Firialta

Finerenone.

Each Firialta tablet contains 10 mg or 20 mg of finerenone.
Firialta contains finerenone, a nonsteroidal mineralocorticoid receptor antagonist. Finerenone's chemical name is (4S)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide. The molecular formula is C₂₁H₂₂N₄O₃ and the molecular weight is 378.43 g/mol.
Finerenone is a white to yellow crystalline powder. It is practically insoluble in water; and sparingly soluble in 0.1 M HCl, ethanol, and acetone.
Excipients/Inactive Ingredients: The inactive ingredients of Firialta are lactose monohydrate, cellulose microcrystalline, croscarmellose sodium, hypromellose, magnesium stearate, and sodium lauryl sulfate. The film coating contains hypromellose, titanium dioxide and talc, in addition to ferric oxide red (10 mg strength tablets) or ferric oxide yellow (20 mg strength tablets).

PHARMACOLOGY: Mechanism of Action: Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor (MR), which is activated by aldosterone and cortisol and regulates gene transcription. Finerenone blocks MR mediated sodium reabsorption and MR overactivation in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, and blood vessels) tissues. MR overactivation is thought to contribute to fibrosis and inflammation. Finerenone has a high potency and selectivity for the MR and has no relevant affinity for androgen, progesterone, estrogen, and glucocorticoid receptors.
Pharmacodynamics: In FIDELIO-DKD, a randomized, double-blind, placebo-controlled, multicenter study in adult patients with chronic kidney disease associated with type 2 diabetes, the placebo-corrected relative reduction in urinary albumin-to-creatinine ratio (UACR) in patients randomized to finerenone was 31% at Month 4 (95% CI 29-34%) and remained stable for the duration of the trial.
In patients treated with Firialta, the mean systolic blood pressure decreased by 3 mmHg and the mean diastolic blood pressure decreased by 1-2 mmHg at month 1, remaining stable thereafter.
Cardiac Electrophysiology: At a dose 4 times the maximum approved recommended dose, finerenone does not prolong the QT interval to any clinically relevant extent.
CLINICAL STUDIES: The FIDELIO-DKD study was a randomized, double-blind, placebo-controlled, multicenter study in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D), defined as either having an UACR of 30 to 300 mg/g, eGFR 25 to 60 mL/min/1.73 m² and diabetic retinopathy, or as having an UACR of ≥300 mg/g and an eGFR of 25 to 75 mL/min/1.73 m². The trial excluded patients with known significant non-diabetic kidney disease. All patients were to have a serum potassium ≤4.8 mEq/L at screening and be receiving standard of care background therapy, including a maximum tolerated labeled dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients with a clinical diagnosis of chronic heart failure with reduced ejection fraction and persistent symptoms (New York Heart Association class II to IV) were excluded. The starting dose of Firialta was based on screening eGFR (10 mg once daily in patients with an eGFR of 25 to <60 mL/min/1.73 m² and 20 mg once daily in patients with an eGFR ≥60 mL/min/1.73 m²). The dose of Firialta could be titrated during the study, with a target dose of 20 mg daily.
The primary objective of the study was to determine whether Firialta reduced the incidence of a sustained decline in eGFR of ≥40%, kidney failure (defined as chronic dialysis, kidney transplantation, or a sustained decrease in eGFR to <15 mL/min/1.73m²), or renal death.
A total of 5674 patients were randomized to receive Firialta (N=2833) or placebo (N=2841) and were followed for a median of 2.6 years. The mean age of the study population was 66 years, and 70% of patients were male. The trial population was 63% White, 25% Asian, and 5% Black. At baseline, the mean eGFR was 44 mL/min/1.73m², with 55% of patients having an eGFR <45 mL/min/1.73m². Median urine albumin-to-creatinine ratio (UACR) was 852 mg/g, and mean glycated hemoglobin A1c (HbA1c) was 7.7%. Approximately 46% of patients had a history of atherosclerotic cardiovascular disease.
At baseline, 99.8% of patients were treated with an ACEi or ARB. Approximately 97% were on an antidiabetic agent (insulin [64.1%], biguanides [44%], glucagon-like peptide-1 [GLP-1] receptor agonists [7%], sodium-glucose cotransporter 2 [SGLT2] inhibitors [5%]), 74% were on a statin, and 57% were on an antiplatelet agent.
Firialta reduced the incidence of the primary composite endpoint of a sustained decline in eGFR of ≥40%, kidney failure, or renal death (HR 0.82, 95% CI 0.73-0.93, p=0.001) as shown in Table 1 and Figure 1. The treatment effect reflected a reduction in a sustained decline in eGFR of ≥40% and progression to kidney failure. There were few renal deaths during the trial.
Firialta also reduced the incidence of the composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal stroke or hospitalization for heart failure (HR 0.86, 95% CI 0.75-0.99, p=0.034) as shown in Table 1 and Figure 2. The treatment effect reflected a reduction in CV death, non-fatal MI, and hospitalization for heart failure.
The treatment effect on the primary and secondary composite endpoints was generally consistent across subgroups. (See Table 1 and Figures 1 and 2.)

