Eplerenone

1 INDICATIONS AND USAGE INSPRA is an aldosterone antagonist indicated for: • Improving survival of stable adult patients with symptomatic heart failure with reduced ejection fraction (HFrEF) after an acute myocardial infarction. ( 1.1 ) • The treatment of hypertension in adults, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.2 ) 1.1 Heart Failure Post-Myocardial Infarction INSPRA is indicated to improve survival of stable adult patients with symptomatic heart failure with reduced ejection fraction (≤40%) (HFrEF) after an acute myocardial infarction (MI). 1.2 Hypertension INSPRA is indicated for the treatment of hypertension in adults, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and MI. 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 CV 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 CV 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 CV outcome benefit has been a reduction in the risk of stroke, but reductions in MI and CV mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased CV 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. INSPRA may be used alone or in combination with other antihypertensive agents.

2 DOSAGE AND ADMINISTRATION HFrEF Post-MI: Initiate treatment with 25 mg once daily. Titrate to maximum of 50 mg once daily within 4 weeks, as tolerated. Dose adjustments may be required based on potassium levels. ( 2.1 ) Hypertension: 50 mg once daily, alone or combined with other antihypertensive agents. For inadequate response, increase to 50 mg twice daily. Higher dosages are not recommended. ( 2.2 ) For all patients: Measure serum potassium before starting INSPRA and periodically thereafter. ( 2.3 ) 2.1 Heart Failure Post-Myocardial Infarction Initiate treatment at 25 mg once daily and titrate to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient. Once treatment with INSPRA has begun, adjust the dose based on the serum potassium level as shown in Table 1. Table 1. Dose Adjustment in Heart Failure Post-MI Serum Potassium (mEq/L) Dose Adjustment <5.0 25 mg every other day to 25 mg once daily 25 mg once daily to 50 mg once daily 5.0-5.4 No adjustment 5.5-5.9 50 mg once daily to 25 mg once daily 25 mg once daily to 25 mg every other day 25 mg every other day to withhold ≥6.0 Withhold and restart at 25 mg every other day when potassium levels fall to <5.5 mEq/L 2.2 Hypertension The recommended starting dose of INSPRA is 50 mg administered once daily. The full therapeutic effect of INSPRA is apparent within 4 weeks. For patients with an inadequate blood pressure response to 50 mg once daily increase the dosage of INSPRA to 50 mg twice daily. Higher dosages of INSPRA are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia [see Clinical Studies (14.2) ] . 2.3 Recommended Monitoring Measure serum potassium before initiating INSPRA therapy, within the first week, and at one month after the start of treatment or dose adjustment. Assess serum potassium periodically thereafter. Check serum potassium and serum creatinine within 3-7 days of a patient initiating a moderate CYP3A inhibitor ACE inhibitors, angiotensin II blockers or nonsteroidal anti-inflammatories. 2.4 Dose Modification for Use with Moderate CYP3A Inhibitors In post-MI HFrEF patients receiving a moderate CYP3A inhibitor (e.g., erythromycin, saquinavir, verapamil, and fluconazole), do not exceed 25 mg once daily. In patients with hypertension receiving a moderate CYP3A inhibitor, initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily [see Drug Interactions (7.1) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Hyperkalemia [see Warnings and Precautions (5.1) ] HFrEF Post-MI: Most common adverse reactions (>2% and more frequent than with placebo): hyperkalemia and increased creatinine. ( 6.1 ) Hypertension: In clinical studies, adverse reactions with INSPRA were uncommon. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Heart Failure Post-Myocardial Infarction In EPHESUS, safety was evaluated in 3307 patients treated with INSPRA and 3301 placebo-treated patients. The overall incidence of adverse events reported with INSPRA (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% INSPRA vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, MI, and abnormal renal function. Adverse reactions that occurred more frequently in patients treated with INSPRA than placebo were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%). Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups. Hypertension INSPRA has been evaluated for safety in 3091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year. In placebo-controlled studies, the overall rates of adverse events were 47% with INSPRA and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 3% of patients treated with INSPRA and 3% of patients given placebo. The most common reasons for discontinuation of INSPRA were headache, dizziness, angina pectoris/MI, and increased GGT. Gynecomastia and abnormal vaginal bleeding were reported with INSPRA but not with placebo. The rates increased with increasing duration of therapy. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of INSPRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin: angioedema, rash 6.3 Clinical Laboratory Test Findings Heart Failure Post-Myocardial Infarction Creatinine: Increases of more than 0.5 mg/dL were reported for 6.5% of patients administered INSPRA and for 4.9% of placebo-treated patients. Potassium: In EPHESUS [see Clinical Studies (14.1) ] , the frequencies of patients with changes in potassium (<3.5 mEq/L or >5.5 mEq/L or ≥6.0 mEq/L) receiving INSPRA compared with placebo are displayed in Table 2. Table 2. Hypokalemia (<3.5 mEq/L) or Hyperkalemia (>5.5 or ≥6.0 mEq/L) in EPHESUS Potassium (mEq/L) INSPRA (N=3251) n (%) Placebo (N=3237) n (%) <3.5 273 (8.4) 424 (13.1) >5.5 508 (15.6) 363 (11.2) ≥6.0 180 (5.5) 126 (3.9) Rates of hyperkalemia increased with decreasing renal function. Table 3. Rates of Hyperkalemia (>5.5 mEq/L) in EPHESUS by Baseline Creatinine Clearance* * Estimated using the Cockroft-Gault formula. Baseline Creatinine Clearance INSPRA (N=508) n (%) Placebo (N=363) n (%) ≤30 mL/min 160 (32) 82 (23) 31-50 mL/min 122 (24) 46 (13) 51-70 mL/min 86 (17) 48 (13) >70 mL/min 56 (11) 32 (9) The rates of hyperkalemia in EPHESUS in the INSPRA-treated group vs. placebo were increased in patients with proteinuria (16% vs 11%), diabetes (18% vs. 13%) or both (26% vs. 16%). Hypertension Potassium: In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 4 along with the frequencies of values >5.5 mEq/L. Table 4. Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of INSPRA Mean Increase mEq/L % >5.5 mEq/L Daily Dosage n Placebo 194 0 1 25 97 0.08 0 50 245 0.14 0 100 193 0.09 1

