Kerendia Drug Information
Generic name: FINERENONE
Nonsteroidal Mineralocorticoid-Receptor Antagonist [EPC]
Uses of Kerendia
- 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). cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adult patients with heart failure with left ventricular ejection fraction (LVEF) ≥ 40%
Dosage & Administration of Kerendia
| ≥ 60 | 20 mg orally once daily |
|---|---|
| ≥ 25 to < 60 | 10 mg orally once daily |
| < 25 | Initiation is not recommended |
Side Effects of Kerendia
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. 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 912 448 Hypotension 302 194 Hyponatremia 82 47 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.
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
Warnings & Cautions for Kerendia
Hyperkalemia Kerendia can cause hyperkalemia .
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 . Do not initiate Kerendia if serum potassium is > 5.0 mEq/L. Measure serum potassium periodically during treatment with Kerendia and adjust dose accordingly . 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 .
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 . Measure eGFR in all patients before initiation of treatment or with dose titration of Kerendia and dose accordingly. Initiation of Kerendia in patients with heart failure and an eGFR <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.
Drug Interactions with Kerendia
Effect of Other Drugs on Kerendia Strong
CYP3A4 Inhibitors Kerendia is a CYP3A4 substrate. Concomitant use with a strong CYP3A4 inhibitor increases finerenone exposure , which may increase the risk of Kerendia adverse reactions. Concomitant use of Kerendia with strong CYP3A4 inhibitors is contraindicated . 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 , 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 . Strong and Moderate CYP3A4 Inducers Kerendia is a CYP3A4 substrate.
Concomitant use of Kerendia with a strong or moderate CYP3A4 inducer decreases finerenone exposure, which may reduce the efficacy of Kerendia. Avoid concomitant use of Kerendia with strong or moderate CYP3A4 inducers.
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 , 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.
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..
Pregnancy Safety for Kerendia
Pregnancy Risk Summary There are no available data on Kerendia use in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal studies have shown developmental toxicity at exposures about 2 times those expected in humans (see Data ). The clinical significance of these findings is unclear. 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. Data Animal Data In the embryo-fetal toxicity study in rats, finerenone resulted in reduced placental weights and signs of fetal toxicity, including reduced fetal weights and retarded ossification at the maternal toxic dose of 10 mg/kg/day corresponding to an AUC unbound of at least 7 times that in humans.
At 30 mg/kg/day, the incidence of visceral and skeletal variations was increased (slight edema, shortened umbilical cord, slightly enlarged fontanelle) and one fetus showed complex malformations including a rare malformation (double aortic arch) at an AUC unbound of about 10 times that in humans at the 40 mg dose and about 25 times that in humans at the 20 mg dose. The doses free of any findings (low dose in rats, high dose in rabbits) provide safety margins of 4 to 5 times for the AUC unbound expected in humans. When rats were exposed during pregnancy and lactation in the pre- and postnatal developmental toxicity study, increased pup mortality and other adverse effects (lower pup weight, delayed pinna unfolding) were observed at about 2 or 4 times the AUC unbound expected in humans at the dose of 40 mg and 20 mg, respectively.
In addition, the offspring showed slightly increased locomotor activity, but no other neurobehavioral changes starting at about 2 or 4 times the AUC unbound expected in humans at the dose of 40 mg and 20 mg, respectively. The dose free of findings provides a safety margin of about 2 times for the AUC unbound expected in humans for the 20 mg dose and is in the therapeutic range for the 40 mg dose.
Pediatric Use of Kerendia
Pediatric Use The safety and efficacy of Kerendia have not been established in patients below 18 years of age.
Contraindications for Kerendia
Kerendia is contraindicated in patients: Who are hypersensitive to any component of this product . Who are receiving concomitant treatment with strong CYP3A4 inhibitors. With adrenal insufficiency. Concomitant use with strong CYP3A4 inhibitors.
Patients with adrenal insufficiency. Hypersensitivity to any component of this product.
