Firialta

Firialta 10 mg film-coated tablet: Pink, oval-oblong tablet with a length of 10 mm and a width of 5 mm, marked '10' on one side and 'FI' on the other side.
Each film-coated tablet contains 10 mg finerenone.
Firialta 20 mg film-coated tablet: Pale-yellow, oval-oblong tablet with a length of 10 mm and a width of 5 mm, marked '20' on one side and 'FI' on the other side.
Each film-coated tablet contains 20 mg finerenone.
Excipients/Inactive Ingredients: Tablet core: Cellulose microcrystalline (E 460), Croscarmellose sodium, Hypromellose 5 cP (E 464), Lactose monohydrate, Magnesium stearate (E 470b) and Sodium laurilsulfate (E 487).
Tablet coating: Ferric oxide red (E 172) (Firialta 10 mg film-coated tablet), Ferric oxide yellow (E 172) (Firialta 20 mg film-coated tablet), Hypromellose 5 cP (E 464), Talc (E 553 b) and Titanium dioxide (E 171).

Pharmacotherapeutic group: aldosterone antagonists. ATC Code: C03DA05.
Pharmacology: Pharmacodynamics: Mechanism of action: Finerenone is a nonsteroidal, selective 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 a high potency and 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.
Pharmacodynamic effects: Effects in patients with CKD and T2D: In FIDELIO-DKD and FIGARO-DKD, randomized, double-blind, placebo-controlled, multicenter phase III studies in adults with CKD and T2D, the placebo-corrected relative reduction in urinary albumin-to-creatinine ratio (UACR) in patients randomized to finerenone at Month 4 was 31% and 32%, respectively and UACR remained reduced throughout both studies.
In ARTS DN, a randomized, double-blind, placebo-controlled, multicenter phase IIb dose-finding study in adults with CKD and T2D, the placebo-corrected relative reduction in UACR at Day 90 was 25% and 38% in patients treated with finerenone 10 mg and 20 mg once daily, respectively.
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 efficacy and safety: Chronic kidney disease associated with type 2 diabetes: Firialta was investigated in two randomized, double-blind, placebo-controlled, multicenter phase III studies, FIDELIO-DKD and FIGARO-DKD. In these studies, the effect of Firialta on kidney and cardiovascular outcomes was evaluated in adults with CKD and T2D receiving either Firialta 10 mg or 20 mg once daily, or placebo.
In FIDELIO-DKD patients were eligible based on evidence of persistent albuminuria (≥30 mg/g to <300 mg/g) and eGFR ≥25 but <60 mL/min/1.73 m² and presence of diabetic retinopathy or persistent albuminuria (≥300 mg/g to 5,000 mg/g) and eGFR ≥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 labeled dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The trial excluded patients with known significant non-diabetic kidney disease.
Patients with a clinical diagnosis of chronic heart failure with reduced ejection fraction and persistent symptoms (New York Heart Association class II to IV) were excluded.
The 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 hospitalization for heart failure.
The trial analyzed 5,674 patients randomly assigned to receive either Firialta (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 enrollment 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 hemoglobin 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, 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%).
Firialta demonstrated superiority to placebo by significantly reducing 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. Firialta also significantly reduced the risk of the key secondary composite endpoint of time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure compared to placebo (HR 0.86, 95% CI 0.75-0.99, p=0.0339). See Figure 2. Prespecified secondary time-to-event endpoints are included in Table 1. The treatment effect for the primary and key secondary endpoints was generally consistent across subgroups, including region, eGFR, UACR, systolic blood pressure (SBP) and HbA1c at baseline.
