12.3 )] , 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 [see dosing and administration ( 2.3 ) and drug interaction ( 7.2 )] . strong and moderate cyp3a4 inducers kerendia is a cyp3a4 substrate. concomitant use of kerendia with a strong or moderate cyp3a4 inducer decreases finerenone exposure [see clinical pharmacology ( 12.3 )], which may reduce the efficacy of kerendia. avoid concomitant use of kerendia with strong or moderate cyp3a4 inducers. 7.2 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. [see dosage and administration ( 2.3 ) and warnings and precautions ( 5.1 )].

excretion or increase serum potassium [see drug interactions ( 7.1 , 7.2 )] .

h water or soft foods such as applesauce immediately prior to use and administered orally [see clinical pharmacology ( 12.3 )] . 2.3 monitoring and dose adjustment the target daily dose of kerendia is 20 mg. measure serum potassium 4 weeks after initiating treatment and adjust dose (see table 2); if serum potassium levels are > 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 [see warnings and precautions ( 5.1 )]. monitor serum potassium 4 weeks after a dose adjustment and throughout treatment, and adjust the dose as needed (see table 2) [see warnings and precautions ( 5.1 ) and drug interactions ( 7.1 )]. table 2: dose adjustment based on current serum potassium concentration and current dose 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. * 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. * if egfr has decreased by more than 30% compared to previous measurement, maintain 10 mg dose. 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.

uration of 2.2 years 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 discontinuation due to adverse events also occurred in a similar proportion of patients in the two studies (6-7% of patients receiving kerendia and 5-6% of patients receiving placebo). the most frequently reported (≥ 10%) adverse reaction in both studies was hyperkalemia [see warnings and precautions ( 5.1 )]. 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% of patients receiving kerendia versus 0.6% of patients receiving placebo across both studies. table 3 shows adverse reactions that occurred more commonly on kerendia than on placebo, and in at least 1% of patients treated with kerendia. table 3: 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 (3.9) hyponatremia 82 (1.3) 47 (0.7) laboratory test initiation of kerendia may cause an initial small decrease in estimated gfr that occurs within the first 4 weeks of starting therapy, and then stabilizes. in a study that included patients with chronic kidney disease associated with type 2 diabetes, this decrease was reversible after treatment discontinuation. initiation of kerendia may also cause a small increase in serum uric acid. this increase appears to attenuate over time.

12.3 )] , 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 [see dosing and administration ( 2.3 ) and drug interaction ( 7.2 )] . strong and moderate cyp3a4 inducers kerendia is a cyp3a4 substrate. concomitant use of kerendia with a strong or moderate cyp3a4 inducer decreases finerenone exposure [see clinical pharmacology ( 12.3 )], which may reduce the efficacy of kerendia. avoid concomitant use of kerendia with strong or moderate cyp3a4 inducers. 7.2 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. [see dosage and administration ( 2.3 ) and warnings and precautions ( 5.1 )].

retarded ossification at the maternal toxic dose of 10 mg/kg/day corresponding to an auc unbound of 19 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 25 times that in humans. the doses free of any findings (low dose in rats, high dose in rabbits) provide safety margins of 10 to 13 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 4 times the auc unbound expected in humans. in addition, the offspring showed slightly increased locomotor activity, but no other neurobehavioral changes starting at about 4 times the auc unbound expected in humans. the dose free of findings provides a safety margin of about 2 times for the auc unbound expected in humans. 8.2 lactation risk summary there are no data on the presence of finerenone or its metabolite in human milk, the effects on the breastfed infant or the effects of the drug on milk production. in a pre- and postnatal developmental toxicity study in rats, increased pup mortality and lower pup weight were observed at about 4 times the auc unbound expected in humans. these findings suggest that finerenone is present in rat milk [see use in specific populations ( 8.1 ) and data]. when a drug is present in animal milk, it is likely that the drug will be present in human milk. because of the potential risk to breastfed infants from exposure to kerendia, avoid breastfeeding during treatment and for 1 day after treatment. 8.4 pediatric use the safety and efficacy of kerendia have not been established in patients below 18 years of age. 8.5 geriatric use of the 6510 patients who received kerendia in the fidelio-dkd and figaro-dkd studies, 55% of patients were 65 years and older, and 14% were 75 years and older. no overall differences in safety or efficacy were observed between these patients and younger patients. no dose adjustment is required. 8.6 hepatic impairment avoid use of kerendia in patients with severe hepatic impairment (child pugh c). no dosage adjustment is recommended in patients with mild or moderate hepatic impairment (child pugh a or b). consider additional serum potassium monitoring in patients with moderate hepatic impairment (child pugh b) [see dosing and administration ( 2.3 ) and clinical pharmacology ( 12.3 )].

