FILSPARI 400mg tablets medication leaflet

Filspari 200 mg film-coated tablets

Filspari 400 mg film-coated tablets

Filspari 200 mg film-coated tablets

Each tablet contains 200 mg of sparsentan.

Each tablet contains 42 mg of lactose.

Filspari 400 mg film-coated tablets

Each tablet contains 400 mg of sparsentan.

Each tablet contains 84 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet

Filspari 200 mg film-coated tablets

White to off-white, oval‒shaped, film-coated tablet, debossed with “105” on one side and plain on theother side. The dimensions of the tablets are approximately 13 mm × 7 mm.

Filspari 400 mg film-coated tablets

White to off-white, oval‒shaped, film-coated tablet, debossed with “021” on one side and plain on theother side. The dimensions of the tablets are approximately 18 mm × 8 mm.

Filspari is indicated for the treatment of adults with primary immunoglobulin A nephropathy (IgAN)with a urine protein excretion ≥1.0 g/day (or urine protein-to-creatinine ratio ≥ 0.75 g/g, seesection 5.1).

Sparsentan treatment should be initiated at a dose of 200 mg once daily for 14 days and then increasedto a maintenance dose of 400 mg once daily, dependent upon tolerability.

For titration from the initial dose of 200 mg once daily to the maintenance dose of 400 mg once daily,200 mg and 400 mg film-coated tablets are available to achieve the maintenance dose.

If patients experience tolerability issues (systolic blood pressure [SBP] ≤ 100 mmHg, diastolic bloodpressure ≤ 60 mmHg, worsening edema, or hyperkalaemia), adjustment of concomitant medicinalproducts, followed by temporary down-titration or discontinuation of sparsentan is recommended (seesections 4.4 and 5.1).

When resuming treatment with sparsentan after interruption, repeating the initial dosing schedule maybe considered. Interruption of treatment preceded, or not by dose reduction of sparsentan, may beconsidered based on persisting hypotension or changes in liver function (see section 4.4).

If a dose is missed, the dose should be skipped and the next dose is to be taken at the regularlyscheduled time. Double or extra doses should not be taken.

No dose adjustment is recommended in elderly patients (see section 5.2). In elderly patients sparsentantreatment should be initiated at a dose of 200 mg once daily for 14 days. The increase to amaintenance dose of 400 mg once daily should be performed with caution, based on tolerability (seesection 4.4).

Based on pharmacokinetics data, no dose adjustment of sparsentan is required in patients with mild ormoderate hepatic impairment (Child-Pugh A or Child-Pugh B classification; see section 5.2).

There is limited clinical experience with moderate hepatic impairment. Therefore, sparsentan shouldbe used with caution in these patients (see section 4.4).

Sparsentan has not been studied in patients with severe hepatic impairment (Child-Pugh Cclassification) and is therefore not recommended for use in these patients.

There is limited clinical experience with aspartate aminotransferase (AST)/alanineaminotransferase (ALT) values more than two times the upper limit of the normal range (ULN).

Therefore, sparsentan should not be initiated in patients with AST/ALT > 2 × ULN (see section 4.4).

No dose adjustment is required in patients with mild (chronic kidney disease [CKD] stage 2; estimatedglomerular filtration rate [eGFR] 60 to 89 mL/min/1.73 m2) or moderate (CKD stages 3a and 3b;eGFR 30 to 59 mL/min/1.73 m2) kidney disease. Based on pharmacokinetic data, no dose adjustmentcan be recommended for patients with severe kidney disease (CKD stage 4; eGFR< 30 mL/min/1.73 m2) (see section 5.2). As there is limited clinical experience in patients with severekidney disease, sparsentan is not recommended in these patients (see section 4.4).

Sparsentan has not been studied in patients who have received a kidney transplant, thereforesparsentan should be used with caution is these patients.

Sparsentan has not been studied in patients undergoing dialysis. Initiation of sparsentan is notrecommended in these patients.

The safety and efficacy of Filspari in children below the age of 18 years with IgAN have not yet beenestablished. No data are available.

Oral use.

