone is coadministered [see Clinical

Pharmacology (12.3)] .

7.3 Nonsteroidal anti-inflammatory drugs (NSAIDs)

In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and

antihypertensive effect of diuretics. Therefore, when spironolactone and NSAIDs are used

concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained [see Clinical

Pharmacology (12.3)] .

7.4 Digoxin

Spironolactone and its metabolites interfere with radioimmunoassays for digoxin and increase the

apparent exposure to digoxin. It is unknown to what extent, if any, spironolactone may increase actual

digoxin exposure. In patients taking concomitant digoxin, use an assay that does not interact with

spironolactone.

7.5 Cholestyramine

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

cholestyramine.

7.6 Acetylsalicylic Acid

Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when spironolactone and

acetylsalicylic acid are used concomitantly, spironolactone tablets may need to be titrated to higher

maintenance dose and the patient should be observed closely to determine if the desired effect is

obtained [see Clinical Pharmacology (12.3)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on mechanism of action and findings in animal studies, spironolactone may affect sex

differentiation of the male during embryogenesis (see Data) . Rat embryofetal studies report

feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero.

Limited available data from published case reports and case series did not demonstrate an association of

major malformations or other adverse pregnancy outcomes with spironolactone . There are risks to the

mother and fetus associated with heart failure, cirrhosis and poorly controlled hypertension during

pregnancy (see Clinical Considerations) . Because of the potential risk to the male fetus due to anti-

androgenic properties of spironolactone and animal data, avoid spironolactone in pregnant women or

advise a pregnant woman of the potential risk to a male fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnant women with congestive heart failure are at increased risk for preterm birth. Stroke volume and

heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester.

Clinical classification of heart disease may worsen with pregnancy and lead to maternal death. Closely

monitor pregnant patients for destabilization of their heart failure.

Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure,

variceal hemorrhage, preterm delivery, fetal growth restriction and maternal death. Outcomes are worse

with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully

monitored and managed accordingly.

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes,

premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum

hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine

death.

Data

Animal Data

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. spironolactone has known endocrine effects in animals including progestational and

antiandrogenic effects.

8.2 Lactation

Risk Summary

Spironolactone is not present in breastmilk; however, limited data from a lactating woman at 17 days

postpartum reports the presence of the active metabolite, canrenone, in human breast milk in low amounts

that are expected to be clinically inconsequential. In this case, there were no adverse effects reported

for the breastfed infant after short term exposure to spironolactone; however, long term effects on a

breastfed infant are unknown. There are no data on spironolactone effects on milk production. Consider

the developmental and health benefits of breastfeeding along with the mother's clinical need for

spironolactone and any potential adverse effects on the breastfed child from spironolactone or from the

underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Spironolactone is substantially excreted by the kidney, and the risk of adverse reactions to this drug may

be greater in patients with impaired renal function. Because elderly patients are more likely to have

decreased renal function, monitor renal function.

8.6 Use in Renal Impairment

Spironolactone is substantially excreted by the kidney, and the risk of adverse reactions to this drug may

be greater in patients with impaired renal function. Patients with renal impairment are at increased risk of

hyperkalemia. Monitor potassium closely.

8.7 Use in Hepatic Impairment

Spironolactone can cause sudden alterations of fluid and electrolyte balance which may precipitate

impaired neurological function, worsening hepatic encephalopathy and coma in patients with hepatic

disease with cirrhosis and ascites. In these patients, initiate Spironolactone in the hospital [see Dosage

and Administration (2.4) and Clinical Pharmacology (12.3)] .

Clearance of spironolactone and its metabolites is reduced in patients with cirrhosis. In patients with

cirrhosis, start with lowest initial dose and titrate slowly [see Dosage and Administration (2.4) and

Clinical Pharmacology (12.3)] .

10 OVERDOSAGE

The oral LD

of spironolactone is greater than 1000 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.

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 hyperkalemia. In such cases, discontinue spironolactone.