to an auc unbound of 19 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 25 times that in humans. the doses free of any findings (low dose in rats, high dose in rabbits) provide safety margins of 10 to 13 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 4 times the auc unbound expected in humans. in addition, the offspring showed slightly increased locomotor activity, but no other neurobehavioral changes starting at about 4 times the auc unbound expected in humans. the dose free of findings provides a safety margin of about 2 times for the auc unbound expected in humans.

month 4 and remained stable for the duration of the trial. in arts dn, a randomized, double-blind, placebo-controlled, multicenter phase iib dose finding study in adults with ckd and t2d, the placebo-corrected relative reduction in uacr at day 90 was 25% and 38% in patients treated with finerenone 10 mg and 20 mg once daily, respectively. in patients treated with kerendia, the mean systolic blood pressure decreased by 3 mmhg and the mean diastolic blood pressure decreased by 1-2 mmhg at month 1, remaining stable thereafter. cardiac electrophysiology at a dose 4 times the maximum approved recommended dose, finerenone does not prolong the qt interval to any clinically relevant extent. 12.3 pharmacokinetics finerenone exposure increased proportionally over a dose range of 1.25 to 80 mg (0.06 to 4 times the maximum approved recommended dosage). steady state of finerenone was achieved after 2 days of dosing. the estimated steady-state geometric mean c max,md was 160 µg/l and steady-state geometric mean auc τ,md was 686 µg.h/l following administration of finerenone 20 mg to patients. absorption finerenone is completely absorbed after oral administration but undergoes metabolism resulting in absolute bioavailability of 44%. finerenone c max was achieved between 0.5 and 1.25 hours after dosing. effect of food there was no clinically significant effect on finerenone auc following administration with high fat, high calorie food. distribution the volume of distribution at steady-state (vss) of finerenone is 52.6 l. plasma protein binding of finerenone is 92%, primarily to serum albumin, in vitro. elimination the terminal half-life of finerenone is about 2 to 3 hours, and the systemic blood clearance is about 25 l/h. metabolism finerenone is primarily metabolized by cyp3a4 (90%) and to a lesser extent by cyp2c8 (10%) to inactive metabolites. excretion about 80% of the administered dose is excreted in urine (<1% as unchanged) and approximately 20% in feces (< 0.2% as unchanged). specific populations there are no clinically significant effects of age (18 to 79 years), sex, race/ethnicity (white, asian, black, and hispanic), or weight (58 to 121 kg) on the pharmacokinetics of finerenone. renal impairment there were no clinically relevant differences in finerenone auc or c max values in patients with egfr 15 to < 90 ml/min/1.73m 2 compared to egfr ≥ 90 ml/min/1.73 m 2 . for dosing recommendations based on egfr and serum potassium levels see dosage and administration ( 2 ) . hepatic impairment there was no clinically significant effect on finerenone exposure in cirrhotic patients with mild hepatic impairment (child pugh a). finerenone mean auc was increased by 38% and c max was unchanged in cirrhotic patients with moderate hepatic impairment (child pugh b) compared to healthy control subjects. the effect of severe hepatic impairment (child pugh c) on finerenone exposure was not studied . drug interaction studies clinical studies and model-informed approaches strong cyp3a inhibitors : concomitant use of itraconazole (strong cyp3a4 inhibitor) increased finerenone auc by >400%. moderate cyp3a inhibitors : concomitant use of erythromycin (moderate cyp3a4 inhibitor) increased finerenone mean auc and c max by 248% and 88%, respectively. weak cyp3a inhibitors : concomitant use of amiodarone (weak cyp3a4 inhibitor) increased finerenone auc by 21%. strong or moderate cyp3a inducers : concomitant use of efavirenz (moderate cyp3a4 inducer) and rifampicin (strong cyp3a4 inducer) decreased finerenone auc by 80% and 90%, respectively. other drugs : there was no clinically significant difference in finerenone pharmacokinetics when used concomitantly with gemfibrozil (strong cyp2c8 inhibitor), omeprazole (proton pump inhibitor), or an aluminium hydroxide and magnesium hydroxide antacid. there were no clinically significant pharmacokinetic differences for either finerenone or concomitant digoxin (p-gp substrate) or warfarin (cyp2c9 substrate). there were no clinically significant differences in the pharmacokinetics of either midazolam (cyp3a4 substrate) or repaglinide (cyp2c8 substrate) when used concomitantly with finerenone. multiple doses of 40 mg finerenone once-daily had no clinically relevant effect on auc or c max of the bcrp and oatp substrate rosuvastatin.

