FINERENONE: 1,924 Adverse Event Reports & Safety Profile

Kerendia contains finerenone, a nonsteroidal mineralocorticoid receptor antagonist. Finerenone's chemical name is ( 4S ) - 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide. The molecular formula is C 21 H 22 N 4 O 3 and the molecular weight is 378.43 g/mol. The structural formula is: Finerenone is a white to yellow crystalline powder. It is practically insoluble in water; and sparingly soluble in 0.1 M HCl, ethanol, and acetone.

Each

Kerendia tablet contains 10 mg, 20 mg, or 40 mg of finerenone. The inactive ingredients of Kerendia are lactose monohydrate, cellulose microcrystalline, croscarmellose sodium, hypromellose, magnesium stearate, and sodium lauryl sulfate. The film coating contains hypromellose, titanium dioxide and talc, in addition to ferric oxide red (10 mg and 40 mg strength tablets) or ferric oxide yellow (20 mg and 40 mg strength tablets).

Chemical

Structure

AND USAGE Kerendia is indicated to reduce the risk of: sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2DM). cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adult patients with heart failure with left ventricular ejection fraction (LVEF) ≥ 40%. Kerendia is a non-steroidal mineralocorticoid receptor antagonist (nsMRA) indicated to reduce the risk of: sustained estimated glomerular filtration rate (eGFR) decline, end stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2DM). ( 1 ) cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adult patients with heart failure with left ventricular ejection fraction (LVEF) ≥ 40% ( 1 )

AND ADMINISTRATION The recommended starting dosage is 10 mg or 20 mg orally once daily based on eGFR and serum potassium thresholds. ( 2.1 ) Increase dosage after 4 weeks to the target dose of 20 mg once daily for CKD and T2DM based on eGFR and serum potassium thresholds. ( 2.3 ) Increase dosage after 4 weeks to the target dose of 20 mg or 40 mg once daily for HF with LVEF ≥ 40% based on eGFR and serum potassium thresholds. ( 2.3 ) Tablets may be taken with or without food ( 2.2 )

2.1 Prior to Initiation of Kerendia Measure serum potassium levels and eGFR before initiation. Do not initiate treatment if serum potassium is &gt; 5.0 mEq/L <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

2.2 Recommended Starting Dosage The recommended starting dose of Kerendia is based on eGFR and is presented in Table 1.

Table

1: Recommended Starting Dosage eGFR (mL/min/1.73m 2 )

Starting

Dose ≥ 60 20 mg orally once daily ≥ 25 to < 60 10 mg orally once daily < 25 Initiation is not recommended For patients who are unable to swallow whole tablets, Kerendia may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally [see Clinical Pharmacology (12.3) ] .

2.3 Monitoring and Dosage Adjustment CKD associated with T2DM The target daily dose of Kerendia is 20 mg orally. Measure serum potassium 4 weeks after initiating treatment and adjust dose (see Table 2 ); if serum potassium levels are &gt; 4.8 to 5.0 mEq/L, initiation of Kerendia treatment may be considered with additional serum potassium monitoring within the first 4 weeks based on clinical judgment and serum potassium levels <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>. Measure serum potassium 4 weeks after a dose adjustment and periodically throughout treatment, and adjust the dose as needed (see Table 2 ) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Drug Interactions (7.1) ]</span>.

Table

2: Dose Adjustment Based on Current Serum Potassium Concentration and Current Dose (CKD associated with T2DM)

Current Kerendia Dose

10 mg once daily 20 mg once daily Current Serum Potassium (mEq/L) ≤

4.8 Increase the dose to 20 mg once daily. If eGFR has decreased by more than 30% compared to previous measurement, maintain 10 mg dose.

Maintain

20 mg once daily. > 4.8 –

5.5 Maintain 10 mg once daily.

Maintain

20 mg once daily. >

5.5 Withhold Kerendia. Consider restarting at 10 mg once daily when serum potassium ≤ 5.0 mEq/L.

Withhold

Kerendia. Restart at 10 mg once daily when serum potassium ≤ 5.0 mEq/L.

Heart

Failure with LVEF ≥ 40% The target daily dose of Kerendia for heart failure (LVEF ≥ 40%) is dependent on renal function (eGFR) at initiation of Kerendia treatment (see Table 3 ). The target daily dose is 40 mg orally once daily if eGFR at initiation is ≥ 60 mL/min/1.73m 2 . The target daily dose is 20 mg orally once daily if eGFR at initiation is ≥ 25 to < 60 mL/min/1.73m 2 . Measure serum potassium and eGFR 4 weeks after initiating treatment and adjust dose (see Table 3 ). Measure serum potassium and eGFR 4 weeks after a dose adjustment and monitor periodically throughout treatment, and adjust the dose as needed (see Table 3 ) [see Warnings and Precautions (5.1 & 5.2) and Drug Interactions (7.1) ].