It is recommended to swallow the tablets whole with water to avoid bitter taste. Sparsentan can betaken with or without food.

* Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

* Pregnancy (see sections 4.4 and 4.6)

* Coadministration of angiotensin receptor blockers (ARBs), endothelin receptor antagonists(ERAs), or renin inhibitors (see sections 4.4 and 4.5)

Sparsentan treatment must only be initiated in women of childbearing potential when the absence ofpregnancy has been verified and effective contraception is practised (see sections 4.3 and 4.6).

Hypotension has been associated with the use of renin-angiotensin-aldosterone system (RAAS)inhibitors, including sparsentan. Hypotension may occur during treatment with sparsentan and isreported more frequently in elderly patients (see section 4.8).

In patients at risk for hypotension, eliminating or adjusting other antihypertensive medicinal productsand maintaining appropriate volume status should be considered. If hypotension develops despiteelimination or reduction of other antihypertensive medicinal products, dose reduction or doseinterruption of sparsentan should be considered. A transient hypotensive response is not acontraindication to further dosing of sparsentan; treatment can be resumed once blood pressure hasstabilised.

If hypotension persists despite elimination or reduction of antihypertensive medicinal products,sparsentan dosing should be reduced to the initial starting dose until blood pressure stabilises. Doseinterruption of treatment with sparsentan should be considered if symptoms of hypotension persistafter 2 weeks of dose reduction. Sparsentan should be used with caution in patients with systolic bloodpressure values ≤ 100 mmHg (see section 4.2). Sparsentan should not be uptitrated in patients withsystolic blood pressure values ≤ 100 mmHg (see section 4.2).

Impaired kidney function

A transient increase in serum creatinine has been associated with RAAS inhibitors, includingsparsentan. A transient increase in serum creatinine may occur, especially when initiating treatmentwith sparsentan (see section 4.8). Periodic monitoring of serum creatinine and serum potassium levelsshould be performed in patients at risk. Sparsentan should be used with caution in patients withbilateral renal artery stenosis.

Due to the limited clinical experience in patients with an eGFR < 30 mL/min/1.73 m2, sparsentan isnot recommended in these patients (see section 4.2).

Fluid retention

Fluid retention has been associated with medicinal products that antagonise the endothelin type Areceptor (ETAR), including sparsentan. Fluid retention may occur during the treatment with sparsentan(see section 4.8). If fluid retention develops during treatment with sparsentan, treatment with diureticsis recommended, or the dose of existing diuretics should be increased before modifying the dose ofsparsentan. Treatment with diuretics can be considered in patients with evidence of fluid retentionbefore the start of treatment with sparsentan.

Sparsentan has not been studied in patients with heart failure. Therefore, sparsentan should be usedwith caution in patients with heart failure.

Elevations in ALT or AST of at least 3 × ULN have been observed with sparsentan (see section 4.8).

No concurrent elevations in bilirubin > 2 × ULN or cases of liver failure have been observed insparsentan-treated patients. Therefore, to reduce the risk of potential serious hepatotoxicity, serumaminotransferase levels and total bilirubin should be monitored prior to initiation of treatment and thencontinue monitoring every three months.

Patients should be monitored for signs of hepatic injury. If patients develop sustained, unexplained,clinically significant ALT and/or AST elevation, or if elevations are accompanied by an increase inbilirubin >2 × ULN, or if ALT and/or AST elevation is accompanied by signs or symptoms of hepaticinjury (e.g, jaundice), sparsentan therapy should be discontinued.

Consider re-initiation of sparsentan only when hepatic enzyme levels and bilirubin return topretreatment values and only in patients without clinical symptoms of hepatotoxicity. Avoid initiationof sparsentan in patients with elevated aminotransferase (> 2 × ULN) prior to drug initiation (seesection 4.2).

There is limited clinical experience with moderate hepatic impairment. Therefore, sparsentan shouldbe used with caution in these patients (see section 4.2).

