Leaflet KERENDIA 10mg film-coated tablets

Kerendia 10 mg film-coated tablets

Kerendia 20 mg film-coated tablets

Kerendia 40 mg film-coated tablets

Kerendia 10 mg film-coated tablets

Each film-coated tablet contains 10 mg of finerenone.

Each film-coated tablet contains 45 mg of lactose (as monohydrate), see section 4.4.

Kerendia 20 mg film-coated tablets

Each film-coated tablet contains 20 mg of finerenone.

Each film-coated tablet contains 40 mg of lactose (as monohydrate), see section 4.4.

Kerendia 40 mg film-coated tablets

Each film-coated tablet contains 40 mg of finerenone.

Each film-coated tablet contains 25 mg of lactose (as monohydrate), see section 4.4.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Kerendia 10 mg film-coated tablets

Pink, oval-oblong film-coated tablet with a length of 10 mm and a width of 5 mm, marked ‘10’ on oneside and ‘FI’ on the other side.

Kerendia 20 mg film-coated tablets

Pale yellow, oval-oblong film-coated tablet with a length of 10 mm and a width of 5 mm, marked ‘20’on one side and ‘FI’ on the other side.

Kerendia 40 mg film-coated tablets

Grey-orange, oval-oblong film-coated tablet with a length of 11 mm and a width of 5 mm,marked ‘40’ on one side and ‘FI’ on the other side.

Kerendia is indicated for the treatment of chronic kidney disease (with albuminuria) associated withtype 2 diabetes in adults.

For study results with respect to renal and cardiovascular events, see section 5.1.

Kerendia is indicated for the treatment of symptomatic chronic heart failure with left ventricularejection fraction (LVEF) ≥ 40% in adults.

Chronic kidney disease associated with type 2 diabetes (T2D)

The recommended target dose is 20 mg finerenone once daily.

The maximum recommended dose is 20 mg finerenone once daily.

Initiation of treatment

Serum potassium and estimated glomerular filtration rate (eGFR) have to be measured to determine iffinerenone treatment can be initiated (see also section 4.4) and to determine the starting dose.

For monitoring of serum potassium, see below ‘Continuation of treatment.’

If serum potassium ≤ 4.8 mmol/L, finerenone treatment can be initiated.

If serum potassium > 4.8 to 5.0 mmol/L, initiation of finerenone treatment may be considered withadditional serum potassium monitoring within the first 4 weeks based on patient characteristics andserum potassium levels (see section 4.4).

If serum potassium > 5.0 mmol/L, finerenone treatment should not be initiated (see section 4.4).

The recommended starting dose of finerenone is based on eGFR and is presented in table 1.

Table 1: Initiation of finerenone treatment and recommended doseeGFR (mL/min/1.73 m2) Starting dose (once daily)≥ 60 20 mg≥ 25 to < 60 10 mg< 25 Not recommended

Continuation of treatment

Serum potassium and eGFR have to be remeasured 4 weeks after initiation or re-start of finerenonetreatment or increase in dose (see table 2 to determine continuation of finerenone treatment and doseadjustment).

Thereafter, serum potassium has to be remeasured periodically and as needed based on patientcharacteristics and serum potassium levels.

See sections 4.4 and 4.5 for more information.

Table 2: Continuation of finerenone treatment and dose adjustment

Current finerenone dose (once daily)10 mg 20 mg

Current ≤ 4.8 Increase to 20 mg finerenone once Maintain 20 mg once dailyserum daily*potassium > 4.8 to 5.5 Maintain 10 mg once daily Maintain 20 mg once daily(mmol/L) > 5.5 Withhold finerenone. Withhold finerenone.

Consider re-starting at 10 mg Re-start at 10 mg once daily whenonce daily when serum potassium serum potassium ≤ 5.0 mmol/L.≤ 5.0 mmol/L.

* maintain 10 mg once daily, if eGFR has decreased > 30% compared to the previous measurement

Heart failure with LVEF ≥ 40%

The recommended target dose depends on renal function (eGFR) at initiation of finerenone treatment(see table 4):

- 40 mg once daily if eGFR ≥ 60 mL/min/1.73 m2

- 20 mg once daily if eGFR ≥ 25 to ˂ 60 mL/min/1.73 m2

The maximum recommended dose is 40 mg finerenone once daily.

Initiation of treatment

If serum potassium ≤ 5.0 mmol/L, finerenone treatment can be initiated.

Serum potassium and estimated glomerular filtration rate (eGFR) have to be measured to determine iffinerenone treatment can be initiated (see also section 4.4) and to determine the starting dose.

For monitoring of serum potassium, see below ‘Continuation of treatment.’

The recommended starting dose of finerenone is based on eGFR and is presented in table 3.

Table 3: Initiation of finerenone treatment and recommended doseeGFR (mL/min/1.73 m2) Starting dose (once daily)≥ 60 20 mg≥ 25 to < 60 10 mg< 25 Not recommended

Continuation of treatment

Serum potassium and eGFR have to be remeasured 4 weeks after initiation or re-start of finerenonetreatment or change in dose (see table 4 to determine continuation of finerenone treatment and doseadjustment).

Thereafter, serum potassium and eGFR have to be remeasured periodically and as needed based onpatient characteristics.

See sections 4.4 and 4.5 for more information.

Table 4: Continuation of finerenone treatment and dose adjustment

Current finerenone dose (once daily)10 mg 20 mg 40 mg

Current ˂ 5.0 Increase to 20 mg Increase to 40 mg once Maintain 40 mg onceserum finerenone once daily daily if eGFR has not dailypotassium if eGFR has not decreased > 30%(mmol/L) decreased > 30% compared to the Decrease to 20 mgcompared to the previous measurement once daily if eGFRprevious measurement has decreased > 30%

Maintain 20 mg once compared to thedaily if eGFR previous< 60 mL/min/1.73 m2 measurementat initiation5.0 to Maintain 10 mg once Maintain 20 mg once Maintain 40 mg once˂ 5.5 daily daily daily

Decrease to 20 mgonce daily if eGFRhas decreased > 30%compared to thepreviousmeasurement5.5 to Withhold finerenone Decrease to 10 mg Decrease to 20 mg˂ 6.0 Re-start at 10 mg once once daily once dailydaily when serumpotassium˂ 5.5 mmol/L.

≥ 6.0 Withhold finerenone.

Re-start at 10 mg once daily when serum potassium ˂ 5.5 mmol/L or ifrepeatedly ≥ 5.5 mmol/L, wait to re-start until ˂ 5.0 mmol/L.

If eGFR decreases by ≥ 40% compared to the previous measurement, consider reducing the dose orwithholding finerenone. Once eGFR levels have stabilised, according to the individual patient´scharacteristics, consider increasing the dose or restarting treatment.

A missed dose should be taken as soon as the patient notices, but only on the same day.

The patient should not take 2 doses to make up for a missed dose.

No dose adjustment is necessary in elderly patients (see section 5.2) but regular monitoring of renalfunction is recommended (see section 4.4).

Initiation of treatment

In patients with eGFR < 25 mL/min/1.73 m2, finerenone treatment should not be initiated due tolimited clinical data (see sections 4.4 and 5.2).

