Carospir Drug Information

General Considerations

CAROSPIR is not therapeutically equivalent to Aldactone. Follow dosing instructions given here. In patients requiring a dose greater than 100 mg, use another formulation.

Doses of the suspension greater than 100 mg may result in spironolactone concentrations higher than expected . CAROSPIR can be taken with or without food, but should be taken consistently with respect to food .

Treatment of Heart Failure

In patients with serum potassium ≤5.0 mEq/L and eGFR >50 mL/min/1.73m 2, initiate treatment at 20 mg (4 mL) once daily. Patients who tolerate 20 mg (4 mL) once daily may have their dosage increased to 37.5 mg (7.5 mL) once daily as clinically indicated. Patients who develop hyperkalemia on 20 mg (4 mL) once daily may have their dosage reduced to 20 mg (4 mL) every other day . In patients with an eGFR between 30 and 50 mL/min/1.73m 2, consider initiating treatment at 10 mg (2 mL) because of the risk of hyperkalemia .

Treatment of Essential Hypertension

The recommended initial daily dose is 20 mg (4 mL) to 75 mg (15 mL) administered in either single or divided doses. Dosage can be titrated at two-week intervals. Doses >75 mg/day generally do not provide additional reductions in blood pressure.

Treatment of Edema associated with Hepatic Cirrhosis

In patients with cirrhosis, initiate therapy in a hospital setting and titrate slowly and Clinical Pharmacology ]. The recommended initial daily dose is 75 mg (15 mL) administered in either single or divided doses. In patients requiring titration above 100 mg, use another formulation . When given as the sole agent for diuresis, administer for at least five days before increasing dose to obtain desired effect.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hyperkalemia 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: Gynecomastia, 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, chloasma. The most common adverse reaction (incidence > 5%) with CAROSPIR treatment is gynecomastia To report SUSPECTED ADVERSE REACTIONS, contact CMP Pharma at 1-844-321-1443 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drugs and Supplements Increasing Serum Potassium

Concomitant administration of CAROSPIR 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 CAROSPIR . Check serum potassium levels when ACE inhibitor or ARB therapy is altered in patients receiving CAROSPIR. Examples of drugs that can increase potassium include: ACE inhibitors angiotensin receptor blockers aldosterone blockers non-steroidal anti-inflammatory drugs (NSAIDs) heparin and low molecular weight heparin trimethoprim

Lithium Like other diuretics

CAROSPIR reduces the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when CAROSPIR is coadministered .

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. Therefore, when CAROSPIR and NSAIDs are used concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained .

Digoxin Spironolactone and its metabolites increase the apparent exposure to digoxin.

In patients taking concomitant digoxin, measure serum digoxin concentrations before initiating spironolactone using an assay that does not interact with spironolactone. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring .

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

with cholestyramine.

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

CAROSPIR and acetylsalicylic acid are used concomitantly, CAROSPIR may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained .

CYP2C8 and

CYP3A Substrates Spironolactone is an irreversible inhibitor for CYP2C8 and CYP3A4/5 in vitro . Therefore, spironolactone may increase the exposure of other coadministered drugs that are metabolized by CYP2C8 and CYP3A4/5. Dosage adjustments of the drugs metabolized by CYP2C8 (e.g., repaglinide) and CYP3A4/5 (e.g., midazolam, sirolimus and tacrolimus) may be necessary if they are given concurrently with spironolactone.

Pregnancy Risk Summary Based on mechanism of action and findings in animal studies, spironolactone may affect sex differentiation of the male during embryogenesis . 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 congenital anomalies 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 congenital anomalies and miscarriage in the 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 embryo toxic 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, CAROSPIR may have the potential for adversely affecting sex differentiation of the male during embryogenesis.

When administered to rats at 200 mg/kg/day, a dose 10 times the human dose of 200 mg/day, when based on body surface area, 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 (CAROSPIR) has known endocrine effects in animals including progestational and antiandrogenic effects.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. CAROSPIR is not recommended for the treatment of hypertension in pediatric patients because of the potential risks associated with the antiandrogenic, progestogenic, and estrogenic properties of spironolactone in pediatric patients.

is contraindicated for patients with the following conditions: Hyperkalemia Addison’s disease Concomitant use of eplerenone CAROSPIR is contraindicated in patients with Hyperkalemia Addison’s disease Concomitant use of eplerenone

The oral LD50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. Acute overdosage of CAROSPIR 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 CAROSPIR.