Dual blockade of the Renin Angiotensin Aldosterone System (RAAS)

There is evidence that the concomitant use of Angiotensin-converting enzyme (ACE) inhibitors,angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia anddecreased renal function (including acute renal failure). Dual blockade of RAAS through thecombined use of ACE inhibitors, angiotensin II receptor blockers (partly a mechanism of sparsentan)or renin inhibitors is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy isconsidered absolutely necessary, this should only occur under specialist supervision and subject tofrequent close monitoring of renal function, electrolytes and blood pressure.

Treatment should not be initiated in patients with serum potassium level > 5.5 mmol/l. As with othermedicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occurduring the treatment with sparsentan, especially in the presence of renal impairment and/or heartfailure. Close monitoring of serum potassium in patients at risk is recommended. If patients experienceclinically significant hyperkalaemia adjustment of concomitant medicinal products, or temporarydown-titration or discontinuation is recommended. If serum potassium level is > 5.5 mmol/ldiscontinuation should be considered.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, orglucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Concomitant use with ARBs, ERAs and renin inhibitors

Concomitant use of sparsentan with ERAs such as bosentan, ambrisentan, macitentan, sitaxentan,

ARBs such as irbesartan, losartan, valsartan, candesartan, telmisartan, or renin inhibitors such asaliskiren is contraindicated (see section 4.3).

Concomitant use with ACE and mineralcorticoid receptor inhibitors

Coadministration of sparsentan with mineralocorticoid (aldosterone) receptor inhibitors such asspironolactone and finerenone is expected to be associated with increased risk of hyperkalaemia.

There are no data on the combination of sparsentan with ACE inhibitors such as enalapril or lisinopril.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS)through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting agent (seesection 5.1).

The use of sparsentan in combination with ACE inhibitors such as enalapril or lisinopril should bedone with caution, and blood pressure, potassium, and kidney function should be monitored (seesection 4.4).

Concomitant use with potassium supplements and potassium-sparing diuretics

As hyperkalaemia may occur in patients treated with medicinal products that antagonise theangiotensin II receptor type 1 (AT1R) (see section 4.8), concomitant use of potassium supplements,potassium-sparing diuretics such as spironolactone, eplerenone, triamterene or amiloride, or saltsubstitutes containing potassium may increase the risk of hyperkalaemia and is not recommended.

Effect of other medicinal products on sparsentan

Sparsentan is primarily metabolised by cytochrome P450 (CYP)3A.

Strong and moderate CYP3A inhibitors

Co-administration of sparsentan with itraconazole (strong CYP3A inhibitor) increased sparsentan Cmaxby 1.3-fold and AUC0-inf by 2.7-fold. Co-administration with a strong CYP3A inhibitor such asboceprevir, telaprevir, clarithromycin, indinavir, lopinavir/ritonavir, itraconazole,nefazodone,ritonavir, grapefruit and grapefruit juice is not recommended.

Co-administration of sparsentan with ciclosporin (moderate inhibitor of CYP3A) increased sparsentan

Cmax by 1.4-fold and AUC0-inf by 1.7-fold. Co-administration with a moderate CYP3A inhibitor such asconivaptan, fluconazole and nelfinavir inhibitor should be done with caution.

Sparsentan is a CYP3A substrate. Concomitant use with a moderate or strong CYP3A inducer such asrifampicin, efavirenz, dexamethasone, carbamazepine, phenytoin and phenobarbital decreasessparsentan exposure, which may reduce the efficacy of sparsentan. Therefore, co-administration with amoderate or strong CYP3A inducer is not recommended.

Gastric acid reducing agents

Based on population pharmacokinetic (PK) analysis, concomitant use of an acid-reducing agent duringsparsentan treatment would not have a statistically significant impact on the variability of sparsentan

PK. Gastric pH modifying agents such as antacids, proton-pump inhibitors, and histamine 2 receptorantagonists can be used concomitantly with sparsentan.

Effect of sparsentan on other medicinal products

In vitro, sparsentan both inhibited and induced CYP3A and induced CYP2B6, CYP2C9, and

CYP2C19.