Overdosage Information for Kerendia
In the event of suspected overdose, immediately interrupt Kerendia treatment. The most likely manifestation of overdose is hyperkalemia. If hyperkalemia develops, standard treatment should be initiated.
Finerenone is unlikely to be efficiently removed by hemodialysis given its fraction bound to plasma proteins of about 90%.
Clinical Studies of Kerendia
CKD associated with T2DM
FIDELIO-DKD (NCT: 02540993) and FIGARO-DKD (NCT: 02545049) studies were randomized, double-blind, placebo-controlled, multicenter studies in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2DM). In FIDELIO-DKD, patients needed to either have an UACR of 30 to < 300 mg/g, eGFR 25 to < 60 mL/min/1.73 m 2 and diabetic retinopathy, or an UACR of ≥ 300 mg/g and an eGFR of 25 to < 75 mL/min/1.73 m 2 to qualify for enrollment. In FIGARO-DKD, patients needed to have an UACR of 30 mg/g to < 300 mg/g and an eGFR of 25 to 90 mL/min/1.73m 2, or an UACR ≥ 300 mg/g and an eGFR ≥ 60 mL/min/1.73m 2. Both trials excluded patients with known significant non-diabetic kidney disease. All patients were to have a serum potassium ≤ 4.8 mEq/L at screening and be receiving standard of care background therapy, including a maximum tolerated labeled dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients with a clinical diagnosis of chronic heart failure with reduced ejection fraction and persistent symptoms (New York Heart Association class II to IV) were excluded.
The starting dose of Kerendia was based on screening eGFR (10 mg once daily in patients with an eGFR of 25 to < 60 mL/min/1.73 m 2 and 20 mg once daily in patients with an eGFR ≥ 60 mL/min/1.73 m 2 ). The dose of Kerendia could be titrated during the study, with a target dose of 20 mg daily. The primary objective of the FIDELIO-DKD study was to determine whether Kerendia reduced the incidence of a sustained decline in eGFR of ≥ 40%, kidney failure (defined as chronic dialysis, kidney transplantation, or a sustained decrease in eGFR to < 15 mL/min/1.73 m 2 ), or renal death. The secondary outcome was a composite of time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure.
The primary objective of the FIGARO-DKD study was to determine whether Kerendia reduced the time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure. The secondary outcome was a composite of time to kidney failure, a sustained decline in eGFR of 40% or more compared to baseline over at least 4 weeks, or renal death. In FIDELIO-DKD, a total of 5674 patients were randomized to receive Kerendia (N=2833) or placebo (N=2841) and were followed for a median of 2.6 years.
The mean age of the study population was 66 years, and 70% of patients were male. This global trial population was 63% White, 25% Asian, and 5% Black. At baseline, the mean eGFR was 44 mL/min/1.73m 2, with 55% of patients having an eGFR < 45 mL/min/1.73m 2. Median urine albumin-to-creatinine ratio (UACR) was 852 mg/g, mean glycated hemoglobin A1c (HbA1c) was 7.7%, and the mean blood pressure was 138/76 mmHg.
Approximately 46% of patients had a history of atherosclerotic cardiovascular disease and 8% had a history of heart failure. At baseline, 99.8% of patients were treated with an ACEi or ARB. Approximately 97% were on an antidiabetic agent (insulin, biguanides, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors ), 74% were on a statin, and 57% were on an antiplatelet agent. In FIGARO-DKD, a total of 7352 patients were randomized to receive Kerendia (N=3686) or placebo (N=3666) and were followed for 3.4 years.
