Kerendia

Finerenone.

KERENDIA 10mg tablet contains 10 mg finerenone.
KERENDIA 20mg tablet contains 20 mg finerenone.
KERENDIA contains lactose monohydrate.
Physicochemical Properties: CAS Number: 1050477-31-0.
Chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.
Empirical formula: C₂₁H₂₂N₄O₃.
Molecular weight: 378.43 g/mol.
Excipients/Inactive Ingredients: Tablet core: Croscarmellose sodium, Hypromellose 5 cP, Lactose monohydrate, Magnesium stearate, Cellulose microcrystalline, Sodium laurilsulfate.
Tablet coating: Hypromellose 5 cP, Talc, Titanium dioxide, Ferric oxide yellow (for KERENDIA 20mg tablet), Ferric oxide red (for KERENDIA 10mg tablet).

ATC code: C03DA05.
Pharmacology: Pharmacodynamics: Mechanism of Action: Finerenone is a nonsteroidal antagonist of the mineralocorticoid receptor (MR) that potently attenuates inflammation and fibrosis mediated by MR overactivation. The MR is expressed in the kidneys, heart and blood vessels where finerenone also counteracts sodium retention and hypertrophic processes. Finerenone has high selectivity for the MR due to its nonsteroidal structure and bulky binding mode. Finerenone has no relevant affinity for androgen, progesterone, estrogen and glucocorticoid receptors and therefore does not cause sex hormone-related adverse events (e.g., gynecomastia). Its binding to the MR leads to a specific receptor ligand complex that blocks recruitment of transcriptional coactivators implicated in the expression of pro-inflammatory and pro-fibrotic mediators.
Effects in healthy participants: Finerenone (multiple doses of 10 mg and 20 mg twice daily or 40 mg once daily over 10 days) had no consistent effect on natriuresis or urine potassium in healthy male participants. These regimens led to activation of the renin-angiotensin-aldosterone system (RAAS), i.e., reversible increases of plasma renin activity and serum aldosterone concentrations with baseline values reached again within 48 hours after the last dose.
However, following activation of the MR with the MR agonist fludrocortisone (0.5 mg), finerenone (single doses of 2.5, 5, 10, 20 mg PEG solution or 20 mg tablets) showed dose-dependent natriuretic effects in healthy male participants. Moreover, finerenone (at doses of 5 to 20 mg) significantly decreased urinary potassium excretion as compared to placebo.
Single or multiple doses of finerenone did not influence vital signs parameters in healthy participants.
Cardiac electrophysiology: In a thorough QT study in 57 healthy participants, there was no indication of a QT/QTc prolonging effect of finerenone after single doses of 20 mg (therapeutic) or 80 mg (supratherapeutic), indicating that finerenone has no effect on cardiac repolarization.
Clinical Trials: The FIDELIO-DKD study was a randomised, double-blind, placebo-controlled, multicentre Phase III study investigating the effect of KERENDIA compared to placebo on kidney and cardiovascular outcomes in adult patients with chronic kidney disease and type 2 diabetes. 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, serum potassium ≤4.8 mmol/L at screening, and were required to be receiving standard of care, including a maximum tolerated labelled dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).
The primary endpoint in the FIDELIO-DKD study was a composite of time to first occurrence of kidney failure (defined as chronic dialysis or kidney transplantation, or a sustained decrease in eGFR to <15 mL/min/1.73 m² over at least 4 weeks), a sustained decline in eGFR of 40% or more compared to baseline over at least 4 weeks, or renal death. The key secondary endpoint was a composite of time to first occurrence of cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal stroke or hospitalisation for heart failure.
The trial analysed 5,674 patients randomly assigned to receive either KERENDIA 10 mg or 20 mg once daily (N=2833), or placebo (N=2841), with a median follow-up duration of 2.6 years. After the end of study notification, vital status was obtained for 99.7% of patients. The trial population was 63% White, 25% Asian and 5% Black. The mean age at enrolment was 66 years and 70% of patients were male. At baseline, the mean eGFR was 44.3 mL/min/1.73 m², with 55% of patients having an eGFR <45 mL/min/1.73 m², median urine albumin-to-creatinine ratio (UACR) was 852 mg/g, and mean glycated haemoglobin A1c (HbA1c) was 7.7%, 46% had a history of atherosclerotic cardiovascular disease, 30% had history of coronary artery disease, 8% had a history of cardiac failure, and the mean blood pressure was 138/76 mmHg. The mean duration of type 2 diabetes at baseline was 16.6 years and a history of diabetic retinopathy and diabetic neuropathy was reported in 47% and 26% of patients at baseline, 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-like peptide-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 channel blockers (63%).
KERENDIA significantly reduced the risk of the primary composite endpoint compared to placebo in a time to event analysis using the Cox proportional hazards model and log rank test (HR 0.82, 95% CI 0.73-0.93, p=0.0014). See Figure 1/Table 1 as follows. The key secondary endpoint results (composite of CV death, non-fatal MI, non-fatal stroke, hospitalisation for heart failure) were favourable overall (HR (95% CI): 0.86 (0.75-0.99), p=0.0339), but with an indeterminate effect observed for the 'non-fatal stroke' component with a HR (95% CI): 1.027 (0.765-1.380). Prespecified secondary time-to-event endpoints are included in Table 1. For the secondary endpoint of change in UACR from baseline to month 4, a relative reduction of 31.2% was observed in the KERENDIA group compared to placebo. The treatment effect for the primary and key secondary endpoints was generally consistent across subgroups, including region, eGFR, UACR, systolic blood pressure (BP) and HbA1c at baseline.
In the FIDELIO-DKD study, hyperkalaemia events were reported in 18.3% of KERENDIA-treated patients compared with 9.0% of placebo-treated patients. Hospitalisation due to hyperkalaemia for the KERENDIA group was 1.4% versus 0.3% in the placebo group. Hyperkalaemia leading to permanent discontinuation in patients who received KERENDIA was 2.3% versus 0.9% in the placebo group.
In the FIDELIO-DKD study, glomerular filtration rate decreased events were reported in 6.3% of KERENDIA-treated patients compared with 4.7% of placebo-treated patients, and those leading to permanent discontinuation in patients receiving KERENDIA were 0.2% versus 0.3% in the placebo group. Patients on KERENDIA experienced an initial decrease in eGFR (mean 2 mL/min/1.73 m²) that attenuated over time compared to placebo. This decrease has been shown to be reversible after treatment discontinuation. The initial decrease in eGFR was associated with long-term preservation of kidney function. (See Table 1 and Figures 1 and 2.)