Co-administration of sparsentan at steady state with the CYP3A4 substrate midazolam had no effecton the systemic exposure of midazolam. Co-administration of sparsentan at steady state with the

CYP2B6 substrate bupropion decreased bupropion Cmax by 1.5-fold and AUC0-inf by 1.5-fold. No doseadjustment is required when combining sparsentan at steady state with a CYP3A4 or CYP2B6substrate.

The significance of the CYP2C9 and CYP2C19 induction by sparsentan has not been evaluated in aclinical study. Co-administration of sparsentan with a CYP2C9 substrate such as s-warfarin, phenytoinand ibuprofen or CYP2C19 substrates such as omeprazole and phenytoin should be done with caution.

The significance of the CYP3A4 inhibition following a single dose of sparsentan has not beenevaluated in a clinical study. Sparsentan is an inhibitor of CYP3A4 and could therefore affect the PKof medicinal products that are substrates of CYP3A4 when treatment with sparsentan is initiated.

Therefore, initiation of sparsentan as co-medication with a CYP3A4 substrate such as alfentanil,conivaptan, indinavir, cyclosporin and tacrolimus should be done with caution.

In vitro, sparsentan is an inhibitor of P-gp, BCRP, OATP1B3, and OAT3 transporters at relevantconcentrations.

The significance of P-gp inhibition by sparsentan has not been evaluated in a clinical study. Co-administration of sparsentan with P-gp inhibition substrate should be done with caution if it is knownthat P-gp inhibition has a significant effect on the absorption.

Co-administration of sparsentan with pitavastatin (a substrate of OATP1B1, OATP1B3, and BCRP)decreased pitavastin Cmax by 1.2-fold and AUC0-inf by 1.4-fold. No dose adjustment is required whencombining sparsentan with an OATP1B1, OATP1B3, or BCRP substrate.

No clinical study was conducted investigating the effect of sparsentan on a sensitive OAT3 substrate.

However, at a dose of 800 mg, sparsentan does not appear to affect the biomarker 6β-hydroxycortisol(substrate of OAT3), indicating that the clinical effect is most likely limited.

Sparsentan treatment must only be initiated in women of childbearing potential when the absence ofpregnancy has been verified. Women of childbearing potential have to use effective contraceptionduring and up to 1 month after treatment has stopped.

There are no or limited amount of data from the use of sparsentan in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Filspari is contraindicated during pregnancy (see section 4.3).

Physicochemical data suggest excretion of sparsentan in human milk. A risk to newborns/infantscannot be excluded. Sparsentan should not be used during breastfeeding.

There are no data on the effects of sparsentan on human fertility. Animal data did not indicate anyimpairment of male or female fertility (see section 5.3).

Filspari may have minor influence on the ability to drive and use machines.

No studies on the effects of sparsentan on the ability to drive and use machines have been performed.

It should, however, be taken into account that dizziness may occur when taking sparsentan (seesection 4.8). Patients with dizziness, should be advised to refrain from driving or using machines untilsymptoms have subsided.

The most commonly reported adverse drug reactions (ADRs) were hypotension (10.8 %),hyperkalaemia (9.6 %), dizziness (7.8 %), and oedema peripheral (5.4 %). The most common seriousadverse reaction reported was acute kidney injury (0.9 %).

The adverse reactions reported in the active-controlled phase 2 and phase 3 clinical trials in patientsexposed to sparsentan in chronic kidney disease population including IgAN and FSGS (N=446) arelisted in the table below by MedDRA system organ class and frequency convention: very common(> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1 000 to < 1/100); rare (> 1/10 000 to< 1/1000); very rare (< 1/10 000).

Table 1: Adverse drug reactions observed during clinical trials

System organ class Very common Common Uncommon

Blood and lymphatic - Anaemiasystem disorders

Metabolism and Hyperkalaemia -nutrition disorders

Nervous system Dizziness -disorders Headache

Vascular disorders Hypotension Orthostatic hypotension -

Renal and urinary Renal impairment -disorders Acute kidney injury

General disorders and Oedema peripheral -administration site Fatigueconditions

Investigations Blood creatinine -increased

Elevated transaminaseaa Elevated transaminase includes preferred terms of alanine aminotransferase increased, aspartate aminotransferase increased,gamma-glutamyltransferase increased, and hepatic enzyme increased.