Table

3: Dose Adjustment Based on Current Serum Potassium Concentration, eGFR, and Current Dose (Heart Failure (LVEF ≥ 40%))

Current Kerendia Dose

10 mg once daily 20 mg once daily 40 mg once daily Current Serum Potassium (mEq/L) <

5.0 Increase the dose to 20 mg once daily If eGFR has decreased by more than 30% compared to previous measurement, maintain current dose.

Maintain

20 mg once daily if eGFR < 60 mL/min/1.73 m 2 at initiation. Otherwise increase the dose to 40 mg once daily Maintain 40 mg once daily. ≥ 5.0 to <

5.5 Maintain current dose. ≥ 5.5 to &lt;

6.0 Withhold Kerendia. Restart at 10 mg once daily when serum potassium &lt; 5.5 mEq/L. Decrease to 10 mg once daily. Decrease to 20 mg once daily. ≥

6.0 Withhold Kerendia. Restart at 10 mg once daily when serum potassium &lt; 5.5 mEq/L. If repeated serum potassium measurements are ≥5.5 mEq/L, restart Kerendia at 10 mg once daily when serum potassium &lt; 5.0 mEq/L.

2.4 Missed Doses Direct a patient to take a missed dose as soon as possible after it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed.

Kerendia is contraindicated in patients: Who are hypersensitive to any component of this product [see Adverse Reactions (6.2) ] . Who are receiving concomitant treatment with strong CYP3A4 inhibitors [see Drug Interactions (7.1) ]. With adrenal insufficiency. Concomitant use with strong CYP3A4 inhibitors. ( 4 , 7.1 ) Patients with adrenal insufficiency. ( 4 ) Hypersensitivity to any component of this product. ( 4 )

REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hyperkalemia [see Warnings and Precautions (5.1) ] Adverse reactions occurring in ≥ 1% of patients on Kerendia and more frequently than placebo are hyperkalemia, hypotension, and hyponatremia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 the clinical trials of another drug and may not reflect the rates observed in practice. CKD associated with T2DM The safety of Kerendia in patients with CKD associated with T2DM was evaluated in 2 randomized, double-blind, placebo-controlled, multicenter pivotal phase 3 studies, FIDELIO-DKD and FIGARO-DKD, in which a total of 6510 patients were treated with 10 or 20 mg once daily over a mean duration of 2.2 and 2.9 years, respectively. Overall, serious adverse events occurred in 32% of patients receiving Kerendia and in 34% of patients receiving placebo in the FIDELIO-DKD study; the findings were similar in the FIGARO-DKD study. Permanent discontinuations due to adverse events also occurred in a similar proportion of patients in the two studies (6-7% of patients receiving Kerendia and in 5-6% of patients receiving placebo). The most frequently reported (≥ 10%) adverse reaction was hyperkalemia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>. Hospitalization due to hyperkalemia for the Kerendia group was 0.9% vs 0.2% in the placebo group across both studies. Hyperkalemia led to permanent discontinuation of treatment in 1.7% receiving Kerendia versus 0.6% of patients receiving placebo across both studies.

Table

4 shows adverse reactions that occurred more commonly on Kerendia than on placebo, and in at least 1% of patients treated with Kerendia.

Table

4: Adverse reactions reported in ≥ 1% of patients on Kerendia and more frequently than placebo (Pooled data from FIDELIO-DKD and FIGARO-DKD) Adverse reactions Kerendia N = 6510 n (%) Placebo N = 6489 n (%)

Hyperkalemia

912 (14.0) 448 (6.9)

Hypotension

302 (4.6) 194 (3.0)

Hyponatremia

82 (1.3) 47 (0.7)

Heart

Failure with LVEF ≥ 40% The safety of Kerendia in patients with heart failure (LVEF ≥40%) was evaluated in the randomized, double-blind, placebo-controlled, multicenter pivotal phase 3 study, FINEARTS-HF, in which a total of 2,993 patients were treated with 10 mg, 20 mg, or 40 mg once daily of Kerendia with a mean duration of treatment of 2.3 years. The overall safety profile of Kerendia in the FINEARTS-HF study was largely consistent with the adverse reactions reported in patients with CKD and T2DM (Table 4). However, adverse reactions related to worsening renal function were reported more frequently in the Kerendia group (18%) compared with placebo (12%) in FINEARTS-HF. The most frequently reported adverse reactions included renal impairment (7% vs. 4%), eGFR decreased (5% vs. 4%), acute kidney injury (4% vs. 2%) and renal failure (3% vs. 2%). The majority of events were reported to be mild to moderate. These events led to dose modifications in 9% of patients receiving Kerendia versus 4% of patients receiving placebo. Hospitalization due to events related to worsening of renal function for the Kerendia group was 2.0% versus 1.3% in the placebo group.