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Pharmacokinetics: The concentration-effect relationship over time for UACR was characterised by a maximum effect model 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 hours and PK steady state was achieved after 2 days, indicating timescale separation.
Absorption: Finerenone is almost completely absorbed after oral administration. Absorption is rapid with maximum plasma concentrations (C_max) appearing between 0.5 and 1.25 hours after tablet intake in the fasted state. The absolute bioavailability of finerenone is 43.5% due to first-pass metabolism in the gut-wall and liver. Finerenone is not a substrate of the efflux transporter P-gp in vivo. Intake with high fat, high calorie food increased finerenone AUC by 21%, reduced C_max by 19% and prolonged the time to reach C_max to 2.5 hours. This is not clinically relevant. Therefore, finerenone can be taken with or without food (see Dosage & Administration).
Distribution: The volume of distribution at steady state (V_ss) of finerenone is 52.6 L. The human plasma protein binding of finerenone in vitro is 91.7%, with serum albumin being the main binding protein.
Metabolism: Approximately 90% of finerenone metabolism is mediated by CYP3A4 and 10% by CYP2C8. Four major metabolites were found in plasma, resulting from oxidation of the dihydropyridine moiety to a pyridine (M1a, M1b), subsequent hydroxylation of a methyl group (M2a) and formation of a carboxyl function (M3a). All metabolites are pharmacologically inactive.
Excretion: The elimination of finerenone from plasma is rapid with an elimination half-life (t_1/2) of about 2 to 3 hours. Excretion of unchanged finerenone represents a minor route (<1% of dose in the urine due to glomerular filtration, <0.2% in the faeces). About 80% of the administered dose was excreted via urine and approximately 20% of the dose was excreted via faeces, almost exclusively in the form of metabolites. With a systemic blood clearance of about 25 L/h, finerenone can be classified as a low clearance drug.
Special populations: Patients with renal impairment: Mild renal impairment (CLCR 60 - <90 mL/min) did not affect finerenone AUC and C_max. Compared to subjects with normal renal function (CLCR ≥90 mL/min), the effect of moderate (CLCR 30 - <60 mL/min) or severe (CLCR <30 mL/min) renal impairment on AUC of finerenone was similar with increases by 34-36%. Moderate or severe renal impairment had no effect on C_max (see Dosage & Administration).
Due to the high plasma protein binding, finerenone is not expected to be dialyzable.
Patients with hepatic impairment: There was no change in finerenone exposure in cirrhotic subjects with mild hepatic impairment (Child Pugh A) (see Dosage & Administration).
In cirrhotic subjects with moderate hepatic impairment (Child Pugh B), finerenone mean AUC was increased by 38% and C_max was unchanged compared to healthy control subjects (see Dosage & Administration).
There are no data in patients with severe hepatic impairment (Child Pugh C) (see Dosage & Administration and Precautions).
Elderly patients: Of the 2827 patients who received KERENDIA in the FIDELIO-DKD study, 58% of patients were 65 years and older, and 15% were 75 years and older. No overall differences in safety or efficacy were observed between these patients and younger patients.
Elderly subjects (≥65 years of age) exhibited higher finerenone plasma concentrations than younger subjects (≤45 years of age), with mean AUC and C_max values being 34% and 51% higher in the elderly (see Dosage & Administration). Report No. R-13179 Population-pharmacokinetic analyses did not identify age as a covariate for finerenone AUC or C_max.
Body Weight: Population-pharmacokinetic analyses identified body weight as a covariate for finerenone C_max. The C_max of a subject with a body weight of 50 kg was estimated to be 43% to 51% higher compared to a subject of 100 kg. Dose adaptation based on body weight is not warranted (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Genotoxicity: Finerenone was non-genotoxic in assays for mutagenicity in bacteria and for chromosomal aberrations in vitro (in Chinese hamster V79 cells), and the mouse bone marrow micronucleus test.
Carcinogenicity: In 2-year carcinogenicity studies, finerenone did not increase tumour incidence in male or female rats at oral doses up to 20 and 10 mg/kg/day, or in female mice at oral doses up to 7.5 mg/kg/day (yielding exposure 19-28 times higher than in patients at the maximum recommended human dose of 20 mg/day, based on plasma AUC for unbound drug). In male mice, finerenone resulted in an increase in Leydig cell adenoma at 30 mg/kg/day, representing 26 times the AUC_unbound in humans. No carcinogenicity was evident with treatment at 10 mg/kg/day, representing 17 times the AUC_unbound in humans. Based on the known sensitivity of rodents to develop these tumours and the pharmacology-based mechanism at supratherapeutic doses as well as the margin of exposure, the increase in Leydig cell tumours observed in male mice is not considered to indicate a particular carcinogenic risk to patients treated with KERENDIA.

