Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Vifor France, 100–101 Terrasse Boieldieu, Tour Franklin La Défense 8, 92042 Paris La Défense Cedex, France
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 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).
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 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.
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).
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.
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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-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 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).
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).
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.
Sparsentan is primarily metabolised by cytochrome P450 (CYP)3A.
Co-administration of sparsentan with itraconazole (strong CYP3A inhibitor) increased sparsentan Cmax by 1.3-fold and 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.
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.
Sparsentan is a CYP3A substrate. Concomitant use with a moderate or strong CYP3A inducer such as rifampicin, efavirenz, dexamethasone, carbamazepine, phenytoin and phenobarbital decreases sparsentan exposure, which may reduce the efficacy of sparsentan. Therefore, co-administration with a moderate or strong CYP3A inducer is not recommended.
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 agonists can be used concomitantly with sparsentan.
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 effect on 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 dose adjustment is required when combining sparsentan at steady state with a CYP3A4 or CYP2B6 substrate.
The significance of the CYP2C9 and CYP2C19 induction by sparsentan has not been evaluated in a clinical study. Co-administration of sparsentan with a CYP2C9 substrate such as s-warfarin, phenytoin and 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 been evaluated in a clinical study. Sparsentan is an inhibitor of CYP3A4 and could therefore affect the PK of 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 relevant concentrations.
The significance of P-gp inhibition by sparsentan has not been evaluated in a clinical study. Coadministration of sparsentan with P-gp inhibition substrate should be done with caution if it is known that 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 when combining 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 of pregnancy has been verified. Women of childbearing potential have to use effective contraception during 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/infants cannot 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 any impairment 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 (see section 4.8). Patients with dizziness, should be advised to refrain from driving or using machines until symptoms have subsided.
Supportive safety data were obtained from 27 clinical trials that involved more than 500 patients exposed to sparsentan in chronic kidney disease population including IgAN and FSGS (see section 5.1).
Adverse reactions reported 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 | 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, hepatic enzyme increased, and transaminases increased.
In PROTECT, anaemia or decreased haemoglobin was reported as an ADR in 2 (<1%) subjects treated with sparsentan compared to 2 (<1%) irbesartan-treated subjects. Overall, haemoglobin ≤9 g/dL was reported at any time post treatment in 5 (2.5%) subjects in the sparsentan treatment arm and 3 (1.5 %) 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.
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.
In PROTECT, acute kidney injury ADRs were reported in 4 (2%) subjects in the sparsentan group and 2 (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.
In PROTECT, hyperkalaemia was reported as an ADR in 18 (9%) 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 was reported during treatment with sparsentan. In PROTECT, a SBP <100 mmHg or a reduction in SBP exceeding 30 mmHg, was reported in 10% and 8% of patients on sparsentan, respectively, versus 9% and 6% on irbesartan. In subjects treated with sparsentan only 15 subjects (7.4%) were above 65 years old. Hypotension was reported in 17 (9%) subjects <65 years of age and in 5 (33%) subjects 65 to 74 years of age.
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 national reporting system listed in Appendix V.
Not applicable.
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