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Pharmacokinetics: Finerenone exposure increased proportionally over a dose range of 1.25 to 80 mg (0.06 to 4 times the maximum approved recommended dosage). Steady state of finerenone was achieved after 2 days of dosing. The estimated steady-state geometric mean C_max,md was 160 μg/L and steady-state geometric mean AUC_τ,md was 686 μg.h/L following administration of finerenone 20 mg to patients.
Absorption: Finerenone is completely absorbed after oral administration but undergoes metabolism resulting in absolute bioavailability of 44%. Finerenone C_max was achieved between 0.5 and 1.25 hours after dosing.
Effect of Food: There was no clinically significant effect on finerenone AUC following administration with high fat, high calorie food.
Distribution: The volume of distribution at steady-state (Vss) of finerenone is 52.6 L. Plasma protein binding of finerenone is 92%, primarily to serum albumin, in vitro.
Elimination: The terminal half-life of finerenone is about 2 to 3 hours, and the systemic blood clearance is about 25 L/h.
Metabolism: Finerenone is primarily metabolized by CYP3A4 (90%) and to a lesser extent by CYP2C8 (10%) to inactive metabolites.
Excretion: About 80% of the administered dose is excreted in urine (<1% as unchanged) and approximately 20% in feces (< 0.2% as unchanged).
Specific Populations: There are no clinically significant effects of age (18 to 79 years), sex, race/ethnicity (White, Asian, Black, and Hispanic), or weight (58 to 121 kg) on the pharmacokinetics of finerenone.
Renal Impairment: There were no clinically relevant differences in finerenone AUC or C_max values in patients with eGFR 15 to < 90 mL/min/1.73m² compared to eGFR ≥ 90 mL/min/1.73 m². For dosing recommendations based on eGFR and serum potassium levels see Dosage & Administration.
Hepatic Impairment: There was no clinically significant effect on finerenone exposure in cirrhotic patients with mild hepatic impairment (Child Pugh A).
Finerenone mean AUC was increased by 38% and C_max was unchanged in cirrhotic patients with moderate hepatic impairment (Child Pugh B) compared to healthy control subjects.
The effect of severe hepatic impairment (Child Pugh C) on finerenone exposure was not studied.
Drug Interaction Studies: Clinical Studies and Model-Informed Approaches: Strong CYP3A Inhibitors: Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased finerenone AUC by >400%.
Moderate CYP3A Inhibitors: Concomitant use of erythromycin (moderate CYP3A4 inhibitor) increased finerenone mean AUC and C_max by 248% and 88%, respectively.
Weak CYP3A Inhibitors: Concomitant use of amiodarone (weak CYP3A4 inhibitor) increased finerenone AUC by 21%.
Strong or Moderate CYP3A Inducers: Concomitant use of efavirenz (moderate CYP3A4 inducer) and rifampicin (strong CYP3A4 inducer) decreased finerenone AUC by 80% and 90%, respectively.
Other Drugs: There was no clinically significant difference in finerenone pharmacokinetics when used concomitantly with gemfibrozil (strong CYP2C8 inhibitor), omeprazole (proton pump inhibitor), or an aluminium hydroxide and magnesium hydroxide antacid. There were no clinically significant pharmacokinetic differences for either finerenone or concomitant digoxin (P-gp substrate) or warfarin (CYP2C9 substrate). There were no clinically significant differences in the pharmacokinetics of either midazolam (CYP3A4 substrate) or repaglinide (CYP2C8 substrate) when used concomitantly with finerenone.
NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility: Finerenone was non-genotoxic in an in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in cultured Chinese hamster V79 cells, or the in vivo micronucleus assay in mice.
In 2-year carcinogenicity studies, finerenone did not show a statistically significant increase in tumor response in Wistar rats or in CD1 mice. In male mice, Leydig cell adenoma was numerically increased at a dose representing 26 times the AUC_unbound in humans and is not considered clinically relevant. Finerenone did not impair fertility in male rats but impaired fertility in female rats at 20 times AUC to the maximum human exposure.