KERENDIA is indicated to delay progressive decline of kidney function in adults with chronic kidney disease associated with Type 2 diabetes (with albuminuria), in addition to standard of care (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).

Dosage (dose and interval): The recommended target dose of KERENDIA is 20 mg once daily.
Initiation of treatment: Initiation of KERENDIA treatment is recommended when serum potassium ≤4.8 mmol/L.
For monitoring of serum potassium, see Continuation of treatment as follows.
If serum potassium >4.8 to 5.0 mmol/L, initiation of KERENDIA treatment may be considered with additional serum potassium monitoring within the first 4 weeks based on patient characteristics and serum potassium levels (see Precautions).
If serum potassium >5.0 mmol/L, initiation of KERENDIA treatment is not recommended (see Precautions).
Measure estimated glomerular filtration rate (eGFR) to determine the starting dose. The starting dose of KERENDIA is: 20 mg once daily if eGFR ≥60 mL/min/1.73 m²; 10 mg once daily if eGFR ≥25 to <60 mL/min/1.73 m².
Initiation of KERENDIA treatment is not recommended in patients with eGFR <25 mL/min/1.73 m² as clinical experience is limited.
Continuation of treatment: Four weeks after initiation or restart or up-titration of KERENDIA treatment, remeasure serum potassium and eGFR. See Table 2 to determine continuation of KERENDIA treatment and dose adjustment. Thereafter, remeasure serum potassium periodically and as needed based on patient characteristics and serum potassium levels. (See Precautions and Interactions.) (See Table 2.)

