4.1. Therapeutic indications

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, see section 5.1).

4.2. Posology and method of administration

Posology

Sparsentan treatment should be initiated at a dose of 200 mg once daily for 14 days and then increased to 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 blood pressure ≤ 60 mmHg, worsening edema, or hyperkalaemia), adjustment of concomitant medicinal products, followed by temporary down–titration or discontinuation of sparsentan is recommended (see sections 4.4 and 5.1).

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

Missed dose

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

Special populations

Elderly

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

Hepatic impairment

Based on pharmacokinetics data, no dose adjustment of sparsentan is required in patients with mild or moderate 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 should be used with caution in these patients (see section 4.4).

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

There is limited clinical experience with aspartate aminotransferase (AST)/alanine aminotransferase (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).

Renal impairment

No dose adjustment is required in patients with mild (chronic kidney disease [CKD] stage 2; estimated glomerular 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 adjustment can 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 severe kidney 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, therefore sparsentan should be used with caution is these patients.

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

Paediatric population

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

Method of administration

Oral use.

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

4.3. Contraindications

• 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)

4.4. Special warnings and precautions for use

Women of childbearing potential

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

Hypotension

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

In patients at risk for hypotension, eliminating or adjusting other antihypertensive medicinal products and maintaining appropriate volume status should be considered. If hypotension develops despite elimination or reduction of other antihypertensive medicinal products, dose reduction or dose interruption of sparsentan should be considered. A transient hypotensive response is not a contraindication to further dosing of sparsentan; treatment can be resumed once blood pressure has stabilised.

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. Dose interruption of treatment with sparsentan should be considered if symptoms of hypotension persist after 2 weeks of dose reduction. Sparsentan should be used with caution in patients with systolic blood pressure values ≤ 100 mmHg (see section 4.2). Sparsentan should not be uptitrated in patients with systolic blood pressure values ≤ 100 mmHg (see section 4.2).

Impaired kidney function

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

Due to the limited clinical experience in patients with an eGFR < 30 mL/min/1.73 m2, sparsentan is not recommended in these patients (see section 4.2).

Fluid retention

Fluid retention has been associated with medicinal products that antagonise the endothelin type A receptor (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 diuretics is recommended, or the dose of existing diuretics should be increased before modifying the dose of sparsentan. Treatment with diuretics can be considered in patients with evidence of fluid retention before the start of treatment with sparsentan.

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

Liver function

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 in sparsentan-treated patients. Therefore, to reduce the risk of potential serious hepatotoxicity, serum aminotransferase levels and total bilirubin should be monitored prior to initiation of treatment and then continue 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 in bilirubin >2 × ULN, or if ALT and/or AST elevation is accompanied by signs or symptoms of hepatic injury (e.g, jaundice), sparsentan therapy should be discontinued.

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

There is limited clinical experience with moderate hepatic impairment. Therefore, sparsentan should be 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 and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined 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 is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

Hyperkalaemia

Treatment should not be initiated in patients with serum potassium level > 5.5 mmol/l. As with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with sparsentan, especially in the presence of renal impairment and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended. If patients experience clinically significant hyperkalaemia adjustment of concomitant medicinal products, or temporary down–titration or discontinuation is recommended. If serum potassium level is > 5.5 mmol/l discontinuation should be considered.

Lactose

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

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

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 as aliskiren is contraindicated (see section 4.3).

Concomitant use with ACE and mineralcorticoid receptor inhibitors

Coadministration of sparsentan with mineralocorticoid (aldosterone) receptor inhibitors such as spironolactone 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 associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see section 5.1).

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

Concomitant use with potassium supplements and potassium-sparing diuretics

As hyperkalaemia may occur in patients treated with medicinal products that antagonise the angiotensin 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 salt substitutes 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 maximum plasma concentration (Cmax) by 1.3‑fold and area under curve from zero extrapolated to infinity (AUC0-inf) by 2.7‑fold. Co-administration with a strong CYP3A inhibitor such as boceprevir, telaprevir, clarithromycin, indinavir, lopinavir/ritonavir, itraconazole, nefazodone, ritonavir, grapefruit and grapefruit juice is not recommended. If use of a strong CYP3A inhibitor cannot be avoided, consider interrupting treatment with sparsentan. Treatment with sparsentan can be resumed following discontinuation of the strong CYP3A inhibitor.

