Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

ALDACTONE (NDA-012151)

(SPIRONOLACTONE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/19/2022 (SUPPL-79)

Approved Drug Label (PDF)

7 Drug Interactions

7.7 Abiraterone

Newly added subsection:

Spironolactone binds to the androgen receptor and may increase prostate-specific antigen (PSA) levels in abiraterone-treated prostate cancer patients. Concomitant use of spironolactone and abiraterone is not recommended.

03/06/2018 (SUPPL-75)

Approved Drug Label (PDF)

6 Adverse Reactions

(additions underlined)

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

Hyperkalemia Hypotension and Worsening Renal Function
Hypotension and Worsening Renal Function
Electrolyte and Metabolic Abnormalities
Gynecomastia
Impaired neurological function/ coma in patients with hepatic impairment, cirrhosis and ascites

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, 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

(new subsection added)

Concomitant administration of ALDACTONE 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 ALDACTONE.

Check serum potassium levels when ACE inhibitor or ARB therapy is altered in patients receiving ALDACTONE.

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

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

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%-4% and 15%-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 ALDACTONE 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, ALDACTONE 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 ALDACTONE 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. ALDACTONE has known endocrine effects in animals including progestational and antiandrogenic effects.

8.2 Lactation

(PLLR conversion)

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.

8.5 Geriatric Use

(new sunsection added)

ALDACTONE 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

(additions underlined)

ALDACTONE 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

(new subsection added)

ALDACTONE 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 ALDACTONE in the hospital

Other

Revisions to labeling to conform to the Physician’s Labeling Rule (PLR).