In the FIDELIO-DKD study, hyperkalemia events were reported in 18.3% of Firialta-treated patients compared with 9.0% of placebo-treated patients. Hospitalization due to hyperkalemia for the Firialta group was 1.4% versus 0.3% in the placebo group. Hyperkalemia leading to permanent discontinuation in patients who received Firialta 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 Firialta-treated patients compared with 4.7% of placebo-treated patients, and those leading to permanent discontinuation in patients receiving Firialta were 0.2% versus 0.3% in the placebo group. Patients on Firialta experienced an initial decrease in eGFR (mean 2 mL/min/1.73 m²) that attenuated over time compared to placebo. This decrease was reversible after treatment discontinuation. The initial decrease in eGFR was associated with long term preservation of kidney function.
The FIGARO-DKD study included adults with CKD and T2D, based on having a UACR of ≥30 mg/g to <300 mg/g and an eGFR of 25 to 90 mL/min/1.73 m², or a UACR ≥300 mg/g and an eGFR ≥60 mL/min/1.73 m² at screening. Patients were required to have a serum potassium of ≤4.8 mmol/L at screening and received standard of care, including a maximum tolerated labeled dose of a RAS inhibitor (either an ACEi or ARB).
The primary endpoint in the FIGARO-DKD study was a composite of time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure. Secondary endpoints included a composite of time to kidney failure, a sustained decline in eGFR of 40% or more compared to baseline over at least 4 weeks, or renal death and a composite of time to kidney failure, a sustained decline in eGFR of 57% or more compared to baseline, or renal death.
The trial analyzed 7,352 patients randomly assigned to receive either Firialta (N=3686), or placebo (N=3666) that were followed for a median duration of 3.4 years. After the end of study notification, vital status was obtained for 99.8% of patients. The trial population was 72% White, 20% Asian and 4% Black. The mean age at enrollment was 64 years and 69% of patients were male. At baseline, the mean eGFR was 67.8 mL/min/1.73 m², with 62% of patients having an eGFR ≥60 mL/min/1.73 m², median UACR was 308 mg/g, and mean glycated HbA1c was 7.7%, 45% of patients had a history of atherosclerotic cardiovascular disease, 8% had a history of cardiac failure, and the mean blood pressure was 136/77 mmHg. The mean duration of type 2 diabetes at baseline was 14.5 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 a RAS-inhibitor and 98% of patients used one or more antidiabetic medications (insulin [54%], biguanides [69%], GLP-1 receptor agonists [7%], SGLT2 inhibitors [8%]). The other most frequent medication class taken at baseline was statins (71%).
Firialta 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 0.87, 95% CI 0.76-0.98, p=0.0264). See Figure 3/Table 2 as follows. The treatment effect for the primary endpoint was consistent across subgroups, including region, eGFR, UACR, SBP and HbA1c at baseline. A lower incidence rate of the secondary composite outcome of kidney failure, sustained eGFR decline of 40% or more or renal death was observed in the Firialta group compared to placebo, however this difference did not achieve statistical significance (HR 0.87, 95% CI 0.76-1.01, p=0.0689). See Figure 4/Table 2 as follows. A lower risk of the secondary outcome of kidney failure, sustained eGFR decline of 57% or more or renal death was observed in the Firialta group compared to placebo (HR 0.77, 95% CI 0.60-0.99). Prespecified secondary time-to-event endpoints are included in Table 2.
In the FIGARO-DKD study, hyperkalemia events were reported in 10.8% of Firialta-treated patients compared with 5.3% of placebo-treated patients. Hospitalization due to hyperkalemia for the Firialta group was 0.6% versus <0.1% in the placebo group. Hyperkalemia leading to permanent discontinuation in patients who received Firialta was 1.2% versus 0.4% in the placebo group.
In the FIGARO-DKD study, Glomerular filtration rate decreased events were reported in 4.6% of Firialta-treated patients compared with 3.9% of placebo-treated patients, and those leading to permanent discontinuation in patients receiving Firialta were 0.2% versus 0.1% in the placebo group. Patients on Firialta experienced an initial decrease in eGFR of around 2 mL/min/1.73 m² that attenuated over time compared to placebo. This decrease was reversible after treatment discontinuation. The initial decrease in eGFR was associated with long term preservation of kidney function. (See Tables 1 and 2, and Figures 1, 2, 3 and 4.)