Haemoglobin decrease

In PROTECT, anaemia or decreased haemoglobin was reported as an ADR in 2 ( 1 %) subjects treatedwith sparsentan compared to 4 (2 %) irbesartan-treated subjects. Overall, haemoglobin ≤ 9 g/dL wasreported at any time post treatment in 7 (3 %) subjects in the sparsentan treatment arm and 4 (2 %)subjects in the irbesartan treatment arm. This decrease is thought to be in part due to haemodilution.

There were no treatment discontinuations due to anaemia.

Hepatic associated adverse events

In PROTECT, a total of 6 (3 %) subjects in the sparsentan group and 4 (2 %) subjects in the irbesartangroup had elevation of liver transaminases exceeding 3 times upper-limit-of-normal without elevationof total bilirubin, after receiving study medication for 168 to 407 days, respectively. All events werenon-serious and asymptomatic, the majority were mild or moderate in intensity, all were reversible,and other reasons have been identified as potential causal factors or as potentially contributing totransaminase elevations. No clinical symptoms of hepatic injury were observed. In the sparsentangroup, the study drug was discontinued in 3 subjects after positive rechallenge while in 2 subjectssparsentan treatment, was restarted with no repeated hepatic enzyme elevations.

Acute kidney injury (AKI)

In PROTECT, acute kidney injury ADRs were reported in 4 (2 %) subjects in the sparsentan groupand 3 (1 %) subjects in the irbesartan group. Four subjects (2 %) who received sparsentan reportedserious AKI all of which were reversible. None of the serious AKI required dialysis. In the sparsentangroup, the study drug was discontinued in 3 subjects.

In PROTECT, hyperkalaemia was reported as an ADR in 20 (10 %) subjects treated with sparsentancompared to 16 (8 %) irbesartan-treated subjects. All events were non-serious in subjects treated withsparsentan, the majority were mild to moderate in intensity and all were reversible. There were notreatment discontinuations due to hyperkalaemia. The risk of hyperkalaemia is increasing for patientswith a lower eGFR.

Hypotension was reported during treatment with sparsentan. In PROTECT, a SBP <= 100 mmHg or areduction in SBP exceeding 30 mmHg, was reported in 12 % and 10 % of patients on sparsentan,respectively, versus 11 % and 10 % on irbesartan. In subjects treated with sparsentan only 15 subjects(7.4 %) were ≥ 65 years old. Hypotension was reported in 20 (11 %) subjects < 65 years of age and in6 (40 %) subjects 65 to 74 years of age.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Sparsentan has been administered in doses of up to 1600 mg/day in healthy subjects without evidenceof dose limiting toxicities. Patients who experience overdose (possibly experiencing signs andsymptoms of hypotension) should be monitored closely and appropriate symptomatic treatment given.

Pharmacotherapeutic group: agents acting on the renin-angiotensin system, ATC code: C09XX01

Sparsentan is a dual endothelin angiotensin receptor antagonist.

It is a single molecule that functions as a high affinity, dual-acting antagonist of both the ETAR and

AT1R. Endothelin 1, via ETAR, and angiotensin II, via AT1R, mediate processes that lead to IgANprogression through haemodynamic actions and mesangial cell proliferation, increased expression andactivity of proinflammatory and profibrotic mediators, podocyte injury, and oxidative stress.

Sparsentan inhibits activation of both ETAR and AT1R and thereby reduces proteinuria and slows theprogression of kidney disease.

In a randomised, positive- and placebo-controlled study with healthy subjects, sparsentan caused mild

QTcF prolongation with a peak effect of 8.8 ms (90 % CI: 5.9, 11.8) at 800 mg and 8.1 ms (5.2, 11.0)at 1600 mg. In an additional study with healthy subjects, at sparsentan exposure exceeding exposure atmaximum recommended human dose by more than 2-fold, the peak effect was 8.3 (6.69, 9.90) ms.