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Method of administration: Oral use.
Tablets may be taken with a glass of water and with or without food (see Pharmacology: Pharmacokinetics under Actions).
Avoid taking KERENDIA with grapefruit or grapefruit juice (see Precautions and Interactions).
For patients who are unable to swallow whole tablets, KERENDIA tablet may be crushed and mixed with water or soft foods, such as apple sauce, immediately prior to use and administered orally (see Pharmacology: Pharmacokinetics under Actions).
Missed dose: A missed dose should be taken as soon as possible after it is noticed, but only on the same day. If this is not possible, the dose should be skipped and the next dose taken as prescribed. Two doses should not be taken to make up for a missed dose.
The maximum daily dose of KERENDIA is 20 mg.
Patients with hepatic impairment: In patients with severe hepatic impairment (Child Pugh C), avoid treatment with KERENDIA (see Precautions and Pharmacology: Pharmacokinetics under Actions). In patients with mild or moderate hepatic impairment, no initial dose adjustment is required (Child Pugh A or B) (see Pharmacology: Pharmacokinetics under Actions).
In patients with moderate hepatic impairment (Child Pugh B), consider additional serum potassium monitoring and adapt monitoring according to patient characteristics (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: Initiation of KERENDIA treatment: In patients with eGFR ≥25 to <60 mL/min/1.73 m², the starting dose of KERENDIA is 10 mg once daily. See Initiation of treatment as previously mentioned.
In patients with eGFR <25 mL/min/1.73 m², initiation of KERENDIA treatment is not recommended as clinical experience is limited (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Continuation of KERENDIA treatment: In patients with mild, moderate or severe renal impairment, continue KERENDIA treatment and adjust dose based on serum potassium. Measure eGFR 4 weeks after initiation to determine up-titration. See Table 2 and Continuation of treatment as previously mentioned.
In patients with end-stage renal disease (eGFR <15 mL/min/1.73 m²), continue KERENDIA treatment with caution regarding serum potassium levels as clinical experience is limited (see Precautions).
Patients taking concomitant medications: In patients taking KERENDIA concomitantly with moderate or weak CYP3A4 inhibitors, potassium supplements, trimethoprim, or trimethoprim-sulfamethoxazole, consider additional serum potassium monitoring and adapt monitoring according to patient characteristics, and make KERENDIA treatment decisions as directed in Table 2. Temporary discontinuation of KERENDIA when taking trimethoprim, or trimethoprim-sulfamethoxazole, may be necessary (see Precautions and Interactions).
Elderly patients: No dose adjustment is required in the elderly (see Pharmacology: Pharmacokinetics under Actions).

No cases of adverse events associated with finerenone overdose in humans have been reported. The most likely manifestation of overdose is anticipated to be hyperkalaemia. If hyperkalaemia develops, standard treatment should be initiated.
Finerenone is unlikely to be efficiently removed by haemodialysis given its fraction bound to plasma proteins of about 90%.

Finerenone is contraindicated in patients: taking concomitant medications that are strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, cobicistat, clarithromycin, telithromycin and nefazodone) (see Interactions); with adrenal insufficiency.