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In a pre-specified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone reduced the risk of the CV composite endpoint of time to CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure compared to placebo (HR 0.86 [95% CI 0.78; 0.95]). See Figure 5. The risk of the kidney composite endpoint of time to kidney failure, a sustained decrease in eGFR of 40% or more compared to baseline or renal death was also reduced with finerenone compared to placebo (HR 0.85 [95% CI 0.77; 0.93]), as was the composite endpoint of time to kidney failure, a sustained decrease in eGFR of 57% or more compared to baseline or renal death (HR 0.77 [95% CI 0.67; 0.88]). See Figure 5.

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Pharmacokinetics: Pharmacokinetic/Pharmacodynamic relationships: The concentration-effect relationship over time for UACR was characterized 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 (Vss) 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/Biotransformation: 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.
Elimination/Excretion: The elimination of finerenone from plasma is rapid with an elimination half-life (t½) 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 feces). About 80% of the administered dose was excreted via urine and approximately 20% of the dose was excreted via feces, 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.
Linearity/Non-linearity: Finerenone pharmacokinetics are linear across the investigated dose range from 1.25 to 80 mg.
Additional information on special populations: Patients with renal impairment: Mild renal impairment (CL_CR 60-<90 mL/min) did not affect finerenone AUC and C_max. Compared to subjects with normal renal function (CL_CR ≥90 mL/min), the effect of moderate (CL_CR 30-<60 mL/min) or severe (CL_CR <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).
Geriatric patients: Of the 2827 patients who received Firialta 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.
Of the 3683 patients who received Firialta in the FIGARO-DKD study, 52% of patients were 65 years and older, and 13% 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).
Population-pharmacokinetic analyses did not identify age as a covariate for finerenone AUC or C_max.
Gender: Gender had no effect on the pharmacokinetics of finerenone (see Dosage & Administration).
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 38% to 51% higher compared to a subject of 100 kg. Dose adaptation based on body weight is not warranted (see Dosage & Administration).
Ethnic differences: Population-pharmacokinetic analyses in patients demonstrated no clinically relevant difference in finerenone exposure between Asian and Caucasian patients (see Dosage & Administration).
Smoking status: Finerenone is not metabolized by an enzyme that is inducible by tobacco smoke (see Dosage & Administration).
Toxicology: Preclinical safety data: Embryotoxicity/Teratogenicity: In the embryo-fetal toxicity in rats, finerenone resulted in reduced placental weights and signs of fetal toxicity including reduced fetal weights and retarded ossification at the maternal toxic dose of 10 mg/kg/day corresponding to an AUC_unbound of 19 times that in humans. At 30 mg/kg/day, the incidence of visceral and skeletal variations was increased (slight edema, shortened umbilical cord, slightly enlarged fontanelle) and one fetus showed complex malformations including a rare malformation (double aortic arch) at an AUC_unbound of about 25 times that in humans. The doses free of any findings (low dose in rats, high dose in rabbits) provided safety margins of 10 to 13 times for AUC_unbound. Therefore, the findings in rats do not indicate an increased concern for fetal harm (see Use in Pregnancy & Lactation).
When rats were exposed during pregnancy and lactation in the pre- and postnatal developmental toxicity study, increased pup mortality and other adverse effects (lower pup weight, delayed pinna unfolding) were observed at about 4 times the AUC_unbound expected in humans. In addition, the offspring showed slightly increased locomotor activity, but no other neurobehavioral changes starting at about 4 times the AUC_unbound expected in humans. The dose free of findings provided a safety margin of about 2 for AUC_unbound. The increased locomotor activity in offspring may indicate a potential risk for the fetus. In addition, because of the findings in pups, a risk for the nursing infant cannot be excluded (see Precautions and Use in Pregnancy & Lactation).
Reproduction toxicity: Male fertility was not affected by Firialta (see Use in Pregnancy & Lactation).
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 number of viable fetuses) at about 21 times the human AUC_unbound. In addition, reduced ovarian weights were found at about 17 times the human AUC_unbound. No effects on female fertility and early embryonic development were found at 10 times the human AUC_unbound. Therefore, the findings in female rats are of little clinical relevance (see Use in Pregnancy & Lactation).
Genotoxicity and carcinogenicity: Finerenone was non-genotoxic in an in vitro bacterial reverse mutation (Ames assay), the in vitro chromosomal aberration assay and the in vivo micronucleus assay.
In 2-year carcinogenicity studies, finerenone did not show a carcinogenic potential in Wistar rats as well as CD1 mice. In male mice, finerenone resulted in an increase in Leydig cell adenoma at doses representing 26 times the AUC_unbound in humans. A dose representing 17 times the AUC_unbound in humans did not cause any tumors. Based on the known sensitivity of rodents to develop these tumors and the pharmacology-based mechanism at supratherapeutic doses as well as adequate safety margins, the increase in Leydig cell tumors in male mice is not clinically relevant.

Firialta is indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D).

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 Firialta with grapefruit or grapefruit juice (see Precautions and Interactions).
For patients who are unable to swallow whole tablets, Firialta tablet may be crushed and mixed with water or soft foods, such as applesauce, immediately prior to use and administered orally (see Pharmacology: Pharmacokinetics under Actions).
Dosage regimen: The recommended target dose of Firialta is 20 mg once daily.
Initiation of treatment: Initiation of Firialta 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 Firialta 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 Firialta treatment is not recommended (see Precautions).
Measure estimated glomerular filtration rate (eGFR) to determine the starting dose. The starting dose of Firialta is: 20 mg once daily if eGFR ≥60 mL/min/1.73 m² or 10 mg once daily if eGFR ≥25 to <60 mL/min/1.73 m².
Initiation of Firialta 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 re-start or up-titration of Firialta treatment, remeasure serum potassium and eGFR. See Table 3 to determine continuation of Firialta 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 3.)

