KERENDIA 10mg tablets medication leaflet

Kerendia 10 mg film-coated tablets

Kerendia 20 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.

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

Yellow, oval-oblong film-coated tablet with a length of 10 mm and a width of 5 mm, marked ‘20’ onone 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.

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 and to determine the starting dose.

If serum potassium ≤ 4.8 mmol/L, finerenone treatment can be initiated. For monitoring of serumpotassium, see below ‘Continuation of treatment.’

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

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).

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 to the recommended daily dose of 20 mg (see ‘Posology,

Continuation of treatment’ and table 2).

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 medication

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 table 2 (‘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, higher serum potassium and previous episodes of hyperkalaemia. Inthese patients more frequent monitoring has to be considered.

Initiation and continuation of treatment (see section 4.2)

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

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.

Serum potassium and eGFR have to be remeasured in all patients 4 weeks after initiation, re-start orincrease in dose of finerenone. Thereafter, serum potassium has to be assessed periodically and asneeded based on patient characteristics and serum potassium levels (see section 4.2).

Concomitant medications

The risk of hyperkalaemia also may increase with the intake of concomitant medications that mayincrease 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.

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

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 diagnosed heart failure with reduced ejection fraction and New York Heart

Association II-IV were excluded from the phase III clinical studies (see section 5.1).

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.

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(14.0%). See ‘Description of selected adverse reactions, Hyperkalaemia’ below and section 4.4.

The safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) wasevaluated in 2 pivotal phase III studies, FIDELIO-DKD (diabetic kidney disease) and FIGARO-DKD.

In the FIDELIO-DKD study 2,827 patients received finerenone (10 or 20 mg once daily) with a meanduration of treatment of 2.2 years. In the FIGARO-DKD study, 3,683 patients received finerenone(10 or 20 mg once daily) with a mean duration of treatment of 2.9 years.

The adverse reactions observed are listed in table 3. They are classified according to MedDRA`ssystem organ class database 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 3: Adverse reactions

System Organ Class

Very common Common Uncommon(MedDRA)

Metabolism and Hyponatraemia

Hyperkalaemianutrition disorders Hyperuricaemia

Vascular disorders Hypotension

Skin and subcutaneous

Pruritustissue disorders

Glomerular filtration rate

Investigations Haemoglobin decreaseddecreased

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. An increasefrom baseline in mean serum potassium in the first month of treatment of 0.17 mmol/L was observedin the finerenone group compared to placebo, which remained stable thereafter. The majority ofhyperkalaemia events were mild to moderate and resolved in patients treated with finerenone. 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 1.2% 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.

For specific recommendations, refer to sections 4.2 and 4.4.

In the pooled data of FIDELIO-DKD and FIGARO-DKD studies, hypotension events were reported in4.6% 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%).

The majority of hypotension events were mild or moderate and resolved in patients treated withfinerenone. The mean systolic blood pressure decreased by 2-4 mm Hg and the mean diastolic bloodpressure decreased by 1-2 mm Hg at month 1, remaining stable thereafter.

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. Allevents were non-serious and did not result in permanent discontinuation in patients who receivedfinerenone. An increase from baseline in mean serum uric acid of 0.3 mg/dL was seen in thefinerenone group compared to placebo up to month 16, which attenuated over time. No differencebetween the finerenone group and the placebo group was observed for reported events of gout (3.0%).

Glomerular filtration rate (GFR) decreased

In the pooled data of FIDELIO-DKD and FIGARO-DKD studies, GFR decreased events werereported in 5.3% 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%). The majority of GFR decreased events were mild or moderate andresolved in patients treated with finerenone. Patients on finerenone experienced an initial decrease ineGFR (mean 2 mL/min/1.73 m2) that attenuated over time compared to placebo. This decreaseappeared to be reversible during continuous treatment.

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 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).