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).

Prior to Initiation of Firialta: Measure serum potassium levels and estimated glomerular filtration rate (eGFR) before initiation. Do not initiate treatment if serum potassium is > 5.0 mEq/L [see Hyperkalemia under Precautions].
Recommended Starting Dosage: The recommended starting dose of Firialta is based on eGFR and is presented in Table 2. (See Table 2.)

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For patients who are unable to swallow whole tablets, Firialta 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].
Monitoring and Dose Adjustment: The target daily dose of Firialta is 20 mg.
Measure serum potassium 4 weeks after initiating treatment and adjust dose (see Table 3); if serum potassium levels are >4.8 to 5.0 mEq/L, initiation of Firialta treatment may be considered with additional serum potassium monitoring within the first 4 weeks based on clinical judgement and serum potassium levels [see Hyperkalemia under Precautions]. Monitor serum potassium 4 weeks after a dose adjustment and throughout treatment, and adjust the dose as needed (see Table 3) [see Hyperkalemia under Precautions and CYP3A4 Inhibitors and Inducers under Interactions]. (See Table 3.)

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Missed doses: Direct a patient to take a missed dose as soon as possible after it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed.

In the event of suspected overdose, immediately interrupt Firialta treatment. The most likely manifestation of overdose is 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: Who are receiving concomitant treatment with strong CYP3A4 inhibitors [see CYP3A4 Inhibitors and Inducers under Interactions].
With adrenal insufficiency.

Hyperkalemia: Firialta can cause hyperkalemia [see Clinical Trials Experience under Adverse Reactions].
The risk for developing hyperkalemia increases with decreasing kidney function and is greater in patients with higher baseline potassium levels or other risk factors for hyperkalemia. Measure serum potassium and eGFR in all patients before initiation of treatment with Firialta and dose accordingly [see Prior to Initiation of Firialta under Dosage & Administration]. Do not initiate Firialta if serum potassium is > 5.0 mEq/L.
Measure serum potassium periodically during treatment with Firialta and adjust dose accordingly [see Monitoring and Dose Adjustment under Dosage & Administration]. More frequent monitoring may be necessary for patients at risk for hyperkalemia, including those on concomitant medications that impair potassium excretion or increase serum potassium [see CYP3A4 Inhibitors and Inducers and Drugs That Affect Serum Potassium under Interactions].
Hepatic Impairment: Avoid use of Firialta in patients with severe hepatic impairment (Child Pugh C).
No dosage adjustment is recommended in patients with mild or moderate hepatic impairment (Child Pugh A or B).
Consider additional serum potassium monitoring in patients with moderate hepatic impairment (Child Pugh B) [see Monitoring and Dose Adjustment under Dosage & Administration and PHARMACOLOGY: Pharmacokinetics under Actions].
Use in Children: The safety and efficacy of Firialta have not been established in patients below 18 years of age.
Use in the Elderly: 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. No dose adjustment is required.

Pregnancy: Risk Summary: There are no available data on Firialta use in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal studies have shown developmental toxicity at exposures about 4 times those expected in humans (see Data as follows). The clinical significance of these findings is unclear.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data: Animal Data: In the embryo-fetal toxicity study 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) provide safety margins of 10 to 13 times for the AUC_unbound expected in humans.
When rats were exposed during pregnancy and lactation in the pre- and postnatal developmental toxicity study, increased pup mortality and other adverse effects (lower pup weight, delayed pinna unfolding) were observed at about 4 times the AUC_unbound expected in humans. In addition, the offspring showed slightly increased locomotor activity, but no other neurobehavioral changes starting at about 4 times the AUC_unbound expected in humans. The dose free of findings provides asafety margin of about 2 times for the AUC_unbound expected in humans.
Lactation: Risk Summary: There are no data on the presence of finerenone or its metabolite in human milk, the effects on the breastfed infant or the effects of the drug on milk production. In a pre- and postnatal developmental toxicity study in rats, increased pup mortality and lower pup weight were observed at about 4 times the AUC_unbound expected in humans. These findings suggest that finerenone is present in rat milk [see previous text]. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential risk to breastfed infants from exposure to Firialta, avoid breastfeeding during treatment and for 1 day after treatment.