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Missed doses: 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 Firialta is 20 mg.
Additional information on special populations: Patients with renal impairment: Initiation of Firialta treatment: In patients with eGFR >25 to <60 mL/min/1.73 m², the starting dose of Firialta is 10 mg once daily. See Initiation of treatment as previously mentioned.
In patients with eGFR <25 mL/min/1.73 m², initiation of Firialta treatment is not recommended as clinical experience is limited (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Continuation of Firialta treatment: In patients with mild, moderate or severe renal impairment, continue Firialta treatment and adjust dose based on serum potassium. Measure eGFR 4 weeks after initiation to determine up-titration. See Table 3 and Continuation of treatment as previously mentioned.
In patients with end-stage renal disease (eGFR <15 mL/min/1.73 m²), continue Firialta treatment with caution regarding serum potassium levels as clinical experience is limited (see Precautions).
Patients with hepatic impairment: In patients with severe hepatic impairment (Child-Pugh C), avoid treatment with Firialta (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 taking concomitant medications: In patients taking Firialta 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 Firialta treatment decisions as directed in Table 3. Temporary discontinuation of Firialta when taking trimethoprim, or trimethoprim-sulfamethoxazole, may be necessary (see Precautions and Interactions).
Pediatric patients: The safety and efficacy of Firialta have not been established in patients under 18 years of age. Therefore, Firialta is not recommended for use in pediatric patients.
Geriatric patients: No dose adjustment is required in the elderly (see Pharmacology: Pharmacokinetics under Actions).
Gender: No dose adjustment is required based on gender (see Pharmacology: Pharmacokinetics under Actions).
Body weight: No dose adjustment is required based on body weight (see Pharmacology: Pharmacokinetics under Actions).
Ethnic differences: No dose adjustment is required based on ethnic differences (see Pharmacology: Pharmacokinetics under Actions).
Smoking status: No dose adjustment is required based on smoking status (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 hyperkalemia. If hyperkalemia develops, standard treatment should be initiated.
Finerenone is unlikely to be efficiently removed by hemodialysis given its fraction bound to plasma proteins of about 90%.

Firialta 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 Addison's disease.

Hyperkalemia: Hyperkalemia has been observed in patients treated with Firialta.
Some patients are at a higher risk to develop hyperkalemia. Risk factors include low eGFR, higher serum potassium and previous episodes of hyperkalemia. Consider more frequent monitoring in these patients.
Initiation of Firialta treatment is not recommended if serum potassium >5.0 mmol/L. If serum potassium >4.8 to 5.0 mmol/L, initiation of Firialta 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 Firialta in treated patients if serum potassium >5.5 mmol/L. Follow local guidelines for the management of hyperkalemia. Restart Firialta 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 re-start or up-titration of Firialta 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 hyperkalemia 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 Firialta with the following medications: potassium-sparing diuretics (e.g., amiloride, triamterene), other mineralocorticoid receptor antagonists (MRAs) (e.g., eplerenone, esaxerenone, spironolactone, canrenone).
Use Firialta with caution and monitor serum potassium when taken concomitantly with the following medications: potassium supplements, trimethoprim, or trimethoprim-sulfamethoxazole. Temporary discontinuation of Firialta may be necessary.
Renal impairment: The risk of hyperkalemia increases with decreasing renal function. Ongoing monitoring of renal function should be performed as needed according to standard practice (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Initiation of Firialta treatment is not recommended in patients with eGFR <25 mL/min/1.73 m² as clinical experience is limited (see Dosage & Administration).
Continue Firialta 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).
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 Firialta 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).
Concomitant use of substances that affect finerenone exposure: Moderate and weak CYP3A4 inhibitors: The concomitant use of Firialta 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 Firialta or the CYP3A4 inhibitor (see Dosage & Administration).
Strong and moderate CYP3A4 inducers: Avoid concomitant use of Firialta 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).
Embryo-fetal toxicity: Animal data have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The relevance for humans is unknown. Firialta should not be used during pregnancy unless there has been careful consideration of the benefit for the mother and the risk to the fetus. If the patient becomes pregnant while taking Firialta, the patient should be informed of potential risks to the fetus. Advise women of childbearing potential to use effective contraception during treatment with Firialta. Advise women not to breastfeed during treatment with Firialta (see Use in Pregnancy & Lactation).
Effects on ability to drive or use machines: No effects on ability to drive and use machines have been observed.