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 as conivaptan, fluconazole and nelfinavir inhibitor should be done with caution. When using a moderate CYP3A inhibitor, patients should be monitored for hypotension, hyperkalaemia, edema, and/or kidney function.

CYP3A inducers

Sparsentan is a CYP3A substrate. Co-administration of sparsentan with a moderate CYP3A inducer (efavirenz) resulted in a decrease in AUC0-inf and Cmax of sparsentan by 62% and 38%, respectively. Due to the potential for decreased therapeutic efficacy of sparsentan, co-administration with strong CYP3A inducers (e.g., rifampicin, carbamazepine, phenytoin and St. John's wort) with sparsentan is not recommended. Co-administration with a moderate CYP3A inducer (e.g., efavirenz, dexamethasone, and phenobarbital) should be done with caution. When corticosteroid therapy is required, agents with no known or minimal in vivo CYP3A induction potential (e.g., budesonide, prednisone, prednisolone, methylprednisolone) are recommended.

Gastric acid reducing agents

Based on population pharmacokinetic (PK) analysis, concomitant use of an acid-reducing agent during sparsentan 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 receptor antagonists can be used concomitantly with sparsentan.

Effect of sparsentan on other medicinal products

CYP Enyzmes

In vivo, sparsentan both inhibited and induced CYP3A4 and induced CYP2B6, CYP2C9 and CYP2C19.

Sparsentan is both a moderate inhibitor and an inducer of CYP3A4. In vivo, co-administration of single dose of 800 mg sparsentan with CYP3A4 substrate (midazolam) increased midazolam Cmax by 1.4-fold and AUC0-inf by 1.6-fold. Co-administration of multiple doses of 800 mg sparsentan with CYP3A4 substrate (midazolam) had no effect on the systemic exposure of midazolam. Caution is advised when initiating sparsentan treatment with medicinal products metabolized by CYP3A4 (e.g., alfentanil, conivaptan, indinavir, simvastatin). If co-administration is unavoidable, especially with CYP3A4 substrates with a narrow therapeutic index (e.g., cyclosporine, fentanyl and tacrolimus), patients should be monitored for adverse reactions and dose of these substrates may need to be adjusted.

Sparsentan is a weak inducer of CYP2B6. In vivo, co-administration of multiple doses of 800 mg sparsentan with the CYP2B6 substrate (bupropion) decreased bupropion Cmax by 32% and AUC0-inf by 33%. No dose adjustment is needed for drugs mainly metabolized by CYP2B6. However, caution is advised when co-administering sparsentan with narrow therapeutic index CYP2B6 substrates (e.g., efavirenz), as it may lower their plasma levels.

Sparsentan is a weak inducer of CYP2C9. In vivo, co-administration of multiple doses of 800 mg sparsentan with CYP2C9 substrate (tolbutamide) decreased tolbutamide Cmax by 9% and AUC0-inf by 25%. No dose adjustment is needed for drugs mainly metabolized by CYP2C9. However, caution is advised when co-administering sparsentan with narrow therapeutic index CYP2C9 substrates (e.g., coumarin, warfarin, phenytoin), as sparsentan may lower their plasma levels.

Sparsentan is a moderate inducer of CYP2C19. In vivo, co-administration of multiple doses of 800 mg sparsentan decreased CYP2C19 substrate (omeprazole) Cmax by 49% and AUC0-inf by 60% suggesting sparsentan is a moderate inducer of CYP2C19. Use CYP2C19 substrates with caution, as sparsentan may lower their plasma levels potentially resulting in subtherapeutic levels. If co-administration of sparsentan, especially with narrow therapeutic index drugs (e.g., S-mephenytoin, diazepam), is necessary, dose of these substrates may need to be adjusted.

Transporters

Sparsentan is a weak inhibitor of P-gp. In vivo, co-administration of multiple doses of 800 mg sparsentan increased P-gp substrate (digoxin) Cmax by 1.6-fold and AUC0-inf by 1.2-fold. Sparsentan may increase plasma levels of P-gp substrates. Patients should be monitored for adverse reactions when sparsentan is used with narrow therapeutic index drugs (e.g., dabigatran), and dose of these substrates may need to be adjusted.