Therefore, it is unlikely that sparsentan has a clinically relevant effect on QT prolongation

The efficacy and safety of sparsentan, a non-immunossupressive drug, has been evaluated in

PROTECT in patients with IgAN.

PROTECT is a randomised, double-blind (110 weeks), active -controlled, multicentre, global phase 3trial in patients with IgAN. The trial enrolled patients aged ≥ 18 years, including 15 (7.4 %)sparsentan -treated patients aged >= 65 years, with an eGFR ≥ 30 mL/min/1.73 m2 and total urineprotein excretion ≥ 1.0 g/day. Prior to enrolment, patients were on the maximum tolerated dose of an

ACE inhibitor and/or an ARB for at least 3 months. The ACE inhibitors and/or ARB therapy werediscontinued prior to initiation of sparsentan. Patients with a baseline potassium value exceeding5.5 mmol/L were excluded.

A total of 404 patients were randomised and received sparsentan (n = 202) or irbesartan (n = 202).

Treatment was initiated with sparsentan at 200 mg once daily or irbesartan 150 mg once daily. After14 days, the dose was to be titrated, as tolerated, to the recommended dose of sparsentan 400 mg oncedaily or irbesartan 300 mg once daily. Dose tolerance was defined as systolic blood pressure> 100 mmHg and diastolic blood pressure > 60 mmHg after 2 weeks and no AEs (e.g, worseningoedema) or laboratory findings (e.g, serum potassium > 5.5 mEq/L [5.5 mmol/L]). Inhibitors of the

RAAS or endothelin system were prohibited during the trial. Other classes of antihypertensive agentswere permitted as needed to achieve target blood pressure. Treatment with immunosuppressive agentswas permitted during the trial at the discretion of the investigator.

Baseline characteristics for eGFR and proteinuria were comparable between treatment groups. Theoverall population had a mean (SD) eGFR of 57 (24) mL/min/1.73 m2 and a median urineprotein/creatinine (UP/C) ratio of 1.24 g/g (interquartile range: 0.83, 1.77). The mean age was 46 years(range 18 to 76 years); 70 % were male, 67 % White, 28 % Asian, 1 % Black or African American,and 3 % were other race.

The primary analysis of proteinuria was conducted after 36 weeks following randomization ofapproximately 280 subjects, to determine whether the treatment effect of the primary efficacyendpoint, the change from baseline in UP/C at week 36, is statistically significant. The trial met itsprimary endpoint, which was change from baseline in the UP/C ratio at week 36. Geometric mean

UP/C at week 36 was 0.62 g/g in the sparsentan arm versus 1.07 g/g in the irbesartan arm. Thegeometric least squares mean percent change in UP/C from baseline at week 36 was -49.8 %(95 % confidence interval [CI]: -54.98, -43.95) in the sparsentan arm versus -15.1 %(95 % CI: -23.72, -5.39) in the irbesartan arm (p < 0.0001). At the final analysis, sparsentandemonstrated a rapid and durable antiproteinuric treatment effect over 2 years, with a geometric mean

UP/C at week 110 of 0.64 g/g in the sparsentan arm versus 1.09 g/g in the irbesartan arm representinga 42.8 % mean reduction from baseline (95 % CI: -49.75, -34.97) compared to only 4.4 % forirbesartan (95 % CI: -15.84, 8.70). Improvement in proteinuria reduction was consistently observedwith sparsentan as early as 4 weeks and sustained through week 110 (Figure 1).

Figure 1: Percent change from baseline urine protein/creatinine ratio by visit (PROTECT)

Visit Week

Notes: Adjusted geometric least squares mean ratio of UP/C relative to baseline was based on a longitudinal repeatedmeasures model stratified by screening eGFR and proteinuria, reported as percentage change along with the respective95 % CI. Analysis includes UP/C data during the double-blind period from all patients who were randomised and received atleast 1 dose of study medication. Baseline was defined as the last non-missing observation prior to and including the start ofdosing.

Abbreviations: CI = confidence interval; eGFR = estimated glomerular filtration rate; LS = least squares; UP/C = urineprotein/creatinine ratio.