, and the systemic blood clearance is about 25 l/h. metabolism finerenone is primarily metabolized by cyp3a4 (90%) and to a lesser extent by cyp2c8 (10%) to inactive metabolites. excretion about 80% of the administered dose is excreted in urine (<1% as unchanged) and approximately 20% in feces (< 0.2% as unchanged). specific populations there are no clinically significant effects of age (18 to 79 years), sex, race/ethnicity (white, asian, black, and hispanic), or weight (58 to 121 kg) on the pharmacokinetics of finerenone. renal impairment there were no clinically relevant differences in finerenone auc or c max values in patients with egfr 15 to < 90 ml/min/1.73m 2 compared to egfr ≥ 90 ml/min/1.73 m 2 . for dosing recommendations based on egfr and serum potassium levels see dosage and administration ( 2 ) . hepatic impairment there was no clinically significant effect on finerenone exposure in cirrhotic patients with mild hepatic impairment (child pugh a). finerenone mean auc was increased by 38% and c max was unchanged in cirrhotic patients with moderate hepatic impairment (child pugh b) compared to healthy control subjects. the effect of severe hepatic impairment (child pugh c) on finerenone exposure was not studied . drug interaction studies clinical studies and model-informed approaches strong cyp3a inhibitors : concomitant use of itraconazole (strong cyp3a4 inhibitor) increased finerenone auc by >400%. moderate cyp3a inhibitors : concomitant use of erythromycin (moderate cyp3a4 inhibitor) increased finerenone mean auc and c max by 248% and 88%, respectively. weak cyp3a inhibitors : concomitant use of amiodarone (weak cyp3a4 inhibitor) increased finerenone auc by 21%. strong or moderate cyp3a inducers : concomitant use of efavirenz (moderate cyp3a4 inducer) and rifampicin (strong cyp3a4 inducer) decreased finerenone auc by 80% and 90%, respectively. other drugs : there was no clinically significant difference in finerenone pharmacokinetics when used concomitantly with gemfibrozil (strong cyp2c8 inhibitor), omeprazole (proton pump inhibitor), or an aluminium hydroxide and magnesium hydroxide antacid. there were no clinically significant pharmacokinetic differences for either finerenone or concomitant digoxin (p-gp substrate) or warfarin (cyp2c9 substrate). there were no clinically significant differences in the pharmacokinetics of either midazolam (cyp3a4 substrate) or repaglinide (cyp2c8 substrate) when used concomitantly with finerenone. multiple doses of 40 mg finerenone once-daily had no clinically relevant effect on auc or c max of the bcrp and oatp substrate rosuvastatin.

rb). 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/1.73m 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 (24% black in the us). 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 [64.1%], biguanides [44%], glucagon-like peptide-1 [glp-1] receptor agonists [7%], sodium-glucose cotransporter 2 [sglt2] inhibitors [5%]), 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=3683) 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 4 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 4 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 4 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 4 and figure 2. table 4: 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 composite of kidney failure, sustained egfr decline ≥40% or renal death 7.6 9.1 0.82 [0.73; 0.93] 0.001 3.2 3.6 0.87 [0.76; 1.01] - kidney failure 3.0 3.4 0.87 [0.72; 1.05] - 0.4 0.5 0.72 [0.49;1.05] - sustained egfr decline ≥40% 7.2 8.7 0.81 [0.72; 0.92] - 3.0 3.5 0.87 [0.75;>1.00] - renal death - - - - - - - - composite of cv death, non-fatal mi, non-fatal stroke or hospitalization for heart failure 5.1 5.9 0.86 [0.75; 0.99] 0.034 3.9 4.5 0.87 [0.76; 0.98] 0.026 cv death 1.7 2.0 0.86 [0.68;1.08] - 1.6 1.7 0.90 [0.74; 1.09] - non-fatal mi 0.9 1.2 0.80 [0.58;1.09] - 0.9 0.9 0.99 [0.76; 1.31] - non-fatal stroke 1.2 1.2 1.03 [0.76;1.38] - 0.9 0.9 0.97 [0.74; 1.26] - hospitalization for heart failure 1.9 2.2 0.86 [0.68;1.08] - 1.0 1.4 0.71 [0.56; 0.90] - 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. 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 renal failure composite endpoint graph fidelio-dkd renal failure composite endpoint graph figaro-dkd cardiovascular compiste endpoint for fidelio-dkd study cardiovascular compiste endpoint for figaro-dkd study