FINEREN 10/ 20 mg

  Finerenone Film-Coated Tablets

PRESENTATION

Brand Name: Fineren

Generic Name: Finerenone

Strength: 10/20 mg

Dosage Form: Tablets

Packing: Blister

Pack Size: 3*10

Clinical Particulars

Therapeutic Indications

Fineren 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).

Posology and Method of Administration

• The recommended starting dosage is 10 mg or 20 mg orally once daily based on estimated glomerular filtration rate (eGFR) and serum potassium thresholds.
• Increase dosage after 4 weeks to the target dose of 20 mg once daily, based on eGFR and serum potassium thresholds.
• Tablets may be taken with or without food.

Initiation of Treatment

Serum potassium and estimated glomerular filtration rate (eGFR) have to be measured to determine if finerenone treatment can be initiated and to determine the starting dose.

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

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

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

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

Table 1: Initiation of Finerenone Treatment and Recommended Dose

Continuation of Treatment

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

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

Table 2: Continuation of Finerenone Treatment and Dose Adjustment

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

Missed Dose

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

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

Special populations

Elderly

No dose adjustment is necessary in elderly patients.

Renal Impairment

Initiation of Treatment

In patients with eGFR < 25 mL/min/1.73 m², finerenone treatment should not be initiated due to limited clinical data.

Continuation of Treatment

In patients with eGFR ≥ 15 mL/min/1.73 m², finerenone treatment can be continued with dose adjustment based on serum potassium. eGFR should be measured 4 weeks after initiation to determine whether the starting dose can be increased to the recommended daily dose of 20 mg.

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

Hepatic Impairment

Patients with Severe Hepatic Impairment:

Finerenone should not be initiated. No data are available.

Moderate Hepatic Impairment:

No initial dose adjustment is required. Consider additional serum potassium monitoring and adapt monitoring according to patient characteristics.

Mild Hepatic Impairment:

No initial dose adjustment is required.

Concomitant Medication

In patients taking finerenone concomitantly with moderate or weak CYP3A4 inhibitors, potassium supplements, trimethoprim, or trimethoprim/sulfamethoxazole, additional serum potassium monitoring and adaptation of monitoring according to patient characteristics should be considered. Finerenone treatment decisions should be made as directed in table 2 ('Posology, Continuation of treatment').

Temporary discontinuation of finerenone may be necessary, when patients have to take trimethoprim, or trimethoprim/sulfamethoxazole.

Body Weight

No dose adjustment is necessary based on body weight.

Pediatric Population

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

Method of Administration

Oral Use

• Tablets may be taken with a glass of water and with or without food.
• Tablets should not be taken with grapefruit or grapefruit juice.

Crushing of Tablets

For patients who are unable to swallow whole tablets, Fineren tablets may be crushed and mixed with water or soft foods, such as apple sauce, directly before oral use.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Concomitant treatment with strong inhibitors of CYP3A4, e.g.:

• Addison's Disease

Special Warnings and Precautions for Use

• Hyperkalemia
• Hyperkalemia has been observed in patients treated with finerenone.
• Some patients are at a higher risk to develop hyperkalemia.
• Risk factors include low eGFR, higher serum potassium and previous episodes of hyperkalemia. In these patients more frequent monitoring has to be considered.

Initiation and Continuation of Treatment 

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

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

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

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

Monitoring

Serum potassium and eGFR have to be remeasured in all patients 4 weeks after initiation, re-start or increase in dose of finerenone. Thereafter, serum potassium has to be assessed periodically and as needed based on patient characteristics and serum potassium levels.

Concomitant Medications

The risk of hyperkalemia also may increase with the intake of concomitant medications that may increase serum potassium. See also 'Concomitant use of substances that affect finerenone exposure'.

Finerenone Should Not Be Given Concomitantly With

• • Potassium-sparing diuretics (e.g., amiloride, triamterene) and
  • Other mineralocorticoid receptor antagonists (MRAs), e.g., eplerenone, esaxerenone, spironolactone, canrenone.

Finerenone should be used with caution and serum potassium should be monitored when taken concomitantly with

• • Potassium supplements.
  • Trimethoprim, or trimethoprim/sulfamethoxazole. Temporary discontinuation of finerenone 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.

Initiation of Treatment

Finerenone treatment should not be initiated in patients with eGFR < 25 mL/min/1.73 m² as clinical data are limited.

Continuation of Treatment

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

Hepatic Impairment

Finerenone treatment should not be initiated in patients with severe hepatic impairment. These patients have not been studied but a significant increase in finerenone exposure is expected.

The use of finerenone in patients with moderate hepatic impairment may require additional monitoring due to an increase in finerenone exposure. Additional serum potassium monitoring and adaptation of monitoring have to be considered according to patient characteristics.

Heart Failure

Patients with diagnosed heart failure with reduced ejection fraction and New York Heart Association II-IV were excluded from the phase III clinical studies.

Concomitant use of substances that affect finerenone exposure

Moderate and Weak CYP3A4 Inhibitors

Serum potassium should be monitored during concomitant use of finerenone with moderate or weak CYP3A4 inhibitors.

Strong and Moderate CYP3A4 Inducers

Finerenone should not be used concomitantly with strong or moderate CYP3A4 inducers.

Grapefruit

Grapefruit or grapefruit juice should not be consumed during finerenone treatment.

Embryo-Fetal Toxicity

Finerenone 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 a woman becomes pregnant while taking finerenone, she should be informed of potential risks to the fetus.