Estimated GFR

At the time of confirmatory analysis, the improvement in 2 year eGFR chronic slope (from 6 weeksonwards) was 1.1 mL/min/1.73 m2 per year with sparsentan compared to irbesartan (95 % CI: 0.07,2.12; p = 0.037), and the corresponding improvement in 2 year eGFR total slope (from baselineonwards) was 1.0 mL/min/1.73 m2 per year (95 % CI: -0.03, 1.94; p = 0.058). The absolute changefrom baseline in eGFR at 2 years was -5.8 mL/min/1.73 m2 (95 % CI: -7.38, -4.24) for sparsentancompared to -9.5 mL/min/1.73 m2 (95 % CI: -11.17, -7.89) for irbesartan.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and incombination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs

Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with anangiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history ofcardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence ofend-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus anddiabetic nephropathy. These studies have shown no significant beneficial effect on renal and/orcardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury

Geometric LS Mean Percent Change (95 % CI)and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamicproperties, these results are also relevant for other ACE inhibitors and angiotensin II receptor blockers.

ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly inpatients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using

Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of addingaliskiren to a standard therapy of an ACE inhibitor or an angiotensin II receptor blocker in patientswith type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The studywas terminated early because of an increased risk of adverse outcomes. Cardiovascular death andstroke were both numerically more frequent in the aliskiren group than in the placebo group andadverse events and serious adverse events of interest (hyperkalaemia, hypotension and renaldysfunction) were more frequently reported in the aliskiren group than in the placebo group.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Filspari in one or more subsets of the paediatric population in the treatment of immunoglobulin Anephropathy (see section 4.2 for information on paediatric use).

Following a single oral dose of 400 mg sparsentan, the median time to peak plasma concentration isapproximately 3 hours.

Following a single oral dose of 400 mg sparsentan, the geometric mean Cmax and AUC are 6.97 μg/mLand 83 μg × h/mL, respectively. Steady-state plasma levels are reached within 7 days with noaccumulation of exposure at the recommended dosage.

Following a dose of 400 mg sparsentan daily, the steady-state geometric mean Cmax and AUC are6.47 μg/mL and 63.6 μg × h/mL, respectively.

At doses of 400 mg and below, the effect of a high fat meal on sparsentan exposure was not clinicallyrelevant. Sparsentan can be taken with or without food.

Based on population pharmacokinetic analysis, the apparent volume of distribution at steady state is61.4 L.

Sparsentan is highly bound (> 99 %) to human plasma proteins with preferential binding to albuminand moderate binding to α1-acid glycoprotein.

Sparsentan is primarily metabolised by CYP3A4 with a minor contribution of CYP2C8, 2C9 and 3A5.

Parent compound is the predominant entity in human plasma, representing approximately 90 % of thetotal radioactivity in circulation. A minor hydroxylated metabolite was the only metabolite in plasmathat accounted for > 1 % of the total radioactivity (approximately 3 %). The main metabolic pathwayof sparsentan was oxidation and dealkylation, and 9 metabolites were identified in human faeces,plasma and urine.

The clearance of sparsentan is time dependent. Based on population pharmacokinetic analysis, theapparent clearance is 3.88 L/h, increasing to 5.11 L/h at steady state.

The half-life of sparsentan at steady state is estimated to be 9.6 hours.

Following a single 400 mg dose of radiolabelled sparsentan, 82 % of the dosed radioactivity wasrecovered within a 10 day collection period: 80 % via the faeces with 9 % as unchanged, and 2 % viathe urine with a negligible amount as unchanged.

The Cmax and AUC of sparsentan increase less than proportionally following administration of singledoses of 200 mg to 1600 mg. Sparsentan showed time -dependent pharmacokinetics with no Cmaxaccumulation and decreased AUC at steady state following a dose of 400 or 800 mg daily.

Population pharmacokinetic analysis found no significant effect of age on the plasma exposure ofsparsentan. No dosage adjustment is necessary for elderly patients (see section 4.2). Sparsentan hasnot been studied in patients > 75 years of age.