Continuation of treatment

In patients with eGFR ≥ 15 mL/min/1.73 m2, finerenone treatment can be continued with doseadjustment based on serum potassium. eGFR should be measured 4 weeks after initiation to determinewhether the starting dose can be increased (see ‘Posology, Continuation of treatment’ and tables 2and 4).

Due to limited clinical data, finerenone treatment should be discontinued in patients who haveprogressed to end-stage renal disease (eGFR < 15 mL/min/1.73 m2) (see section 4.4).

Patients with

- severe hepatic impairment:

Finerenone should not be initiated (see sections 4.4 and 5.2). No data are available.

- moderate hepatic impairment:

No initial dose adjustment is required. Consider additional serum potassium monitoring andadapt monitoring according to patient characteristics (see sections 4.4 and 5.2).

- mild hepatic impairment:

No initial dose adjustment is required.

Concomitant use of other medicinal products

In patients taking finerenone concomitantly with moderate or weak CYP3A4 inhibitors, potassiumsupplements, trimethoprim, or trimethoprim/sulfamethoxazole, additional serum potassium monitoringand adaptation of monitoring according to patient characteristics should be considered (seesection 4.4). Finerenone treatment decisions should be made as directed in tables 2 and 4 (see‘Posology, Continuation of treatment’).

Temporary discontinuation of finerenone may be necessary, when patients have to take trimethoprim,or trimethoprim/sulfamethoxazole. See sections 4.4 and 4.5 for more information.

No dose adjustment is necessary based on body weight (see section 5.2).

The safety and efficacy of finerenone in children and adolescents aged under 18 years have not yetbeen established. No data are available.

Oral use

Tablets may be taken with a glass of water and with or without food (see section 5.2).

Tablets should not be taken with grapefruit or grapefruit juice (see section 4.5).

Crushing of tablets

For patients who are unable to swallow whole tablets, Kerendia tablets may be crushed and mixedwith water or soft foods, such as apple sauce, directly before oral use (see section 5.2).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Concomitant treatment with strong inhibitors of CYP3A4 (see section 4.5), e.g.,

- itraconazole

- ketoconazole

- ritonavir

- nelfinavir

- cobicistat

- clarithromycin

- telithromycin

- nefazodone

- Addison's disease

Hyperkalaemia has been observed in patients treated with finerenone (see section 4.8).

Some patients are at a higher risk to develop hyperkalaemia. Risk factors include low eGFR, higherserum potassium and previous episodes of hyperkalaemia. In these patients more frequent monitoringhas to be considered.

If serum potassium > 5.0 mmol/L, finerenone treatment should not be initiated.

Serum potassium and eGFR have to be remeasured 4 weeks after initiation, restart or dose adjustmentof finerenone. Thereafter, serum potassium has to be assessed periodically and as needed based onpatient characteristics and serum potassium levels (see section 4.2).

Chronic kidney disease associated with T2D

Initiation and continuation of treatment (see section 4.2)

If serum potassium > 4.8 to 5.0 mmol/L, initiation of finerenone treatment may be considered withadditional serum potassium monitoring within the first 4 weeks based on patient characteristics andserum potassium levels.

If serum potassium > 5.5 mmol/L, finerenone treatment has to be withheld. Local guidelines for themanagement of hyperkalaemia have to be followed.

Once serum potassium ≤ 5.0 mmol/L, finerenone treatment can be restarted at 10 mg once daily.

Heart failure with LVEF ≥ 40%

Initiation and continuation of treatment (see section 4.2)

If serum potassium  6.0 mmol/L, finerenone treatment has to be withheld. Local guidelines for themanagement of hyperkalaemia have to be followed. Once serum potassium ˂ 5.5 mmol/L, finerenonetreatment can be restarted at 10 mg once daily. In case of repeated measurements of serum potassium 5.5 mmol/L, finerenone treatment can only be restarted, when serum potassium is ˂ 5.0 mmol/L.

Concomitant use of other medicinal products

The risk of hyperkalaemia also may increase with the intake of concomitant medicinal products thatmay increase serum potassium (see section 4.5). See also ‘Concomitant use of substances that affectfinerenone exposure’.

Finerenone should not be given concomitantly with

- potassium-sparing diuretics (e.g., amiloride, triamterene) and

- other mineralocorticoid receptor antagonists (MRAs), e.g., eplerenone, esaxerenone,spironolactone, canrenone.

Finerenone should be used with caution and serum potassium should be monitored when takenconcomitantly with

- potassium supplements or potassium-enriched salt substitutes.

- trimethoprim, or trimethoprim/sulfamethoxazole. Temporary discontinuation of finerenone maybe necessary.

Worsening of renal function in patients with heart failure with LVEF ≥ 40%

An increased incidence of worsening of renal function has been reported in patients with heart failurewith LVEF ≥ 40% treated with finerenone (see section 4.8). Monitoring of renal function isrecommended periodically during treatment and as needed based on patient characteristics. Elderlypatients and patients with impaired renal function (eGFR ˂ 60 mL/min/1.73 m2) are at higher risk forworsening of renal function and should be monitored more frequently (see section 4.2).

The risk of hyperkalaemia increases with decreasing renal function. Ongoing monitoring of renalfunction should be performed as needed according to standard practice (see section 4.2).

Initiation of treatment

Finerenone treatment should not be initiated in patients with eGFR < 25 mL/min/1.73 m2 as clinicaldata are limited (see sections 4.2 and 5.2).

Continuation of treatment

Due to limited clinical data, finerenone treatment should be discontinued in patients who haveprogressed to end-stage renal disease (eGFR < 15 mL/min/1.73 m2).

Finerenone treatment should not be initiated in patients with severe hepatic impairment (seesection 4.2). These patients have not been studied (see section 5.2) but a significant increase infinerenone exposure is expected.

The use of finerenone in patients with moderate hepatic impairment may require additional monitoringdue to an increase in finerenone exposure. Additional serum potassium monitoring and adaptation ofmonitoring have to be considered according to patient characteristics (see sections 4.2 and 5.2).

Patients with New York Heart Association (NYHA) class IV

Experience with finerenone in heart failure patients classified as NYHA class IV is limited (seesection 5.1).

Elderly are more likely to have impaired renal function and to be treated with medicinal productswhich may cause changes in renal function. Therefore, regular monitoring of renal function isrecommended.

Concomitant use of substances that affect finerenone exposure

Moderate and weak CYP3A4 inhibitors

Serum potassium should be monitored during concomitant use of finerenone with moderate or weak

CYP3A4 inhibitors (see sections 4.2 and 4.5).

Strong and moderate CYP3A4 inducers

Finerenone should not be used concomitantly with strong or moderate CYP3A4 inducers (seesection 4.5).

Grapefruit

Grapefruit or grapefruit juice should not be consumed during finerenone treatment (see sections 4.2and 4.5).

Embryo-foetal toxicity

Finerenone should not be used during pregnancy unless there has been careful consideration of thebenefit for the mother and the risk to the foetus. If a woman becomes pregnant while takingfinerenone, she should be informed of potential risks to the foetus.

Women of childbearing potential should be advised to use effective contraception during treatmentwith finerenone.

Women should be advised not to breast-feed during treatment with finerenone.

See sections 4.6 and 5.3 for more information.

Kerendia contains lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

Kerendia contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Interaction studies have only been performed in adults.