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 New York Heart Association

II-IV were excluded 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 5,674 patients were randomised to receive either finerenone (N = 2,833) or placebo(N = 2,841) 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, 30% 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 44.3 mL/min/1.73 m2, with 55% of patients having aneGFR < 45 mL/min/1.73 m2, median UACR was 852 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 medications (insulin [64%], biguanides [44%], glucagon-likepeptide-1 [GLP-1] receptor agonists [7%], sodium-glucose cotransporter 2 [SGLT2] inhibitors [5%]).

The other most frequent medications taken at baseline were statins (74%) and calcium channelblockers (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 4 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 a serumpotassium 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 7,352 patients were randomised to receive either finerenone (N = 3,686), or placebo(N = 3,666) 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 308 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 medications (insulin [54%], biguanides [69%], GLP-1receptor agonists [7%], SGLT2 inhibitors [8%]). The other most frequent medication taken at baselinewas statins (71%).

A statistically significant difference in favour of finerenone was shown for the CV primary compositeendpoint (see figure 2/table 5 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 5 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 0.62; 0.90).

Additional prespecified secondary time-to-event endpoints are included in table 5.

Table 4: Analysis of the primary and secondary time-to-event endpoints (and their individualcomponents) in phase III study FIDELIO-DKD

Kerendia* (N = 2,833) Placebo (N = 2,841) Treatment effect

Events/ Events/ HR (95% CI)

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

Primary renal composite endpoint and its components

Composite of kidney failure, 504 (17.8) 7.59 600 (21.1) 9.08 0.82 (0.73; 0.93)sustained eGFR decline ≥ 40%or renal death p = 0.0014

Kidney failure 208 (7.3) 2.99 235 (8.3) 3.39 0.87 (0.72; 1.05)

Sustained eGFR479 (16.9) 7.21 577 (20.3) 8.73 0.81 (0.72; 0.92)decline ≥ 40%

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 367 (13.0) 5.11 420 (14.8) 5.92 0.86 (0.75; 0.99)or hospitalisation for heart p = 0.0339failure

CV death 128 (4.5) 1.69 150 (5.3) 1.99 0.86 (0.68;1.08)

Non-fatal MI 70 (2.5) 0.94 87 (3.1) 1.17 0.80 (0.58;1.09)

Non-fatal stroke 90 (3.2) 1.21 87 (3.1) 1.18 1.03 (0.76;1.38)

Hospitalisation for heart139 (4.9) 1.89 162 (5.7) 2.21 0.86 (0.68;1.08)failure

Secondary efficacy endpoints

All-cause mortality 219 (7.7) 2.90 244 (8.6) 3.23 0.90 (0.75; 1.07) **

All-cause hospitalisation 1,263 (44.6) 22.56 1,321 (46.5) 23.87 0.95 (0.88; 1.02) **

Composite of kidney failure, 252 (8.9) 3.64 326 (11.5) 4.74 0.76 (0.65; 0.90) **sustained eGFR decline ≥ 57%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=2,833)2: Placebo (N=2,841)0.400.350.300.250.200.150.100.050.00

Number of subjects at risk1 2,833 2,705 2,607 2,397 1,808 1,274 787 441 832 2,841 2,724 2,586 2,379 1,759 1,248 792 453 82

Table 5: Analysis of the primary and secondary time-to-event endpoints (and their individualcomponents) in phase III study FIGARO-DKD

Kerendia* (N = 3,686) Placebo (N = 3,666) Treatment effect

Events/ Events/ HR (95% CI)

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

Primary CV composite endpoint and its components

Composite of CV death,non-fatal MI, non-fatal stroke 458 (12.4) 3.87 519 (14.2) 4.45 0.87 (0.76; 0.98)or hospitalisation for heart p = 0.0264failure

CV death 194 (5.3) 1.56 214 (5.8) 1.74 0.90 (0.74; 1.09)

Non-fatal MI 103 (2.8) 0.85 102 (2.8) 0.85 0.99 (0.76; 1.31)