11 DESCRIPTION

Spironolactone oral 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, which has the following structural formula:

Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in

chloroform.

Inactive ingredients include lactose monohydrate, dibasic calcium phosphate, povidone, peppermint oil,

purified talc, pregelatinised starch, colloidal anhydrous silica, magnesium stearate, hypromellose,

polyethylene glycol 400, titanium dioxide and iron oxide yellow. In addition iron oxide red (50 mg and

100 mg tablets) is included in the film coating of specific strengths.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Spironolactone and its active metabolites are specific pharmacologic antagonists of aldosterone, acting

primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium

exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium

and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an

antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act

more proximally in the renal tubule.

12.2 Pharmacodynamics

Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in

primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is

usually involved include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome. By

competing with aldosterone for receptor sites, spironolactone provides effective therapy for the edema

and ascites in those conditions. Spironolactone counteracts secondary aldosteronism induced by the

volume depletion and associated sodium loss caused by active diuretic therapy.

12.3 Pharmacokinetics

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 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-β-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 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 reduces the renal clearance of lithium, inducing a high risk of lithium toxicity

[see 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 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. No increased

tumors were seen at doses of 100 mg/kg/day. This dose represents about 5× the human recommended

daily dose of 200 mg/day, when based on body surface area.

Mutagenesis

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.

Impairment of Fertility

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 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 (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

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: 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 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

Product: 63629-8132

NDC: 63629-8132-1 30 TABLET, FILM COATED in a BOTTLE

Product: 63629-8133

NDC: 63629-8133-1 30 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Patients who receive spironolactone tablets should be advised to avoid potassium supplements and

foods containing high levels of potassium, including salt substitutes.

Manufactured For:

Accord Healthcare, Inc.,

1009 Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No 5 to 14, Pharmez,

Sarkhej-Bavla, National Highway No 8-A,

Near Village Matoda, Tal Sanand,

Ahmedabad - 382 213, Gujarat, India

51 2946 0 715630

Issued May 2019

SPIRONOLACTONE 100MG TABLET

SPIRONOLACTONE 25MG TABLET

SPIRONOLACTONE

spironolactone tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 132(NDC:16 729 -227)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SPIRO NO LACTO NE (UNII: 27O7W4T232) (SPIRONOLACTONE - UNII:27O7W4T232)

SPIRONOLACTONE

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

DIBASIC CALCIUM PHO SPHATE DIHYDRATE (UNII: O7TSZ9 7GEP)

PO VIDO NE K2 5 (UNII: K0 KQV10 C35)

PEPPERMINT O IL (UNII: AV0 9 2KU4JH)

TALC (UNII: 7SEV7J4R1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

Product Characteristics

Color

o range (Light peach to peach)

S core

2 pieces

S hap e

ROUND

S iz e

11mm

Flavor

PEPPERMINT

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 132-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/29 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 3512

0 6 /0 2/20 17

SPIRONOLACTONE

spironolactone tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 133(NDC:16 729 -225)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SPIRO NO LACTO NE (UNII: 27O7W4T232) (SPIRONOLACTONE - UNII:27O7W4T232)

SPIRONOLACTONE

25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

DIBASIC CALCIUM PHO SPHATE DIHYDRATE (UNII: O7TSZ9 7GEP)

PO VIDO NE K2 5 (UNII: K0 KQV10 C35)

PEPPERMINT O IL (UNII: AV0 9 2KU4JH)

TALC (UNII: 7SEV7J4R1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

Product Characteristics

Color

yello w (Light yello w to yello w)

S core

no sco re

S hap e

ROUND

S iz e

8 mm

Flavor

PEPPERMINT

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 133-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/29 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 3512

0 6 /0 2/20 17

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Bryant Ranch Prepack

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 133, 6 36 29 -8 132) , RELABEL(6 36 29 -8 132, 6 36 29 -8 133)

Revised: 8/2019

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