Hyperkalaemia: Hyperkalaemia has been observed in patients treated with KERENDIA.
Some patients are at a higher risk to develop hyperkalaemia. Risk factors include low eGFR, higher serum potassium and previous episodes of hyperkalaemia. Consider more frequent monitoring in these patients.
Initiation of KERENDIA treatment is not recommended if serum potassium >5.0 mmol/L.
If serum potassium >4.8 to 5.0 mmol/L, initiation of KERENDIA treatment may be considered with additional serum potassium monitoring within the first 4 weeks based on patient characteristics and serum potassium levels (see Dosage & Administration).
Withhold KERENDIA in treated patients if serum potassium >5.5 mmol/L. Follow local guidelines for the management of hyperkalaemia. Restart KERENDIA at 10 mg once daily if serum potassium ≤5.0 mmol/L (see Dosage & Administration).
Remeasure serum potassium and eGFR in all patients 4 weeks after initiation or restart or up-titration of KERENDIA treatment. Thereafter, remeasure serum potassium periodically and as needed based on patient characteristics and serum potassium levels (see Dosage & Administration).
Concomitant medications: The risk of hyperkalaemia also may increase with the intake of concomitant medications that may increase serum potassium (see Interactions). See also Concomitant use of substances that affect finerenone exposure as follows.
Avoid concomitant use of KERENDIA with the following medications: potassium-sparing diuretics (e.g., amiloride, triamterene); other mineralocorticoid receptor antagonists (MRAs) (e.g., eplerenone, spironolactone).
Use KERENDIA with caution and monitor serum potassium when taken concomitantly with the following medications: potassium supplements; trimethoprim, or trimethoprim-sulfamethoxazole. Temporary discontinuation of KERENDIA may be necessary.
Use in Hepatic Impairment: Patients with severe hepatic impairment (Child Pugh C) have not been studied (see Pharmacology: Pharmacokinetics under Actions). Due to an expected significant increase in finerenone exposure, avoid use of KERENDIA in patients with severe hepatic impairment (see Dosage & Administration).
Due to an increase in finerenone exposure, consider additional serum potassium monitoring and adapt monitoring according to patient characteristics in patients with moderate hepatic impairment (Child Pugh B) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Use in Renal Impairment: The risk of hyperkalaemia increases with decreasing renal function. Ongoing monitoring of renal function should be performed as needed according to standard practice (see Dosage & Administration).
Initiation of KERENDIA treatment is not recommended in patients with eGFR <25 mL/min/1.73 m² as clinical experience is limited (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Continue KERENDIA treatment with caution regarding serum potassium levels in patients with end-stage renal disease (eGFR <15 mL/min/1.73 m²) as clinical experience is limited (see Dosage & Administration).
Effects on Laboratory Tests: See Adverse Reactions, Tables 3 and 5, and Pharmacology: Pharmacodynamics: Clinical Trials under Actions.
Embryo-foetal toxicity: Animal data have shown reproductive toxicity. The relevance for humans is unknown. KERENDIA should not be used during pregnancy unless there has been careful consideration of the benefit for the mother and the risk to the foetus. If the patient becomes pregnant while taking KERENDIA, the patient should be informed of potential risks to the foetus. Advise women of childbearing potential to use effective contraception during treatment with KERENDIA. Advise women not to breastfeed during treatment with KERENDIA (see Use in Pregnancy & Lactation).
Concomitant use of substances that affect finerenone exposure: Moderate and weak CYP3A4 inhibitors: The concomitant use of KERENDIA with moderate CYP3A4 inhibitors (e.g., erythromycin and verapamil) and weak CYP3A4 inhibitors (e.g., amiodarone and fluvoxamine) is expected to increase finerenone exposure (see Interactions). Monitor serum potassium especially during initiation of or changes to dosing of KERENDIA or the CYP3A4 inhibitor (see Dosage & Administration).
Strong and moderate CYP3A4 inducers: Avoid concomitant use of KERENDIA with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, St John's Wort) or moderate CYP3A4 inducers (e.g., efavirenz), which are expected to markedly decrease finerenone plasma concentrations and result in reduced therapeutic effect (see Interactions). Consider selection of an alternate concomitant medicinal product with no or weak potential to induce CYP3A4.
Grapefruit: Avoid concomitant intake of grapefruit or grapefruit juice as it is expected to increase the plasma concentration of finerenone (see Dosage & Administration and Interactions).
Effects on Ability to Drive and Use Machines: No effects on ability to drive and use machines have been observed.
Use in the Elderly: No dose adjustment is required in the elderly (see Pharmacology: Pharmacokinetics under Actions).
Use in Children: The safety and efficacy of KERENDIA have not been established in patients under 18 years of age. Therefore, KERENDIA is not recommended for use in paediatric patients.