As compared to FIDELIO-DKD, baseline eGFR was higher in FIGARO-DKD (mean eGFR 68, with 62% of patients having an eGFR ≥ 60 mL/min/1.73 m 2 ) and median UACR was lower (308 mg/g). Otherwise, baseline patient characteristics and background therapies were similar in the two trials. In FIDELIO-DKD, Kerendia reduced the incidence of the primary composite endpoint of a sustained decline in eGFR of ≥ 40%, kidney failure, or renal death (HR 0.82, 95% CI 0.73-0.93, p=0.001) as shown in Table 5 and Figure 1. The treatment effect reflected a reduction in a sustained decline in eGFR of ≥ 40% and progression to kidney failure. There were few renal deaths during the trial.
Kerendia also reduced the incidence of the secondary composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal stroke or hospitalization for heart failure (HR 0.86, 95% CI 0.75-0.99, p=0.034) as shown in Table 5 and Figure 3. The treatment effect reflected a reduction in CV death, non-fatal MI, and hospitalization for heart failure. The treatment effect on the primary and secondary composite endpoints was generally consistent across subgroups. In FIGARO-DKD, Kerendia reduced the incidence of the primary composite endpoint of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure (HR 0.87, 95% CI 0.76-0.98, p = 0.026) as shown in Table 5 and Figure 4. The treatment effect was mainly driven by an effect on hospitalization for heart failure, though CV death also contributed to the treatment effect.
The treatment effect on the primary composite endpoint was generally consistent across subgroups, including patients with and without pre-existing cardiovascular disease. The findings for the renal composite endpoint are shown in Table 5 and Figure 2. Table 5: Analysis of the Primary and Secondary Time-to-Event Endpoints (and their Individual Components) in Phase 3 Studies FIDELIO-DKD and FIGARO-DKD FIDELIO-DKD FIGARO-DKD Kerendia N=2833 Placebo N=2841 Treatment Effect Kerendia / Placebo Kerendia N=3686 Placebo N=3666 Treatment Effect Kerendia / Placebo Time-to-event Endpoints: Event Rate (100 pt-yr) Event Rate (100 pt-yr) Hazard Ratio (95% CI) p-value Event Rate (100 pt-yr) Event Rate (100 pt-yr) Hazard Ratio (95% CI) p-value p-value: two-sided p-value from stratified logrank test CI = confidence interval, CV = cardiovascular, eGFR = estimated glomerular filtration rate, MI = myocardial infarction, N = number of subjects, n = number of subjects with event, pt-yr = patient year. NOTE: Time to first event was analyzed in a Cox proportional hazards model.
For patients with multiple events, only the first event contributed to the composite endpoint. Sums of the numbers of first events for the single components do not add up to the numbers of events in the composite endpoint. Composite of kidney failure, sustained eGFR decline ≥40% or renal death 7.6 9.1 0.82 0.001 3.2 3.6 0.87 - Kidney failure 3.0 3.4 0.87 - 0.4 0.5 0.72 - Sustained eGFR decline ≥40% 7.2 8.7 0.81 - 3.1 3.5 0.87 - Renal death - - - - - - - - Composite of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure 5.1 5.9 0.86 0.034 3.9 4.5 0.87 0.026 CV death 1.7 2.0 0.86 - 1.6 1.8 0.90 - Non-fatal MI 0.9 1.2 0.80 - 0.9 0.8 0.99 - Non-fatal stroke 1.2 1.2 1.03 - 0.9 0.9 0.97 - Hospitalization for heart failure 1.9 2.2 0.86 - 1.0 1.4 0.71 - Figure 1: Time to first occurrence of kidney failure, sustained decline in eGFR ≥ 40% from baseline, or renal death in the FIDELIO-DKD study Figure 2: Time to first occurrence of kidney failure, sustained decline in eGFR ≥ 40% from baseline, or renal death in the FIGARO-DKD study Figure 3: Time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure in the FIDELIO-DKD study Figure 4: Time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure in the FIGARO-DKD study Figure 1 Figure 2 Figure 3 Figure 4
Heart Failure (LVEF ≥40%)
FINEARTS-HF (NCT: 04435626) was a randomized, double-blind, placebo-controlled, multicenter study in adult patients with heart failure (New York Heart Association class II–IV) with documented left ventricular ejection fraction (LVEF) ≥40%. Patients were required to have an eGFR ≥25 mL/min/1.73m 2 and serum potassium ≤5.0 mEq/L at screening and randomization and were receiving background heart failure medical treatment, including diuretics. The primary endpoint was the composite of cardiovascular (CV) death and total (first and recurrent) heart failure events comprised of hospitalization for heart failure and urgent heart failure visits. In FINEARTS-HF, 6001 patients were analyzed; 3003 were randomized to Kerendia and 2998 were randomized to placebo and were followed for a median of 2.7 years.