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

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

Interaction with Other Medicinal Products and Other Forms of Interaction

Interaction studies have only been performed in adults.

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

Concomitant Use Contraindicated

Strong CYP3A4 Inhibitors

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

Concomitant use not recommended

Strong and Moderate CYP3A4 Inducers

Fineren should not be used concomitantly with rifampicin and other strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, phenobarbital, St John's Wort) or with efavirenz and other moderate CYP3A4 inducers. These CYP3A4 inducers are expected to markedly decrease finerenone plasma concentration and result in reduced therapeutic effect.

Certain Medicinal Products That Increase Serum Potassium

Fineren should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, triamterene) and other MRAs (e.g., eplerenone, esaxerenone, spironolactone, canrenone). It is anticipated that these medicinal products increase the risk for hyperkalemia.

Grapefruit

Grapefruit or grapefruit juice should not be consumed during finerenone treatment, as it is expected to increase the plasma concentrations of finerenone through inhibition of CYP3A4.

Concomitant use with precautions

Moderate CYP3A4 Inhibitors

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

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

Weak CYP3A4 Inhibitors

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

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

Certain Medicinal Products That Increase Serum Potassium

Concomitant use of Fineren with potassium supplements and trimethoprim, or trimethoprim/sulfamethoxazole is anticipated to increase the risk of hyperkalemia. Monitoring of serum potassium is required.

Temporary discontinuation of Fineren during trimethoprim, or trimethoprim/sulfamethoxazole treatment may be necessary.

Antihypertensive Medicinal Products

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

Fertility, Pregnancy and Lactation

Contraception in Females

Women of childbearing potential should use effective contraception during finerenone treatment.

Pregnancy

• There are no data from the use of finerenone in pregnant women.
• Studies in animals have shown reproductive toxicity.

Fineren should not be used during pregnancy unless the clinical condition of the woman requires treatment with finerenone. If the woman becomes pregnant while taking finerenone, she should be informed of potential risks to the fetus.

Breast-Feeding

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

Available pharmacokinetic/toxicological data in animals have shown excretion of finerenone and its metabolites in milk. Rat pups exposed via this route showed adverse reactions.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fineren therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of finerenone on human fertility. Animal studies have shown impaired female fertility at exposures considered in excess to the maximum human exposure, indicating low clinical relevance.

Effects on Ability to Drive and Use Machines

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

Undesirable Effects

Summary of the Safety Profile

The most frequently reported adverse reaction under treatment with finerenone was hyperkalemia (14.0%).

The safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) was evaluated in 2 pivotal phase III studies, FIDELIO-DKD (diabetic kidney disease) and FIGARO-DKD. In the FIDELIO-DKD study 2,827 patients received finerenone (10 or 20 mg once daily) with a mean duration of treatment of 2.2 years. In the FIGARO-DKD study, 3,683 patients received finerenone (10 or 20 mg once daily) with a mean duration of treatment of 2.9 years.

The adverse reactions observed are listed in table 3. They are classified according to MedDRA`s system organ class database and frequency convention.

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

Frequencies Are Defined, As Follows:

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

Table 3: Adverse Reactions

Overdose

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%.

Pharmacological Properties

Pharmacodynamics Properties

Pharmaco- Therapeutic Group: Diuretics, Aldosterone Antagonists.

Mechanism of Action

Finerenone is a non-steroidal, selective antagonist of the mineralocorticoid receptor (MR) which is activated by aldosterone and cortisol and regulates gene transcription.  It’s binding to the MR leads to a specific receptor-ligand complex that blocks recruitment of transcriptional co-activators implicated in the expression of pro-inflammatory and pro-fibrotic mediators.

Pharmacodynamic Effects

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

In ARTS-DN, a randomized, double-blind, placebo-controlled, multicenter phase IIb study in adult patients 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

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

Pharmacokinetic Properties

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 a substrate of the efflux transporter P-glycoprotein in vitro, which is however not considered relevant for its absorption in vivo due to the high permeability of finerenone.

Effect of food

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. Since this is not considered as clinically relevant, finerenone can be taken with or without food.

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.

Biotransformation

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

Elimination

The elimination of finerenone from plasma is rapid with an elimination half-life (t_½) of about 2 to 3 hours. Systemic blood clearance of finerenone is about 25 L/h. About 80% of the administered dose was excreted via urine and approximately 20% of the dose was excreted via faces. Excretion was almost exclusively in the form of metabolites, while excretion of unchanged finerenone represents a minor route (< 1% of dose in the urine due to glomerular filtration, < 0.2% in the faces).

Linearity

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

Special Populations

Elderly

Of the 2,827 patients who received finerenone in the FIDELIO-DKD study, 58% of patients were 65 years and older, and 15% were 75 years and older. Of the 3,683 patients who received finerenone in the FIGARO-DKD study, 52% of patients were 65 years and older, and 13% were 75 years and older.

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

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

Renal Impairment

Mild renal impairment (creatinine clearance [CL_CR] 60 to < 90 mL/min) did not affect finerenone AUC and C_max.

Compared to patients with normal renal function (CL_CR ≥ 90 mL/min), the effect of moderate (CL_CR 30 to < 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.

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

Hepatic Impairment

There was no change in finerenone exposure in cirrhotic patients with mild hepatic impairment.

In cirrhotic patients with moderate hepatic impairment, finerenone total and unbound AUC were increased by 38% and 55%, respectively, while no change in C_max was observed compared to healthy control participants.

There are no data in patients with severe hepatic impairment.

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.

Special Precautions for Storage

This medicinal product does not require any special storage conditions.