Finerenone is cleared almost exclusively via cytochrome P450 (CYP)-mediated oxidative metabolism(mainly CYP3A4 [90%] with a small contribution of CYP2C8 [10%]).

Strong CYP3A4 inhibitors

Concomitant use of Kerendia with itraconazole, clarithromycin and other strong CYP3A4 inhibitors(e.g., ketoconazole, ritonavir, nelfinavir, cobicistat, telithromycin or nefazodone) is contraindicated(see section 4.3), since a marked increase in finerenone exposure is expected.

Strong and moderate CYP3A4 inducers

Kerendia should not be used concomitantly with rifampicin and other strong CYP3A4 inducers (e.g.,carbamazepine, phenytoin, phenobarbital, St John’s Wort) or with efavirenz and other moderate

CYP3A4 inducers. These CYP3A4 inducers are expected to markedly decrease finerenone plasmaconcentration and result in reduced therapeutic effect (see section 4.4).

Certain medicinal products that increase serum potassium

Kerendia should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride,triamterene) and other MRAs (e.g., eplerenone, esaxerenone, spironolactone, canrenone). It isanticipated that these medicinal products increase the risk for hyperkalaemia (see section 4.4)

Grapefruit

Grapefruit or grapefruit juice should not be consumed during finerenone treatment, as it is expected toincrease the plasma concentrations of finerenone through inhibition of CYP3A4 (see sections 4.2and 4.4).

Concomitant use with precautions

Moderate CYP3A4 inhibitors

In a clinical study, concomitant use of erythromycin (500 mg three times a day) led to a 3.5-foldincrease in finerenone AUC and 1.9-fold increase in its Cₘₐₓ. In another clinical study, verapamil(240 mg controlled-release tablet once daily) led to a 2.7- and 2.2-fold increase in finerenone AUCand Cₘₐₓ, respectively.

Serum potassium may increase, and therefore, monitoring of serum potassium is recommended,especially during initiation or changes to dosing of finerenone or the CYP3A4 inhibitor (seesections 4.2 and 4.4).

Weak CYP3A4 inhibitors

The physiologically based pharmacokinetic (PBPK) simulations suggest that fluvoxamine (100 mgtwice daily), increases finerenone AUC (1.6-fold) and Cₘₐₓ (1.4-fold).

Serum potassium may increase, and therefore, monitoring of serum potassium is recommended,especially during initiation or changes to dosing of finerenone or the CYP3A4 inhibitor (seesections 4.2 and 4.4).

Certain medicinal products that increase serum potassium (see section 4.4)

Concomitant use of Kerendia with potassium supplements and trimethoprim, ortrimethoprim/sulfamethoxazole is anticipated to increase the risk of hyperkalaemia. Monitoring ofserum potassium is required.

Temporary discontinuation of Kerendia during trimethoprim, or trimethoprim/sulfamethoxazoletreatment may be necessary.

Antihypertensive medicinal products

The risk for hypotension increases with concomitant use of multiple other antihypertensive medicinalproducts. In these patients, blood pressure monitoring is recommended.

Effect of 40 mg finerenone on CYP3A4 and CYP2C8 substrates

At 40 mg once daily, finerenone is a weak inhibitor of the CYP3A4 enzyme in vivo. Co-administrationof multiple doses of 40 mg finerenone with the CYP3A4 probe substrate midazolam resulted in a1.31-fold increase in mean midazolam AUC with no effect on Cₘₐₓ. The potentially increased exposureof sensitive CYP3A4 substrates with a narrow therapeutic window needs to be considered when usedconcomitantly with finerenone 40 mg once daily. A multiple-dose regimen of 20 mg finerenone givenonce daily for 10 days had no relevant effect on the AUC of the CYP3A4 probe substrate midazolam.

Therefore, a clinically relevant inhibition or induction of CYP3A4 by finerenone can be excluded atthis dose level.

At 40 mg once daily, finerenone is a weak inhibitor of the CYP2C8 enzyme in vivo. Co-administrationof multiple doses of 40 mg finerenone with the CYP2C8 probe substrate repaglinide resulted in a1.59-fold increase in mean repaglinide AUC and a 1.30-fold increase in Cₘₐₓ. The potentially increasedexposure of CYP2C8 substrates with a narrow therapeutic window needs to be considered when usedconcomitantly with finerenone 40 mg once daily.

A single dose of 20 mg finerenone had no clinically relevant effect on AUC and Cₘₐₓ of the

CYP2C8 probe substrate repaglinide. Thus, finerenone does not inhibit CYP2C8 at this doselevel.

Contraception in females

Women of childbearing potential should use effective contraception during finerenone treatment (seesection 4.4).

There are no data from the use of finerenone in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Kerendia should not be used during pregnancy unless the clinical condition of the woman requirestreatment with finerenone. If the woman becomes pregnant while taking finerenone, she should beinformed of potential risks to the foetus (see section 4.4).

It is unknown whether finerenone/metabolites are excreted in human milk.

Available pharmacokinetic/toxicological data in animals have shown excretion of finerenone and itsmetabolites in milk. Rat pups exposed via this route showed adverse reactions (see section 5.3).

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Kerendia therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman (see section 4.4).

There are no data on the effect of finerenone on human fertility.

Animal studies have shown impaired female fertility at exposures considered in excess to the maximumhuman exposure, indicating low clinical relevance (see section 5.3).

Kerendia has no influence on the ability to drive and use machines.

The most frequently reported adverse reaction under treatment with finerenone was hyperkalaemia(12.6%). See ‘Description of selected adverse reactions, Hyperkalaemia’ below and section 4.4.

The safety of finerenone in patients with chronic kidney disease (CKD) and T2D was evaluated in2 pivotal phase III studies, FIDELIO-DKD (diabetic kidney disease) and FIGARO-DKD. In the

FIDELIO-DKD study 2 818 patients received finerenone (10 mg or 20 mg once daily) with a meanduration of treatment of 2.2 years. In the FIGARO-DKD study, 3 671 patients received finerenone(10 mg or 20 mg once daily) with a mean duration of treatment of 2.9 years.

The safety of finerenone in patients with heart failure (HF) with LVEF ≥ 40% was evaluated in thephase III study, FINEARTS-HF. In this study, 2 993 patients received finerenone (10 mg, 20 mg, or40 mg once daily) with a mean duration of treatment of 2.1 years.

The adverse reactions observed are listed in table 5. They are classified according to MedDRA systemorgan class and frequency convention.

Adverse reactions are grouped according to their frequencies in the order of decreasing seriousness.

Frequencies are defined as follows:

Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare(≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the availabledata).

Table 5: Adverse reactions

System organ class Frequency CKD with T2D HF with LVEF ≥ 40%

Very common Hyperkalaemia -

Metabolism and

Hyponatraemia Hyperkalaemianutrition disorders Common Hyperuricaemia Hyponatraemia

Hyperuricaemia

Vascular disorders Common Hypotension Hypotension

Gastrointestinaldisorders Common - Diarrhoea

Skin andsubcutaneous tissue Common Pruritus -disorders

Renal and urinarydisorders Common - Renal impairment

Acute kidney injury

Blood creatinine Blood creatinine

Common increased/ Glomerular increased/ Glomerular

Investigations filtration rate decreased filtration rate decreased

Uncommon Haemoglobin decreased -

An increase from baseline in mean serum potassium in the first month of treatment of up to0.2 mmol/L was observed in the finerenone group compared to placebo, which remained stablethereafter.