Co-administration of multiple doses of 800 mg sparsentan increased rosuvastatin (a BCRP substrate) Cmax by 1.6-fold and decreased AUC0-inf by 5% % suggesting sparsentan doesn't affect the bioavailability of BCRP substrates. The complexity of BCRP-regulated transport processes in numerous different tissues may have resulted in the observed neutral net effect on AUC.

Administration of sparsentan had no effect on serum creatinine (a substrate of OAT2, OCT2, MATE1, and MATE2K), 6-beta-hydroxycortisol (a substrate of OAT3), or serum bile acid (a substrate of BSEP) levels.

Co-administration of 800 mg sparsentan decreased pitavastatin (a substrate of OATP1B1 and OATP1B3) Cmax by 19% and AUC0-inf by 30% suggesting sparsentan is not an inhibitor of OATP1B1 and OATP1B3.

No dose adjustment is required when combining sparsentan with BCRP, OAT2, OCT2, MATE1, MATE2K, OAT3, BSEP, OATP1B1 and OATP1B3 substrate.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Sparsentan treatment must only be initiated in women of childbearing potential when the absence of pregnancy has been verified. Exclude pregnancy before, during and for 1 month after treatment with sparsentan has stopped. The frequency of recommended pregnancy testing should be determined by the method of contraception used and the associated likelihood of contraceptive failure. Women of childbearing potential have to use effective contraception during and up to 1 month after treatment has stopped.

Pregnancy

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).

Breastfeeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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 (see section 4.8). Patients with dizziness, should be advised to refrain from driving or using machines until symptoms have subsided.

4.8. Undesirable effects

Summary of the safety profile

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 serious adverse reaction reported was acute kidney injury (0.9 %).

Tabulated list of adverse reactions

The adverse reactions reported in the active-controlled phase 2 and phase 3 clinical trials in patients exposed to sparsentan in chronic kidney disease population including IgAN and FSGS (N=446) are listed 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 system disorders

-

Anaemia

Metabolism and nutrition disorders

Hyperkalaemia

-

Nervous system disorders

Dizziness

Headache

-

Vascular disorders

Hypotension

Orthostatic hypotension

-

Renal and urinary disorders

Renal impairment

Acute kidney injury

-

General disorders and administration site conditions

Oedema peripheral

Fatigue

-

Investigations

Blood creatinine increased

Elevated transaminasea

-

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

Description of selected adverse reactions

Haemoglobin decrease

In PROTECT, anaemia or decreased haemoglobin was reported as an ADR in 2 (1 %) subjects treated with sparsentan compared to 4 (2 %) irbesartan-treated subjects. Overall, haemoglobin ≤ 9 g/dL was reported 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 irbesartan group had elevation of liver transaminases exceeding 3 times upper-limit-of-normal without elevation of total bilirubin, after receiving study medication for 168 to 407 days, respectively. All events were non‑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 to transaminase elevations. No clinical symptoms of hepatic injury were observed. In the sparsentan group, the study drug was discontinued in 3 subjects after positive rechallenge while in 2 subjects sparsentan 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 group and 3 (1%) subjects in the irbesartan group. Four subjects (2%) who received sparsentan reported serious AKI all of which were reversible. None of the serious AKI required dialysis. In the sparsentan group, the study drug was discontinued in 3 subjects.

Hyperkalaemia

In PROTECT, hyperkalaemia was reported as an ADR in 20 (10 %) subjects treated with sparsentan compared to 16 (8 %) irbesartan‑treated subjects. All events were non‑serious in subjects treated with sparsentan, the majority were mild to moderate in intensity and all were reversible. There were no treatment discontinuations due to hyperkalaemia. The risk of hyperkalaemia is increasing for patients with a lower eGFR.

Hypotension

Hypotension was reported during treatment with sparsentan. In PROTECT, a SBP ≤ 100 mmHg or a reduction 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 in 6 (40 %) subjects 65 to 74 years of age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at https://yellowcard.mhra.gov.uk or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

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