Effects on Fertility: No human data on the effect of KERENDIA on fertility are available. No effect on male fertility was observed with finerenone in rats at oral doses up to 30 mg/kg/day (estimated to yield 16 times the exposure in patients at the maximum recommended human dose of 20 mg/day [based on plasma AUC for unbound drug]). In female rats, inhibition of ovulation was seen with treatment at 30 mg/kg/day (yielding 21 times the clinical exposure), while no effect on female fertility was observed at 3 mg/kg/day (relative exposure, 10). Based on these animal data and the margin of exposure, impairment of male and female fertility is not expected in patients.
Use in Pregnancy (Category D): There are no data on the use of KERENDIA in pregnant women.
Adverse effects on embryofetal development, including teratogenicity, were observed with finerenone in animals. Placental transfer of finerenone and/or its metabolites was demonstrated in the rat.
Administration of finerenone to pregnant rats reduced fetal weight and impaired fetal ossification at oral doses ≥10 mg/kg/day. Increased external and skeletal variations (slight oedema, shortened umbilical cord and slightly enlarged fontanelle) and malformation of the aortic arch were observed at 30 mg/kg/day. These doses yield exposure 19-25 times higher than in patients at the maximum recommended human dose of 20 mg/day (based on plasma AUC for unbound drug), and were maternotoxic. Maternal dosing with finerenone at ≥3 mg/kg/day during gestation and lactation (relative exposure, 4) decreased birth weight, increased perinatal mortality and slightly increased locomotor activity of rat pups. At 10 mg/kg/day, postnatal body weight gain was reduced and development delayed. The observed effect on neurobehaviour is consistent with a pharmacologically-mediated antidepressant-like effect of finerenone as a result of exposure in the fetal brain in utero. No adverse effects on embryofetal development were observed with finerenone in rabbits up to the highest dose tested (2.5 mg/kg/day, yielding 13 times the clinical exposure).
KERENDIA should not be used during pregnancy unless there has been careful consideration of the benefit for the mother and the risk to the fetus (see Precautions).
Women of childbearing potential / Contraception: KERENDIA may cause embryofetal harm when administered during pregnancy. Women of childbearing potential should use effective contraception during treatment with KERENDIA (see Precautions).
Use in Lactation: It is unknown whether finerenone or its metabolites are excreted in human breast milk. Excretion of finerenone and its metabolites in milk was shown in rats. Rat pups exposed to finerenone in utero and through consumption of maternal milk showed adverse effects (see as previously mentioned). A risk to the nursing infant cannot be excluded. Breastfeeding should be discontinued if use of KERENDIA is considered essential (see Precautions).

Summary of the safety profile: The safety of KERENDIA in patients with chronic kidney disease and type 2 diabetes was evaluated in the pivotal phase III study FIDELIO-DKD. In this study, 2,827 patients received KERENDIA (10 or 20 mg once daily) and 2,831 received placebo. For patients in the KERENDIA group, the mean duration of treatment was 2.2 years.
The most frequently reported (≥10%) adverse reaction was hyperkalaemia. See Description of selected adverse reactions as follows (see Precautions).
Tabulated list of adverse reactions: The adverse reactions reported with KERENDIA are summarised in Table 3 as follows by MedDRA system organ class and by frequency.
Adverse reactions are ranked by system organ class and then by frequency with the most frequent first, using the following convention: 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).
Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Tables 3, 4 and 5.)