In the pooled data of FIDELIO-DKD and FIGARO-DKD studies, hyperkalaemia events were reportedin 14.0% of finerenone-treated patients compared with 6.9% of placebo-treated patients. Seriousevents of hyperkalaemia were reported more frequently for finerenone (1.1%) than for placebo (0.2%).

Serum potassium concentrations > 5.5 mmol/L and > 6.0 mmol/L were reported in 16.8% and 3.3% offinerenone-treated patients and in 7.4% and 1.3% of placebo-treated patients, respectively.

Hyperkalaemia leading to permanent discontinuation in patients who received finerenone was 1.7%versus 0.6% in the placebo group. Hospitalisation due to hyperkalaemia in the finerenone group was0.9% versus 0.2% in the placebo group.

In the FINEARTS-HF study, hyperkalaemia events were reported in 9.7% of finerenone-treatedpatients compared with 4.2% of placebo-treated patients. Hyperkalaemia leading to permanentdiscontinuation in patients who received finerenone was 0.4% versus 0.2% in the placebo group.

Hospitalisation due to hyperkalaemia in the finerenone group was 0.5% versus 0.2% in the placebogroup.

In all studies, the majority of hyperkalaemia events were mild to moderate and resolved in patientstreated with finerenone.

For specific recommendations, see sections 4.2 and 4.4.

Worsening of renal function

In the pooled data of FIDELIO-DKD and FIGARO-DKD studies, GFR decreased events werereported in 5.4% of finerenone-treated patients compared with 4.2% of placebo-treated patients. GFRdecreased events leading to permanent discontinuation were the same in patients receiving finerenoneor placebo (0.2%). Hospitalisation due to decreased GFR was the same in patients receivingfinerenone or placebo (< 0.1%).

Blood creatinine increased events were reported in 2.6% of finerenone-treated patients compared with2.3% of placebo-treated patients.

The majority of GFR decreased/blood creatinine increased events were mild or moderate and resolvedin patients treated with finerenone. Patients on finerenone experienced an initial decrease in eGFR(mean 2 mL/min/1.73 m2) that attenuated over time compared to placebo. This decrease appeared to bereversible during continuous treatment.

In the FINEARTS-HF study, events related to worsening of renal function were reported morefrequently in patients treated with finerenone (17.7%) compared to those receiving placebo (10.9%).

The reported events included renal impairment (6.6% vs. 3.9%), GFR decreased (5.2% vs. 3.6%),acute kidney injury (3.7% vs. 2.1%), renal failure (2.6% vs. 1.6%), and blood creatinine increased(1.2% vs. 0.8%).

Overall, most of the reported events related to worsening of renal function were mild to moderate andresolved in patients treated with finerenone. In some cases where finerenone was permanentlydiscontinued, eGFR did not return to baseline levels. Events related to worsening of renal function thatled to permanent discontinuation were identical in both the finerenone and placebo groups (0.3%).

Events related to worsening of renal function leading to hospitalisation were reported more frequentlyin patients treated with finerenone compared to the placebo group (2.0% vs. 1.3%), with acute kidneyinjury being the most frequently reported event leading to hospitalisation (1.6% in finerenone vs. 0.8%in placebo).

Patients on finerenone experienced an initial decrease in GFR that appeared to be reversible duringcontinuous treatment. The mean difference in GFR between finerenone and placebo wasapproximately 3-4 mL/min/1.73 m2 from month 1 to month 6. After month 6, the decline in GFR wasslightly larger in the placebo group, with a mean difference between finerenone and placebo ofapproximately 2-3 mL/min/1.73 m2.

Finerenone treatment led to a mean systolic blood pressure decrease by 2-4 mm Hg and a meandiastolic blood pressure decrease by 1-2 mm Hg at month 1, remaining stable thereafter.

In the pooled data of FIDELIO-DKD and FIGARO-DKD studies, hypotension events were reported in4.7% of finerenone-treated patients compared with 3.0% of placebo-treated patients. In 3 patients(< 0.1%), finerenone treatment was permanently discontinued due to hypotension. Hospitalisation dueto hypotension was the same in patients receiving finerenone or placebo (0.1%).

In the FINEARTS-HF study, hypotension events were reported in 7.6% of finerenone-treated patientscompared with 4.7% of placebo-treated patients. In 3 patients (0.1%), finerenone treatment waspermanently discontinued due to hypotension. Hospitalisation due to hypotension was 0.4% in thefinerenone group versus 0.3% in the placebo group.

In all studies, the majority of hypotension events were mild or moderate and resolved in patientstreated with finerenone.

Hyperuricaemia

In the pooled data of FIDELIO-DKD and FIGARO-DKD studies, hyperuricaemia events werereported in 5.1% of finerenone-treated patients compared with 3.9% of placebo-treated patients. Anincrease from baseline in mean serum uric acid of 0.3 mg/dL was seen in the finerenone groupcompared to placebo up to month 16, which attenuated over time. Gout reporting was comparable infinerenone-treated patients (3.1%) and in placebo-treated patients (3.0%).

In the FINEARTS-HF study, hyperuricaemia reporting was comparable in finerenone-treated patients(2.7%) and in placebo-treated patients (2.4%). Gout reporting was comparable in finerenone-treatedpatients (2.4%) and in placebo-treated patients (2.8%).

In all studies, hyperuricaemia events were non-serious and did not result in permanent discontinuationin patients who received finerenone.

In the FINEARTS-HF study, diarrhoea (5.7% vs. 4.4%) and constipation (3.8% vs. 2.7%) werereported more frequently for finerenone compared with placebo.

Haemoglobin decreased

In the pooled data of FIDELIO-DKD and FIGARO-DKD studies, finerenone was associated with aplacebo-corrected absolute decrease in mean haemoglobin of 0.15 g/dL and mean haematocrit of 0.5%after 4 months of treatment. Anaemia reporting was comparable in finerenone-treated patients (6.5%)and placebo-treated patients (6.1%). The frequency of serious events of anaemia was low in both thefinerenone-treated and placebo-treated patients (0.5%). Changes in haemoglobin and haematocrit weretransient and reached comparable levels to those observed in the placebo-treated group after about24-32 months.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The most likely manifestation of overdose is anticipated to be hyperkalaemia. If hyperkalaemiadevelops, standard treatment should be initiated.

Finerenone is unlikely to be efficiently removed by haemodialysis given its fraction bound to plasmaproteins of about 90%.

Pharmacotherapeutic group: diuretics, aldosterone antagonists, ATC code: C03DA05

Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor (MR) which isactivated by aldosterone and cortisol and regulates gene transcription. Its binding to the MR leads to aspecific receptor-ligand complex that blocks recruitment of transcriptional coactivators implicated inthe expression of pro-inflammatory and pro-fibrotic mediators.

In FIDELIO-DKD and FIGARO-DKD, randomised, double-blind, placebo-controlled, multicentrephase III studies in adult patients with CKD and T2D, the placebo-corrected relative reduction inurinary albumin-to-creatinine ratio (UACR) in patients randomised to finerenone was 31% and 32%,respectively at month 4 and UACR remained reduced throughout both studies.