Pregnancy: There are no data on the use of Firialta in pregnant women. Animal studies have shown embryo-fetal developmental toxicity at exposures in excess to the maximum human exposure. In the pre- and post-natal developmental toxicity study, slightly increased locomotor activity was found in the offspring, which may have been caused by exposure during pregnancy (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Firialta 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).
Lactation: It is unknown whether finerenone or its metabolites are excreted in human breast milk. Available pharmacokinetic and toxicological data in animals have shown excretion of finerenone and its metabolites in milk. Rat pups exposed by this route showed adverse effects. A risk to the nursing infant cannot be excluded. Breastfeeding should be discontinued if use of Firialta is considered essential (see Precautions).
Fertility: No human data on the effect of Firialta on fertility is available. Animal studies with finerenone did not indicate a risk of impaired male fertility. Animal studies with finerenone indicated impaired female fertility at exposures considered sufficiently in excess to the maximum human exposure indicating no clinical relevance (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Women of childbearing potential/Contraception: Firialta may cause embryo-fetal harm when administered during pregnancy. Women of childbearing potential should use effective contraception during treatment with Firialta (see Precautions).

Summary of the safety profile: The safety of Firialta in patients with chronic kidney disease associated with type 2 diabetes was evaluated in two pivotal phase III studies, FIDELIO-DKD and FIGARO-DKD. In the FIDELIO-DKD study, 2,827 patients received Firialta (10 or 20 mg once daily) with a mean duration of treatment of 2.2 years. In the FIGARO-DKD study, 3683 patients received Firialta (10 or 20 mg once daily) with a mean duration of treatment of 2.9 years.
The most frequently reported (≥10%) adverse reaction was hyperkalemia. See 'Description of selected adverse reactions' as follows (see Precautions).
Tabulated list of adverse reactions: The adverse reactions reported with Firialta are summarized in Table 4 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) and very rare (<1/10,000).
Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Table 4.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Hyperkalemia: In the FIDELIO-DKD study including patients with CKD (mean eGFR 44.3 mL/min/1.73 m²) and T2D, hyperkalemia events were reported in 18.3% of Firialta-treated patients compared with 9.0% of placebo-treated patients. An increase from baseline in mean serum potassium in the first month of treatment of approximately 0.2 mmol/L was observed in the Firialta group compared to placebo, which remained stable thereafter. In the FIGARO-DKD study including patients with CKD (mean eGFR 67.8 mL/min/1.73 m²) and T2D, hyperkalemia events were reported in 10.8% of Firialta-treated patients compared with 5.3% of placebo-treated patients. An increase from baseline in mean serum potassium in the first month of treatment of approximately 0.15 mmol/L was observed in the Firialta group compared to placebo, which remained stable thereafter. In both studies, the majority of hyperkalemia events were mild to moderate in patients treated with Firialta. For specific recommendations, refer to Dosage & Administration and Precautions.

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%]).
Effect of CYP3A4 inhibitors on finerenone: Strong CYP3A4 inhibitors: Simulations suggest that concomitant use of Firialta 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 Firialta 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 122%, 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 Firialta 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).
Effect 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 Firialta 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 aluminum 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.
Effect 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.
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.
Lack of mutual pharmacokinetic interaction was demonstrated between finerenone and the CYP2C9 substrate warfarin. Finerenone had no effect on AUC and C_trough of the P-gp substrate digoxin at steady-state (90% CI of ratio (digoxin + finerenone/digoxin alone) within 90-111%). The ratio of digoxin C_max at steady-state (digoxin + finerenone/digoxin alone) was 105.3% with a 90% CI of 94.65-117.16%.
Multiple doses of 40 mg finerenone once daily had no clinically relevant effect on AUC or C_max of the BCRP and OATP substrate rosuvastatin.
Pharmacodynamic interactions: Medications that increase serum potassium: It is anticipated that medications that increase serum potassium will increase the risk of hyperkalemia when used concomitantly with Firialta.
Concomitant use of Firialta with the following medications should be avoided: potassium-sparing diuretics (e.g., amiloride, triamterene), other mineralocorticoid receptor antagonists (MRAs) (e.g., eplerenone, esaxerenone, spironolactone, canrenone).
Firialta 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 Firialta may be necessary. (See Precautions.)

Incompatibilities: N/A.
Instructions for use/handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C.

Other Agents Affecting Metabolism / Other Drugs Acting on the Genito-Urinary System

C03DA05 - finerenone ; Belongs to the class of aldosterone antagonists. Used in management of chronic kidney disease.

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