In a dedicated hepatic impairment study, systemic exposure following a single dose of 400 mgsparsentan was similar in patients with baseline mild or moderate hepatic impairment (Child-Pugh Aor Child-Pugh B classification) compared to patients with normal hepatic function. No doseadjustment is required in patients with mild or moderate hepatic impairment. Sparsentan should beused with caution in patients with moderate hepatic impairment (see sections 4.2 and 4.4).

No data are available in patients with severe hepatic impairment and sparsentan is therefore notrecommended in these patients (Child-Pugh C classification) (see section 4.2).

Based on population pharmacokinetic analysis in chronic kidney disease patients with mild (creatinineclearance 60 to 89 mL/min), moderate (creatinine clearance 30 to 59 mL/min), and severe (creatinineclearance 15 to 29 mL/min) kidney disease, there is no clinically meaningful effect of kidneyimpairment on pharmacokinetics as compared to normal kidney function (creatinine clearance≥ 90 mL/min). No data are available in patients with end-stage kidney disease (creatinine clearance< 15 mL/min).

Based on limited available data, no dose adjustment can be recommended for patients with severekidney disease (eGFR < 30 mL/min/1.73 m2, see section 4.2). Sparsentan has not been studied inpatients with severe kidney disease or undergoing dialysis, therefore sparsentan is not recommended inthese patients. Sparsentan has not been studied in patients who have received a kidney transplant,therefore in this patient population sparsentan should be used with caution (see section 4.2).

Population pharmacokinetic analyses indicate that there is no clinically meaningful effect of age,gender, or race on the pharmacokinetics of sparsentan.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction,and juvenile development.

Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows:

In embryo-foetal development studies in rat and rabbit, developmental toxicity was seen in bothspecies. In rats, -dose dependent teratogenic effects in the form of craniofacial malformations, skeletalabnormalities, increased embryo-foetal lethality, and reduced foetal weights were observed at all dosesof sparsentan tested at exposures 8-fold and 13-fold over the AUC for 800 mg/day and 400 mg/day inhumans. In rabbits, there were no foetal malformations or effects on embryo-foetal viability or foetalgrowth, but an increase in skeletal variations (supernumerary cervical ribs) occurred at an exposure ofapproximately 0.10 and 0.2 times the AUC in humans at 800 mg/day and 400 mg/day.

In the pre- and postnatal development study in rat, maternal toxicity including death was seen at~8-fold and 13-fold, and maternal toxicity at ~2-fold and 3-fold the AUC in humans at 800 mg/dayand 400 mg/day. An increase in pup deaths and decreased growth occurred at ~8-fold and 13-fold, anddecreased growth at ~2-fold and 3-fold the AUC in humans at 800 mg/day and 400 mg/day.

Juvenile animal studies in rats demonstrated that there were no general toxicological adverse effectsseen up to 10 mg/kg/day and no reproductive toxicity in males or females up to 60 mg/kg/day whendosing started on postnatal day (PND) 14 (equivalent to 1 year old children). Vascular toxicityoccurred at doses ≥ 3 mg/kg/day when dosing started on PND 7 (equivalent to newborn infants).

Conclusions of studies for sparsentan show that sparsentan is considered not to be persistent,bioaccumulative and toxic (PBT) nor very persistent and very bioaccumulative (vPvB). A risk to thesewage treatment plant, surface water, groundwater, sediment and terrestrial compartment is notanticipated based on the prescribed use of sparsentan (see section 6.6).

Microcrystalline cellulose

Sodium starch glycolate (type A)

Colloidal anhydrous silica

Magnesium stearate

Poly(vinyl alcohol)

Macrogol

Talc

Titanium dioxide (E171)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

High-density polyethylene (HDPE) bottle with child-resistant polypropylene cap.

Pack size of 30 film-coated tablets or a multipack containing 90 (3 packs of 30) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vifor France100-101 Terrasse Boieldieu

Tour Franklin La Défense 892042 Paris La Défense Cedex

France

EU/1/23/1788/001

EU/1/23/1788/002

EU/1/23/1788/003

Date of first authorisation: 19 April 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency, https://www.ema.europa.eu.