In FINEARTS-HF, randomised, double-blind, placebo-controlled, multicentre phase III studyin adult patients with HF with LVEF ≥ 40%, the placebo-corrected relative reduction in UACR inpatients randomised to finerenone was 30% at month 6, and UACR remained reduced up to the lastmeasurement at year 2.

In ARTS-DN, a randomised, double-blind, placebo-controlled, multicentre phase IIb study in adultpatients 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.

A dedicated QT study in 57 healthy participants showed that finerenone has no effect on cardiacrepolarisation. There was no indication of a QT/QTc prolonging effect of finerenone after single dosesof 20 mg (therapeutic) or 80 mg (supratherapeutic).

Chronic kidney disease associated with T2D

The FIDELIO-DKD and FIGARO-DKD studies investigated the effect of finerenone compared toplacebo on kidney and cardiovascular (CV) outcomes in adult patients with CKD and T2D.

Patients were required to be receiving standard of care, including a maximum tolerated labelled doseof an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

Patients with diagnosed heart failure with reduced ejection fraction and NYHA class II-IV wereexcluded due to the class 1A recommendation for MRA therapy.

In the FIDELIO-DKD study patients were eligible based on evidence of persistent albuminuria(> 30 mg/g to 5 000 mg/g), an eGFR of 25 to 75 mL/min/1.73 m2 and serum potassium ≤ 4.8 mmol/Lat screening.

The primary endpoint was a composite of time to first occurrence of kidney failure (defined as chronicdialysis or kidney transplantation, or a sustained decrease in eGFR to < 15 mL/min/1.73 m2 over atleast 4 weeks), a sustained decline in eGFR of 40% or more compared to baseline over at least4 weeks, or renal death. The key secondary endpoint was a composite of time to first occurrence of

CV death, non-fatal myocardial infarction (MI), non-fatal stroke or hospitalisation for heart failure.

A total of 5 662 patients were randomised to receive either finerenone (N = 2 824) or placebo(N = 2 838) and included in the analyses. The median follow-up was 2.6 years. The dose of finerenoneor placebo could be adjusted between 10 mg and 20 mg once daily during the course of the study,based mainly on serum potassium concentration. At month 24, of the subjects treated with finerenone,67% were treated with 20 mg once daily, 31% with 10 mg once daily and 3% were on a treatmentinterruption.

After the end of study, vital status was obtained for 99.7% of patients. The study population was 63%

White, 25% Asian and 5% Black. The mean age at enrolment was 66 years and 70% of patients weremale. At baseline, the mean eGFR was 44.4 mL/min/1.73 m2, with 55% of patients having aneGFR < 45 mL/min/1.73 m2, median UACR was 853 mg/g, and mean HbA1c was 7.7%, 46% had ahistory of atherosclerotic CV disease, 30% a history of coronary artery disease, 8% a history of cardiacfailure, and the mean blood pressure was 138/76 mm Hg. The mean duration of T2D at baseline was16.6 years and a history of diabetic retinopathy and diabetic neuropathy was reported in 47% and 26%of patients, respectively. At baseline, almost all patients were on ACEi (34%) or ARB (66%), and 97%of patients used one or more antidiabetic medicinal products (insulin [64%], biguanides [44%],glucagon-like peptide-1 [GLP-1] receptor agonists [7%], sodium-glucose cotransporter 2 [SGLT2]inhibitors [5%]). The other most frequent medicinal products taken at baseline were statins (74%) andcalcium channel blockers (63%).

A statistically significant difference in favour of finerenone was shown for the primary compositeendpoint and the key secondary composite endpoint (see figure 1/table 6 below). The treatment effectfor the primary and key secondary endpoints was generally consistent across subgroups, includingregion, eGFR, UACR, systolic blood pressure (SBP) and HbA1c at baseline.

In the FIGARO-DKD study patients were eligible, based on evidence of persistent albuminuria havingan UACR of ≥ 30 mg/g to < 300 mg/g and an eGFR of 25 to 90 mL/min/1.73 m2, or an

UACR ≥ 300 mg/g and an eGFR ≥ 60 mL/min/1.73 m2 at screening. Patients were required to have aserum potassium of ≤ 4.8 mmol/L at screening.

The primary endpoint was a composite of time to first occurrence of CV death, non-fatal MI, non-fatalstroke or hospitalisation for heart failure. The secondary endpoint was a composite of time to kidneyfailure, a sustained decline in eGFR of 40% or more compared to baseline over at least 4 weeks, orrenal death.

A total of 7 328 patients were randomised to receive either finerenone (N = 3 674), or placebo(N = 3 654) and included in the analyses. The median follow-up was 3.4 years. The dose of finerenoneor placebo could be adjusted between 10 mg and 20 mg once daily during the course of the study,based mainly on serum potassium concentration. At month 24, of the subjects treated with finerenone,82% were treated with 20 mg once daily, 15% with 10 mg once daily and 3% were on a treatmentinterruption. After the end of study, vital status was obtained for 99.8% of patients. The studypopulation was 72% White, 20% Asian and 4% Black. The mean age at enrolment was 64 years and69% of patients were male. At baseline, the mean eGFR was 67.8 mL/min/1.73 m2, with 62% ofpatients having an eGFR ≥ 60 mL/min/1.73 m2, median UACR was 309 mg/g, and mean HbA1c was7.7%, 45% of patients had a history of atherosclerotic CV disease, 8% had a history of cardiac failure,and the mean blood pressure was 136/77 mm Hg. The mean duration of T2D at baseline was14.5 years and a history of diabetic retinopathy and diabetic neuropathy was reported in 31% and 28%of patients, respectively. At baseline, almost all patients were on ACEi (43%) or ARB (57%), and 98%of patients used one or more antidiabetic medicinal product (insulin [54%], biguanides [69%], GLP-1receptor agonists [8%], SGLT2 inhibitors [8%]). The other most frequent medicinal products taken atbaseline were statins (71%).

A statistically significant difference in favour of finerenone was shown for the CV primary compositeendpoint (see figure 2/table 7 below). The treatment effect for the primary endpoint was consistentacross subgroups, including region, eGFR, UACR, SBP and HbA1c at baseline.

A lower incidence rate of the secondary composite outcome of kidney failure, sustained eGFR declineof 40% or more or renal death was observed in the finerenone group compared to placebo, howeverthis difference did not achieve statistical significance (see table 7 below). The treatment effect for thekidney secondary composite endpoint was consistent across subgroups of eGFR at baseline, but for thesubgroup of patients with UACR < 300 mg/g the HR was 1.16 (95% CI 0.91; 1.47) and for thesubgroup of patients with UACR ≥ 300 mg/g the HR was 0.74 (95% CI 0.61; 0.89).

Additional prespecified secondary time-to-event endpoints are included in table 7.