The following serious adverse reactions are discussed elsewhere in the monograph: Hyperkalemia [see Hyperkalemia under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Firialta was evaluated in the randomized, double-blind, placebo-controlled, multicenter pivotal phase 3 study FIDELIO-DKD. In this study, 2827 patients received Firialta (10 or 20 mg once daily) and 2831 received placebo. For patients in the Firialta group, the mean duration of treatment was 2.2 years.
Overall, serious adverse reactions occurred in 32% of patients receiving Firialta and in 34% of patients receiving placebo. Permanent discontinuation due to adverse reactions occurred in 7% of patients receiving Firialta and in 6% of patients receiving placebo. Hyperkalemia led to permanent discontinuation of treatment in 2.3% of patients receiving Firialta versus 0.9% of patients receiving placebo.
The most frequently reported (≥ 10%) adverse reaction was hyperkalemia [see Hyperkalemia under Precautions]. Hospitalization due to hyperkalemia for the Firialta group was 1.4% versus 0.3% in the placebo group.
Table 4 shows adverse reactions in FIDELIO-DKD that occurred more commonly on Firialta than on placebo, and in at least 1% of patients treated with Firialta. (See Table 4.)

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Laboratory Test: Initiation of Firialta may cause an initial small decrease in estimated GFR that occurs within the first 4 weeks of starting therapy, and then stabilizes. In a study that included patients with chronic kidney disease associated with type 2 diabetes, this decrease was reversible after treatment discontinuation.

CYP3A4 Inhibitors and Inducers: Strong CYP3A4 Inhibitors: Firialta is a CYP3A4 substrate. Concomitant use with a strong CYP3A4 inhibitor increases finerenone exposure [see PHARMACOLOGY: Pharmacokinetics under Actions], which may increase the risk of Firialta adverse reactions. Concomitant use of Firialta with strong CYP3A4 inhibitors is contraindicated [see Contraindications]. Avoid concomitant intake of grapefruit or grapefruit juice.
Moderate and Weak CYP3A4 Inhibitors: Firialta is a CYP3A4 substrate. Concomitant use with a moderate or weak CYP3A4 inhibitor increases finerenone exposure [see PHARMACOLOGY: Pharmacokinetics under Actions], which may increase the risk of Firialta adverse reactions. Monitor serum potassium during drug initiation or dosage adjustment of either Firialta or the moderate or weak CYP3A4 inhibitor, and adjust Firialta dosage as appropriate [see Monitoring and Dose Adjustment under Dosage & Administration and Drugs That Affect Serum Potassium as follows].
Strong and Moderate CYP3A4 Inducers: Firialta is a CYP3A4 substrate. Concomitant use of Firialta with a strong or moderate CYP3A4 inducer decreases finerenone exposure [see PHARMACOLOGY: Pharmacokinetics under Actions], which may reduce the efficacy of Firialta. Avoid concomitant use of Firialta with strong or moderate CYP3A4 inducers.
Drugs That Affect Serum Potassium: More frequent serum potassium monitoring is warranted in patients receiving concomitant therapy with drugs or supplements that increase serum potassium. [see Monitoring and Dose Adjustment under Dosage & Administration and Hyperkalemia under Precautions].

Do not store above 30°C.

Advise patients of the need for periodic monitoring of serum potassium levels. Advise patients receiving Firialta to consult with their physician before using potassium supplements or salt substitutes containing potassium [see Hyperkalemia under Precautions].
Advise patients to avoid strong or moderate CYP3A4 inducers and to find alternative medicinal products with no or weak potential to induce CYP3A4 [see CYP3A4 Inhibitors and Inducers under Interactions].
Avoid concomitant intake of grapefruit or grapefruit juice as it is expected to increase the plasma concentration of finerenone [see CYP3A4 Inhibitors and Inducers under Interactions].
Advise women that breastfeeding is not recommended at the time of treatment with Firialta and for 1 day after treatment [see Lactation under Use in Pregnancy & Lactation].

Diuretics

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

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