12.3 Pharmacokinetics Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 3 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone. Absorption and Distribution Mean peak plasma concentrations of eplerenone are reached approximately 1.5 to 2 hours following oral administration. Absorption is not affected by food. The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Both peak plasma levels (C max ) and area under the curve (AUC) are dose proportional for doses of 25 mg to 100 mg and less than proportional at doses above 100 mg. Upon repeat dosing, steady state levels are reached within 2 days. The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 42 to 90 L. Eplerenone does not preferentially bind to red blood cells. Metabolism and Excretion Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma. Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3 to 6 hours. The apparent plasma clearance is approximately 10 L/hr. Age, Gender, and Race The pharmacokinetics of eplerenone at a dose of 100 mg once daily has been investigated in the elderly (≥65 years), in males and females, and in Blacks. At steady state, elderly subjects had increases in C max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, C max was 19% lower and AUC was 26% lower in Blacks [see Dosage and Administration (2.4) and Use in Specific Populations (8.5) ] . Renal Impairment The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. Compared with control subjects, steady state AUC and C max were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis [see Warnings and Precautions (5.1) ] . Hepatic Impairment The pharmacokinetics of eplerenone 400 mg has been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady state C max and AUC of eplerenone were increased by 3.6% and 42%, respectively. Heart Failure The pharmacokinetics of eplerenone 50 mg was evaluated in 8 patients with heart failure (NYHA classification II–IV) and 8 matched (gender, age, weight) healthy controls. Compared with the controls, steady state AUC and C max in patients with stable heart failure were 38% and 30% higher, respectively. Drug-Drug Interactions Eplerenone is metabolized primarily by CYP3A4. Inhibitors of CYP3A cause increased exposure [see Drug Interactions (7.1) ] . Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone. Following a single dose of INSPRA 100 mg and CYP3A inhibitor ketoconazole 200 mg twice a day, eplerenone’s C max was 1.7-fold and AUC was 5.4-fold compared with eplerenone alone. Administration of eplerenone with moderate CYP3A inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in C max of eplerenone ranging from 40% to 60% and AUC from 100% to 190%. Grapefruit juice caused a 25% increase in exposure. Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide, triazolam, verapamil, or warfarin in vitro . Eplerenone is not a substrate or an inhibitor of P-Glycoprotein at clinically relevant doses. No clinically significant drug-drug pharmacokinetic interactions were observed when eplerenone was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John’s wort (a CYP3A inducer) caused a small (about 30%) decrease in eplerenone AUC. No significant changes in eplerenone pharmacokinetics were observed when eplerenone was administered with aluminum- and magnesium-containing antacids.