Table 6: Analysis of the primary and secondary time-to-event endpoints (and their individualcomponents) in phase III study FIDELIO-DKD

Kerendia* (N = 2 824) Placebo (N = 2 838) Treatment effect

N (%) Events/ N (%) Events/ HR (95% CI)100-pyr 100-pyr

Primary renal composite endpoint and its components

Composite of kidney failure,sustained eGFR decline ≥ 40% 498 (17.6) 7.53 600 (21.1) 9.09 0.82 (0.73; 0.92)or renal death p = 0.0009

Kidney failure 205 (7.3) 2.96 235 (8.3) 3.39 0.86 (0.72; 1.05)

Sustained eGFRdecline ≥ 40% 473 (16.7) 7.15 577 (20.3) 8.74 0.81 (0.72; 0.91)

Renal death 2 (< 0.1) - 2 (< 0.1) - -

Key secondary CV composite endpoint and its components

Composite of CV death,non-fatal MI, non-fatal stroke 366 (13.0) 5.11 420 (14.8) 5.93 0.86 (0.75; 0.99)or hospitalisation for heart p = 0.0344failure

CV death 128 (4.5) 1.70 150 (5.3) 1.99 0.86 (0.68;1.09)

Non-fatal MI 70 (2.5) 0.94 87 (3.1) 1.18 0.80 (0.58;1.09)

Non-fatal stroke 90 (3.2) 1.22 87 (3.1) 1.18 1.03 (0.77;1.38)

Hospitalisation for heartfailure 138 (4.9) 1.88 162 (5.7) 2.22 0.85 (0.68;1.07)

Secondary efficacy endpoints

All-cause mortality 219 (7.8) 2.90 244 (8.6) 3.24 0.90 (0.75; 1.08) **

All-cause hospitalisation 1 259 (44.6) 22.59 1 321 (46.5) 23.91 0.95 (0.88; 1.02) **

Composite of kidney failure,sustained eGFR decline ≥ 57% 248 (8.8) 3.60 326 (11.5) 4.74 0.75 (0.65; 0.90) **or renal death

* Treatment with 10 or 20 mg once daily in addition to maximum tolerated labelled doses of ACEi or ARB.

** p = not statistically significant after adjustment for multiplicity

CI: Confidence interval

HR: Hazard ratiopyr: patient-years

Figure 1: Time to first occurrence of kidney failure, sustained decline in eGFR ≥ 40% from baseline,or renal death in the FIDELIO-DKD study0.50

Planned treatment0.45 1: Finerenone (N=2 824)2: Placebo (N=2 838)0.400.350.300.250.200.150.100.050.000 6 12 18 24 30 36 42 48

Time to first event (months)

Number of subjects at risk1 2 824 2 696 2 599 2 390 1 802 1 269 782 437 822 2 838 2 721 2 583 2 376 1 757 1 247 791 452 82

Cumulative incidence probability

Table 7: Analysis of the primary and secondary time-to-event endpoints (and their individualcomponents) in phase III study FIGARO-DKD

Kerendia* (N = 3 674) Placebo (N = 3 654) Treatment effect

N (%) Events/ N (%) Events/ HR (95% CI)100-pyr 100-pyr

Primary CV composite endpoint and its components

Composite of CV death,non-fatal MI, non-fatal stroke 457 (12.4) 3.88 518 (14.2) 4.46 0.87 (0.76; 0.98)or hospitalisation for heart p = 0.0254failure

CV death 193 (5.3) 1.56 214 (5.9) 1.75 0.89 (0.73; 1.08)

Non-fatal MI 103 (2.8) 0.85 101 (2.8) 0.84 1.00 (0.76; 1.32)

Non-fatal stroke 108 (2.9) 0.89 111 (3.0) 0.93 0.97 (0.74; 1.26)

Hospitalisation for heartfailure 117 (3.2) 0.97 163 (4.5) 1.36 0.71 (0.56; 0.90)

Secondary renal composite endpoint and its components

Composite of kidney failure,sustained eGFR decline ≥ 40% 350 (9.5) 3.17 395 (10.8) 3.59 0.87 (0.75; 1.01)or renal death p = 0.0635 **

Kidney failure 46 (1.3) 0.40 62 (1.7) 0.55 0.72 (0.49;1.05)

Sustained eGFRdecline ≥ 40% 338 (9.2) 3.06 385 (10.5) 3.50 0.86 (0.74; < 1.00)

Renal death 0 - 2 (< 0.1) - -

Secondary efficacy endpoints

All-cause mortality 332 (9.0) 2.69 370 (10.1) 3.03 0.89 (0.77; 1.03) **

All-cause hospitalisation 1 569 (42.7) 16.94 1 599 (43.8) 17.54 0.97 (0.90; 1.04) **

Composite of kidney failure,sustained eGFR decline ≥ 57% 108 (2.9) 0.95 139 (3.8) 1.23 0.77 (0.60; 0.99) **or renal death

* Treatment with 10 or 20 mg once daily in addition to maximum tolerated labelled doses of ACEi or ARB.

** p = not statistically significant after adjustment for multiplicity

CI: Confidence interval

HR: Hazard ratiopyr: patient-years

Figure 2: Time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke orhospitalisation for heart failure in the FIGARO-DKD study0.20

Planned treatment0.18 1: Finerenone (N=3 674)2: Placebo (N=3 654)0.160.140.120.100.080.060.040.020.000 6 12 18 24 30 36 42 48 54

Time to first event (months)

Number of subjects at risk1 3 674 3 588 3 505 3 415 3 308 2 771 2 175 1 703 1 085 5902 3 654 3 565 3 467 3 377 3 255 2 718 2 115 1 648 1 067 576

Heart failure with LVEF ≥ 40%

The FINEARTS-HF study investigated the effect of finerenone compared to placebo on cardiovascularoutcomes in adult patients with heart failure.

Patients were eligible with a diagnosis of heart failure with NYHA class II-IV, ambulatory orhospitalised primarily for heart failure, and with documented LVEF ≥ 40%. In addition, patients hadan eGFR ≥ 25 mL/min/1.73 m2 and serum potassium ≤ 5.0 mmol/L at screening and randomisationand were receiving background therapy, including diuretic treatment.

The primary endpoint was the composite of cardiovascular death and total (first and recurrent) heartfailure events comprised of hospitalisation for heart failure and urgent heart failure visits. Amultiple-testing procedure was used for the secondary endpoints, including total (first and recurrent)heart failure events, and change from baseline to month 6, 9, and 12 in Total Symptom Score (TSS) ofthe Kansas City Cardiomyopathy Questionnaire (KCCQ) (which quantifies heart failure symptomfrequency and severity).

The study analysed 6 001 patients randomly assigned to receive either finerenone (N=3 003) orplacebo (N=2 998). The median follow-up was 2.7 years. The study included 3 247 (54%) patientswith a heart failure event in the past 3 months, including 1 219 (20%) patients randomised during thehospitalisation or within 7 days of discharge.

Based on renal parameters, patients received either 10 mg, 20 mg or 40 mg finerenone or placebo oncedaily during the course of the study. At month 24, of the subjects treated with finerenone, 35% weretreated with 40 mg once daily, 32% with 20 mg once daily, 12% with 10 mg once daily and 1% wereon a treatment interruption. At any time during treatment approximately 80% of the patients reachedtheir target dose.