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Description of selected adverse reactions: Hyperkalaemia: In the FIDELIO-DKD study, hyperkalaemia events were reported in 18.3% of KERENDIA-treated patients compared with 9.0% of placebo-treated patients. In patients treated with KERENDIA, the majority of hyperkalaemia events were mild to moderate. An increase from baseline in mean serum potassium in the first month of treatment of approximately 0.2 mmol/L was observed in the KERENDIA arm compared to placebo, with a maximum between-group difference of 0.23 mmol/L observed at Month 4, remaining stable thereafter. For specific recommendations, refer to Dosage & Administration and Precautions.
Reporting Suspected Adverse Effects: Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Effects of other substances on finerenone: Finerenone is cleared almost exclusively via cytochrome P450 (CYP)-mediated oxidative metabolism (mainly CYP3A4 [90%] with a small contribution of CYP2C8 [10%]). Accordingly, agents that affect CYP3A4 may significantly alter exposure to finerenone.
Effects of CYP3A4 inhibitors on finerenone: Strong CYP3A4 inhibitors: Simulations suggest that concomitant use of KERENDIA with itraconazole (200 mg BID), a strong CYP3A4 inhibitor, increases finerenone AUC (+531%) and C_max (+137%). Clarithromycin (500 mg BID), another strong inhibitor, also is predicted to increase finerenone AUC (+428%) and C_max (+125%). Due to an expected marked increase in finerenone exposure, concomitant use of KERENDIA with itraconazole, clarithromycin and other strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, nelfinavir, cobicistat, telithromycin or nefazodone) is contraindicated (see Contraindications).
Moderate CYP3A4 inhibitors: Concomitant use of erythromycin (500 mg thrice daily), a moderate CYP3A4 inhibitor, increased finerenone mean AUC and C_max by 248% and 88%, respectively. Another moderate CYP3A4 inhibitor, verapamil (240 mg controlled-release tablet once daily), increased finerenone mean AUC and C_max by 170% and 120%, respectively. Serum potassium may increase, and therefore, monitoring of serum potassium is recommended (see Dosage & Administration and Precautions).
Weak CYP3A4 inhibitors: In an analysis of KERENDIA in patients, the use of amiodarone, a weak CYP3A4 inhibitor, was estimated to result in a 21% increase of finerenone AUC. Simulations suggest that fluvoxamine (100 mg BID), another weak inhibitor, increases finerenone AUC (+57%) and C_max (+38%). Serum potassium may increase, and therefore, monitoring of serum potassium is recommended (see Dosage & Administration and Precautions).
Grapefruit: Concomitant intake of grapefruit or grapefruit juice is expected to increase the plasma concentration of finerenone and should be avoided (see Dosage & Administration and Precautions).
Effects of strong and moderate CYP3A4 inducers on finerenone: Simulations suggest that rifampicin (600 mg OD), a strong CYP3A4 inducer, decreases finerenone AUC (-93%) and C_max (-86%). Efavirenz (600 mg OD), a moderate CYP3A4 inducer, is predicted to decrease finerenone AUC (-81%) and C_max (-68%).
Concomitant use of KERENDIA with rifampicin and other strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, phenobarbital, St John's Wort), or with efavirenz and other moderate CYP3A4 inducers, markedly decreases finerenone plasma concentration and results in reduced therapeutic effect and should be avoided (see Precautions).
Lack of clinically relevant drug-drug interaction: Concomitant use of gemfibrozil (600 mg twice daily), a strong inhibitor of CYP2C8, increased finerenone mean AUC and C_max by 10% and 16%, respectively. This is not clinically relevant.
Pre- and co-treatment with the proton pump inhibitor omeprazole (40 mg once daily) had no effect on finerenone mean AUC and mean C_max.
Concomitant use of antacid aluminium hydroxide and magnesium hydroxide (70 mVal) had no effect on finerenone mean AUC and reduced its mean C_max by 19%. This is not clinically relevant.
Effects of finerenone on other substances: In vivo, a multiple-dose regimen of 20 mg finerenone once-daily had no effect on the AUC of the CYP3A4 probe substrate midazolam. Finerenone neither inhibits nor induces CYP3A4 in patients at therapeutic doses.
A single dose of 20 mg finerenone also had no effect on AUC and C_max of the CYP2C8 probe substrate repaglinide. Finerenone does not inhibit CYP2C8 in patients at therapeutic doses.
Lack of mutual pharmacokinetic interaction was demonstrated between finerenone and the CYP2C9 substrate warfarin and between finerenone and the P-gp substrate digoxin.
Pharmacodynamic interactions: Medications that increase serum potassium: It is anticipated that medications that increase serum potassium will increase the risk of hyperkalaemia when used concomitantly with KERENDIA.
Concomitant use of KERENDIA with the following medications should be avoided: potassium-sparing diuretics (e.g., amiloride, triamterene); other mineralocorticoid receptor antagonists (MRAs) (e.g., eplerenone, spironolactone).
KERENDIA should be used with caution and serum potassium monitored when taken concomitantly with the following medications: potassium supplements; trimethoprim, or trimethoprim-sulfamethoxazole. Temporary discontinuation of KERENDIA may be necessary. (See Precautions.)

Incompatibilities: Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

Store below 30°C.
Shelf Life: 36 months.

Diuretics

C03DA05 - finerenone ; Belongs to the class of aldosterone antagonists. Used as potassium-sparing diuretics.

P₁S₁S₃