The study included 3247 (54%) patients with a heart failure event in the past 3 months, including 1219 (20%) patients randomized during the hospitalization or within 7 days from the heart failure event. Patients with eGFR ≥ 25 to <60 mL/min/1.73m 2 initiated Kerendia 10 mg and patients with eGFR ≥60 mL/min/1.73m 2 initiated Kerendia 20 mg, and both groups were titrated up to a target dose of Kerendia 20 mg and 40 mg, respectively. At month 6, approximately 65% of the patients reached their target dose.
The trial population was 79% White, 17% Asian, and 1.5% Black. The mean age at enrollment was 72 years and 46% of patients were female. At baseline, the mean LVEF was 53%, with 64% of patients having an LVEF ≥50%, and 69% and 30% of patients were NYHA class II and III, respectively.
Mean blood pressure was 129/75 mmHg and mean body mass index (BMI) was 30 kg/m 2. The median NT-proBNP was 1041 pg/mL, the mean eGFR was 62 mL/min/1.73m 2 with 48% of patients having an eGFR <60 mL/min/1.73m 2. Atrial fibrillation was present on screening/baseline ECG for 38% of patients and 41% had diabetes mellitus. The majority of patients were on loop diuretics (87%), an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) (79%), or an angiotensin receptor neprilysin inhibitor (ARNI) (9%), and 14% were on sodium-glucose cotransporter 2 (SGLT2) inhibitors. Kerendia reduced the risk of the primary composite endpoint compared to placebo (Relative Risk 0.84, 95% CI 0.74-0.95, p=0.007). See Table 6 and Figure 5 below.
The Kerendia and placebo event curves separated early and continued to diverge over the study period, see Figure 5 below. Kerendia reduced the risk of the secondary endpoint of total heart failure events (hospitalization for HF or urgent HF visit) compared to placebo (RR 0.82, 95% CI 0.71-0.94, p=0.006). The treatment effect for the primary endpoint was consistent across all pre-specified subgroups, including sex, LVEF, NYHA class, eGFR, time since latest heart failure event, SGLT2 inhibitor therapy, and diabetes mellitus status. Table 6: Analysis of the Primary Endpoint (and its Individual Components) and Secondary Endpoint in Phase 3 Study FINEARTS-HF FINEARTS-HF Kerendia 10 or 20 or 40 mg OD N=3003 Placebo N=2998 Treatment Effect Kerendia vs Placebo Primary Efficacy Outcome and Components: Value Event Rate (100 pt–yr) Value Event Rate (100 pt–yr) Ratio or difference (95% CI) p-value E = total number of events; n = number of patients with an event ; RR = rate ratio; HR = hazard ratio; HF = Heart Failure; CV = Cardiovascular.
Primary composite of CV death and total HF events – E (n; %) 1083 (624; 20.8%) 14.9 1283 (719; 24.0%)
RR 0.84 0.007 Total HF events – E (n; %) Total HF
events (hospitalization for HF or urgent HF visit) was a prespecified secondary endpoint. 842 (479; 16.0%) 11.6 1024 (573; 19.1%)
RR 0.82 0.006 CV death – n (%) 242 (8.1%) 3.3 260
(8.7%)
HR 0.93 - Figure 5: Mean cumulative functions for primary composite endpoint
of CV death and total HF events in Phase 3 study FINEARTS-HF Figure 5
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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