After the end of study notification, vital status was obtained for 99.7% of patients. The studypopulation was 79% White, 17% Asian and 1.5% Black. The mean age at enrolment was 72 years and46% of patients were female. At baseline, the mean LVEF was 53%, with 64% of patients having an

LVEF ≥ 50%, and 69%, 30% and 1% of patients were NYHA class II, III and IV, respectively. Meanblood pressure was 129/75 mm Hg while BMI was 30 kg/m2. The median N-terminal prohormone ofbrain natriuretic peptide (NT-pro-BNP) was 1 041 pg/mL, the mean eGFR was 62 mL/min/1.73 m2with 48% of patients having an eGFR ˂ 60 mL/min/1.73 m2, and the median UACR was 18 mg/g.

Atrial fibrillation was present for 38% of patients and 41% had diabetes mellitus. The majority ofpatients were on loop diuretics (87%), an ACEi or ARB (79%), or an angiotensin receptor neprilysininhibitor (9%), and 14% were on SGLT2 inhibitors.

Cumulative incidence probability

A statistically significant difference in favour of finerenone was shown for the primary compositeendpoint (see table 8 below). The effect was observed early and was sustained throughout the durationof the study (see figure 3 below). A statistically significant difference in favour of finerenone was alsoshown for the secondary endpoints of total heart failure events. Prespecified secondary efficacyendpoints are also included in table 8 below. The treatment effect for the primary and key secondaryendpoints was consistent across all prespecified subgroups, including gender, LVEF, NYHA class,eGFR, time since latest heart failure event, SGLT2 inhibitor therapy, and diabetes mellitus status.

Table 8: Analysis of the primary and secondary endpoints (and their individual components fortime-to-event endpoints) in phase III study FINEARTS-HF

Kerendia* (N = 3 003) Placebo (N = 2 998) Treatment effect[Event total] Events/ [Event total] Events/ (95% CI)

N (%) 100-pyr N (%) 100-pyr

Primary CV composite endpoint and its components

RR 0.84[1 083] [1 283]

Composite of CV death and 14.88 17.70 (0.74; 0.95)total heart failure events 624 (20.8) 719 (24.0)p = 0.0072[842] [1 024] RR 0.82

Total heart failure event** 11.57 14.12479 (16.0) 573 (19.1) (0.71; 0.94)p = 0.0062

CV death 242 (8.1) 3.33 260 (8.7) 3.59 HR 0.93(0.78; 1.11)

Secondary efficacy endpoints

LSM difference

Change from baseline in LSM LSM 1.56

KCCQ-TSS - -7.99 6.43(0.79; 2.34)p ˂ 0.0001

OR 1.01

Improvement in NYHA class 557 (18.6) - 553 (18.4) - (0.88; 1.15)

N = 3 002 p = 0.9295†

HR 1.33

Renal composite endpoint 75 (2.5) 1.16 55 (1.8) 0.85(0.94; 1.89)p††

Sustained eGFR decrease≥ 50% 68 (2.3) 1.05 51 (1.7) 0.79 -

Sustained eGFR decline to˂ 15mL/min/1.73m2 5 (0.2) 0.08 2 (˂ 0.1) 0.03 -

Initiation of dialysis 2 (˂ 0.1) 0.03 2 (˂ 0.1) 0.03 -

Renal transplantation 0 (0.0) 0.00 0 (0.0) - -

HR 0.93

All-cause mortality 491 (16.4) 6.71 522 (17.4) 7.17 (0.83; 1.06)

Abbreviations: CI: Confidence interval; HR: Hazard ratio; LSM: Least squares mean; OR: Odds ratio;

RR: Rate ratio; pyr: patient-years

* Treatment with 10, 20 or 40 mg once daily in addition to background therapy, including diuretic treatment

** Total (first and recurrent) heart failure events was also a key secondary endpoint† Not significant (testing procedure stopped)†† Endpoint not formally tested (preceding endpoint in testing procedure not significant)

Figure 3: Primary composite endpoint of CV death and total (first and recurrent) heart failure eventsin the FINEARTS-HF study0.6

Planned Treatment1: Finerenone0.5 2: Placebo0.40.30.20.10.00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Number of subjects at risk Time in months1 3 003 2 959 2 909 2 859 2 810 2 760 2 576 2 399 2 202 1 977 1 749 1 430 970 385 65 02 2 998 2 946 2 901 2 855 2 805 2 756 2 571 2 387 2 203 1 964 1 722 1 426 960 377 63 0

The European Medicines Agency has deferred the obligation to submit the results of studies with

Kerendia in one or more subsets of the paediatric population in treatment of chronic kidney diseaseand heart failure (see section 4.2 for information on paediatric use).

Finerenone is almost completely absorbed after oral administration. Absorption is rapid withmaximum plasma concentrations (Cₘₐₓ) appearing between 0.5 and 1.25 hours after tablet intake in thefasted state. The absolute bioavailability of finerenone is 43.5% due to first-pass metabolism in thegut-wall and liver. Finerenone is a substrate of the efflux transporter P-glycoprotein in vitro, which ishowever not considered relevant for its absorption in vivo due to the high permeability of finerenone.

Intake with high fat, high calorie food increased finerenone AUC by up to 21%, reduced Cₘₐₓ by 19%to 23% and prolonged the time to reach Cₘₐₓ up to 2.5 hours. Since this is not considered as clinicallyrelevant, finerenone can be taken with or without food.

The volume of distribution at steady state (Vₛₛ) of finerenone is 52.6 L. The human plasma proteinbinding of finerenone in vitro is 91.7%, with serum albumin being the main binding protein.

Approximately 90% of finerenone metabolism is mediated by CYP3A4 and 10% by CYP2C8. Fourmajor metabolites were found in plasma. All metabolites are pharmacologically inactive.

Mean cumulative function

The elimination of finerenone from plasma is rapid with an elimination half-life (t½) of about 2 to3 hours. Systemic blood clearance of finerenone is about 25 L/h. About 80% of the administered dosewas excreted via urine and approximately 20% of the dose was excreted via faeces. Excretion wasalmost exclusively in the form of metabolites, while excretion of unchanged finerenone represents aminor route (< 1% of dose in the urine due to glomerular filtration, < 0.2% in the faeces).

Finerenone pharmacokinetics are linear across the investigated dose range from 1.25 to 80 mg given assingle dose tablets.

Of the 2 818 patients who received finerenone in the FIDELIO-DKD study, 58% of patients were65 years and older, and 15% were 75 years and older. Of the 3 671 patients who received finerenonein the FIGARO-DKD study, 53% of patients were 65 years and older, and 14% were 75 years andolder. Of the 2 993 patients who received finerenone in the FINEARTS-HF study, 79% of patientswere 65 years and older, and 43% were 75 years and older.

In a phase I study (N = 48) elderly healthy participants (≥ 65 years of age) exhibited higher finerenoneplasma concentrations than younger healthy participants (≤ 45 years of age), with mean AUC and Cₘₐₓvalues being 34% and 51% higher in the elderly (see section 4.2). Population-pharmacokineticanalyses did not identify age as a covariate for finerenone AUC or Cₘₐₓ.

Mild renal impairment (creatinine clearance [CLCR] 60 to < 90 mL/min) did not affect finerenone

AUC and Cₘₐₓ.

Compared to patients with normal renal function (CLCR ≥ 90 mL/min), the effect of moderate(CLCR 30 to < 60 mL/min) or severe (CLCR < 30 mL/min) renal impairment on AUC of finerenone wassimilar with increases by 34-36%. Moderate or severe renal impairment had no effect on Cₘₐₓ (seesection 4.2).