Non-fatal stroke 108 (2.9) 0.89 111 (3.0) 0.92 0.97 (0.74; 1.26)

Hospitalisation for heartfailure 117 (3.2) 0.96 163 (4.4) 1.36 0.71 (0.56; 0.90)

Secondary renal composite endpoint and its components

Composite of kidney failure, 350 (9.5) 3.15 395 (10.8) 3.58 0.87 (0.76; 1.01)sustained eGFR decline ≥ 40%or renal death p = 0.0689 **

Kidney failure 46 (1.2) 0.40 62 (1.7) 0.54 0.72 (0.49;1.05)

Sustained eGFR338 (9.2) 3.04 385 (10.5) 3.49 0.87 (0.75; > 1.00)decline ≥ 40%

Renal death 0 - 2 (< 0.1) - -

Secondary efficacy endpoints

All-cause mortality 333 (9.0) 2.68 370 (10.1) 3.01 0.89 (0.77; 1.04) **

All-cause hospitalisation 1,573 (42.7) 16.91 1,605 (43.8) 17.52 0.97 (0.90; 1.04) **

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

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

** 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 study

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 disease(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 21%, reduced Cₘₐₓ by 19% andprolonged the time to reach Cₘₐₓ to 2.5 hours. Since this is not considered as clinically relevant,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.

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 2,827 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 3,683 patients who received finerenonein the FIGARO-DKD study, 52% of patients were 65 years and older, and 13% were 75 years andolder.

In both studies, no overall differences in safety or efficacy were observed between these patients andyounger patients.

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. The

Cₘₐₓ of a subject with a body weight of 50 kg was estimated to be 38% to 51% higher compared to asubject of 100 kg. Dose adaptation based on body weight 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.

In vivo a multiple-dose regimen of 20 mg finerenone given once daily for 10 days had no relevanteffect on the AUC of the CYP3A4 probe substrate midazolam. Therefore, a clinically relevantinhibition or induction of CYP3A4 by finerenone can be excluded.

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

CYP2C8 probe substrate repaglinide. Thus, finerenone does not inhibit CYP2C8.

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 10 to 60 times that inhumans. The dose free of findings provides a safety margin of about 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 26 times the AUCunbound in humans. A dose representing 17 times the AUCunbound inhumans did not cause any tumours. Based on the known sensitivity of rodents to develop thesetumours and the pharmacology-based mechanism at supratherapeutic doses as well as adequate safetymargins, the increase in Leydig cell tumours 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 19 times that in humans. At 30 mg/kg/day, theincidence of visceral and skeletal variations was increased (slight oedema, shortened umbilical cord,slightly enlarged fontanelle) and one foetus showed complex malformations including a raremalformation (double aortic arch) at an AUCunbound of about 25 times that in humans. The doses free ofany findings (low dose in rats, high dose in rabbits) provided safety margins of 10 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 4 times the AUCunbound expected in humans. In addition, theoffspring showed slightly increased locomotor activity, but no other neurobehavioural changes startingat about 4 times the AUCunbound expected in humans. The dose free of findings provided a safetymargin of about 2 for AUCunbound. The increased locomotor activity in offspring may indicate apotential risk for the foetus. In addition, because of the findings in pups, a risk for the nursingnewborn/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 21 times the human AUCunbound. In addition, reduced ovarian weights werefound at about 17 times the human AUCunbound. No effects on female fertility and early embryonicdevelopment were found at 10 times the human AUCunbound. Therefore, the findings in female rats areof little clinical relevance (see section 4.6).

Cellulose, microcrystalline

Croscarmellose sodium

Hypromellose 2910

Lactose monohydrate

Magnesium stearate

Sodium laurilsulfate

Hypromellose 2910

Titanium dioxide

Talc

Kerendia 10 mg film-coated tablets

Iron oxide red (E 172)

Kerendia 20 mg film-coated tablets

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.

Not all pack sizes may be marketed.

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

Date of first authorisation: 16 February 2022

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