Laboratory Test

Initiation of Kerendia may cause an initial small increase in blood creatinine levels (mean change <0.1 mg/dL) and a small decrease in eGFR (mean change 2-3 ml/min) that occurs within the first 4 weeks of starting therapy and then stabilizes. These changes were reversible after treatment discontinuation. Initiation of Kerendia may also cause a small increase in serum uric acid. This increase appears to attenuate over time.

6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience with finerenone. Because these reactions are 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: Hypersensitivity: Angioedema, Rash and Urticaria

AND PRECAUTIONS Hyperkalemia. Patients with decreased kidney function and higher baseline potassium levels are at increased risk. Monitor serum potassium levels and adjust dose as needed. ( 2.1 , 2.2 , 2.3 , 5.1 ) Worsening of Renal Function in Patients with Heart Failure. Measure eGFR and adjust dose as needed. ( 2.1 , 2.3 , 6.1 )

5.1 Hyperkalemia Kerendia can cause hyperkalemia <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . The risk for developing hyperkalemia increases with decreasing kidney function and is greater in patients with higher baseline potassium levels or other risk factors for hyperkalemia. Measure serum potassium and eGFR in all patients before initiation of treatment with Kerendia and dose accordingly <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . Do not initiate Kerendia if serum potassium is &gt; 5.0 mEq/L. Measure serum potassium periodically during treatment with Kerendia and adjust dose accordingly <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . More frequent monitoring may be necessary for patients at risk for hyperkalemia, including those on concomitant medications that impair potassium excretion or increase serum potassium <span class="opacity-50 text-xs">[see Drug Interactions (7.1 , 7.2) ]</span> .

5.2 Worsening of Renal Function in Patients with Heart Failure Kerendia can cause worsening of renal function in patients with heart failure. Rarely, severe events associated with worsening renal function, including events requiring hospitalization, have been observed <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Measure eGFR in all patients before initiation of treatment or with dose titration of Kerendia and dose accordingly <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.3) ]</span>. Initiation of Kerendia in patients with heart failure and an eGFR &lt;25 mL/min/1.73m 2 is not recommended. Measure eGFR periodically during maintenance treatment with Kerendia in patients with heart failure. Consider delaying up-titration or interrupting treatment with Kerendia in patients who develop clinically significant worsening of renal function.

INTERACTIONS Strong CYP3A4 Inhibitors: Use is contraindicated. ( 7.1 ) Grapefruit or grapefruit juice: Avoid concomitant use. ( 7.1 ) Moderate or weak CYP3A4 Inhibitors: Monitor serum potassium during drug initiation or dosage adjustment of either Kerendia or the moderate or weak CYP3A4 inhibitor, and adjust Kerendia dosage as appropriate ( 7.1 ) Strong or moderate CYP3A4 Inducers: Avoid concomitant use. ( 7.1 ) Sensitive CYP2C8 substrates at Kerendia 40 mg: Monitor more frequently for adverse reactions. ( 7.2 )

7.1 Effect of Other Drugs on Kerendia Strong CYP3A4 Inhibitors Kerendia is a CYP3A4 substrate. Concomitant use with a strong CYP3A4 inhibitor increases finerenone exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may increase the risk of Kerendia adverse reactions. Concomitant use of Kerendia with strong CYP3A4 inhibitors is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Avoid concomitant intake of grapefruit or grapefruit juice. Moderate and Weak CYP3A4 Inhibitors Kerendia is a CYP3A4 substrate. Concomitant use with a moderate or weak CYP3A4 inhibitor increases finerenone exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may increase the risk of Kerendia adverse reactions. Monitor serum potassium during drug initiation or dosage adjustment of either Kerendia or the moderate or weak CYP3A4 inhibitor, and adjust Kerendia dosage as appropriate <span class="opacity-50 text-xs">[see Dosing and Administration (2.3) and Drug Interaction (7.2) ]</span> . Strong and Moderate CYP3A4 Inducers Kerendia is a CYP3A4 substrate. Concomitant use of Kerendia with a strong or moderate CYP3A4 inducer decreases finerenone exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>, which may reduce the efficacy of Kerendia. Avoid concomitant use of Kerendia with strong or moderate CYP3A4 inducers.

7.2 Effect of Kerendia on Other Drugs CYP2C8 Substrates Kerendia is a weak CYP2C8 inhibitor at 40 mg. Kerendia increases exposure of CYP2C8 substrates at 40 mg dose <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may increase the risk of adverse reactions related to these substrates. Monitor patients more frequently for adverse reactions caused by sensitive CYP2C8 substrates if Kerendia 40 mg is co-administered with such substrates since minimal concentration changes may lead to serious adverse reactions.

7.3 Drugs That Affect Serum Potassium More frequent serum potassium monitoring is warranted in patients receiving concomitant therapy with drugs or supplements that increase serum potassium. <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ]</span>.