Due to the high plasma protein binding, finerenone is not expected to be dialysable.

There was no change in finerenone exposure in cirrhotic patients with mild hepatic impairment (seesection 4.2).

In cirrhotic patients with moderate hepatic impairment, finerenone total and unbound AUC wereincreased by 38% and 55%, respectively, while no change in Cₘₐₓ was observed compared to healthycontrol participants (see section 4.2).

There are no data in patients with severe hepatic impairment (see sections 4.2 and 4.5).

Population-pharmacokinetic analyses identified body weight as a covariate for finerenone Cₘₐₓ and

AUC. Cₘₐₓ and AUC of subjects with a body weight of below 57 kg were estimated to be, on average,52% and 30% higher, respectively, and of subjects with a body weight above 122 kg, 32% and 20%lower, respectively, compared to subjects between 57 and 122 kg. Dose adaptation based on bodyweight is not warranted (see section 4.2).

The concentration-effect relationship over time for UACR was characterised by a maximum effectmodel indicating saturation at high exposures. The model-predicted time to reach the full (99%)steady-state drug effect on UACR was 138 days. The pharmacokinetic (PK) half-life was 2-3 hoursand PK steady state was achieved after 2 days, indicating an indirect and delayed effect onpharmacodynamic responses.

Clinical studies with no relevant drug-drug interactions

Concomitant use of gemfibrozil (600 mg twice daily), a strong inhibitor of CYP2C8, increasedfinerenone mean AUC and Cₘₐₓ 1.1-fold and 1.2-fold, respectively. This is not considered as clinicallyrelevant.

Pre- and co-treatment with the proton pump inhibitor omeprazole (40 mg once daily) had no effect onfinerenone mean AUC and mean Cₘₐₓ.

Concomitant use of antacid aluminium hydroxide and magnesium hydroxide (70 mVal) had no effecton finerenone mean AUC and reduced its mean Cₘₐₓ by 19%. This is not considered as clinicallyrelevant.

Lack of mutual pharmacokinetic interaction was demonstrated between finerenone and the CYP2C9substrate warfarin and between finerenone and the P-gp substrate digoxin.

Multiple doses of 40 mg finerenone once daily had no clinically relevant effect on AUC and Cₘₐₓ ofthe breast cancer resistance protein (BCRP) and organic anion transporting polypeptides (OATP)substrate rosuvastatin.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single dose toxicity, repeated dose toxicity, genotoxicity, phototoxicity, carcinogenicpotential and male and female fertility.

In dogs, a reduced prostate weight and size was found at an AUCunbound of about 4 to 60 times that inhumans. The dose free of findings provides a safety margin of about 1-2.

Carcinogenic potential

In 2-year carcinogenicity studies, finerenone did not show carcinogenic potential in male and femalerats or female mice. In male mice, finerenone resulted in an increase in Leydig cell adenoma at dosesrepresenting 10 to 26 times the AUCunbound in humans. A dose representing 7 times the AUCunbound forthe 40 mg dose and 17 times the AUCunbound in humans for the 20 mg did not cause any tumours.

Based on the known sensitivity of rodents to develop these tumours and the pharmacology-basedmechanism at supratherapeutic doses as well as adequate safety margins, the increase in Leydig celltumours in male mice is not clinically relevant.

Toxicity to development

In the embryo-foetal toxicity study in rats, finerenone resulted in reduced placental weights and signsof foetal toxicity, including reduced foetal weights and retarded ossification at the maternal toxic doseof 10 mg/kg/day corresponding to an AUCunbound of at least 7 times that in humans. At 30 mg/kg/day,the incidence of visceral and skeletal variations was increased (slight oedema, shortened umbilicalcord, slightly enlarged fontanelle) and one foetus showed complex malformations including a raremalformation (double aortic arch) at an AUCunbound of about 10 times that in humans at the dose of40 mg and about 25 times that in humans at the dose of 20 mg. The doses free of any findings (lowdose in rats, high dose in rabbits) provided safety margins of 4 to 13 times for AUCunbound. Therefore,the findings in rats do not indicate an increased concern for foetal harm.

When rats were exposed during pregnancy and lactation in the pre- and postnatal developmentaltoxicity study, increased pup mortality and other adverse effects (lower pup weight, delayed pinnaunfolding) were observed at about 2 or 4 times the AUCunbound expected in humans at the dose of40 mg and 20 mg, respectively. In addition, the offspring showed slightly increased locomotoractivity, but no other neurobehavioural changes starting at about 2 or 4 times the AUCunbound expectedin humans at the dose of 40 mg and 20 mg, respectively. The dose free of findings provided a safetymargin of about 2 for AUCunbound for the 20 mg dose and is in the therapeutic range for the 40 mg dose.

The increased locomotor activity in offspring may indicate a potential risk for the foetus. In addition,because of the findings in pups, a risk for the nursing newborn/infant cannot be excluded.

Female fertility

Finerenone caused reduced female fertility (decreased number of corpora lutea and implantation sites)as well as signs of early embryonic toxicity (increased post-implantational loss and decreased numberof viable foetuses) at about 9 times the human AUCunbound for the 40 mg dose and at about 21 times thehuman AUCunbound for the 20 mg dose. In addition, reduced ovarian weights were found at about7 times the human AUCunbound for the 40 mg dose and at about 17 times the human AUCunbound for the20 mg dose. No effects on female fertility and early embryonic development were found at 4 times thehuman AUCunbound for the 40 mg dose and 10 times the human AUCunbound for the 20 mg dose.

Therefore, the findings in female rats are of little clinical relevance (see section 4.6).

Environmental risk assessment studies have shown that finerenone may pose a risk for the surfacewater and groundwater compartment (see section 6.6).

Cellulose, microcrystalline (E 460)

Croscarmellose sodium

Hypromellose 2910 (E 464)

Lactose monohydrate

Magnesium stearate (E 470b)

Sodium laurilsulfate (E 487)

Hypromellose 2910 (E 464)

Titanium dioxide (E 171)

Talc (E 553b)

Kerendia 10 mg film-coated tablets

Iron oxide red (E 172)

Kerendia 20 mg film-coated tablets

Iron oxide yellow (E 172)

Kerendia 40 mg film-coated tablets

Iron oxide red (E 172)

Iron oxide yellow (E 172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/PVDC/Aluminium transparent calendarised blisters with 14 film-coated tablets. Pack sizes of 14,28 or 98 film-coated tablets.

PVC/PVDC/Aluminium transparent perforated unit dose blisters with 10 x 1 film-coated tablets. Packsize of 100 × 1 film-coated tablets.

White opaque HDPE bottle with white opaque polypropylene child-resistant screw cap with sealinginsert. Pack size of 100 film-coated tablets (Kerendia 10 mg and 20 mg film-coated tablets, only).

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bayer AG51368 Leverkusen

Germany

Kerendia 10 mg film-coated tablets

EU/1/21/1616/001-005

Kerendia 20 mg film-coated tablets

EU/1/21/1616/006-010

Kerendia 40 mg film-coated tablets

EU/1/21/1616/011-014

Date of first authorisation: 16 February 2022

Detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu.