Sparsentan

Monitor for signs of worsening renal function with concomitant use with NSAIDs (including selective COX-2 inhibitors). In patients with volume depletion (including those on diuretic therapy) or with impaired kidney function, concomitant use of NSAIDs (including selective COX-2 inhibitors) with drugs that antagonize the angiotensin II receptor may result in deterioration of kidney function, including possible kidney failure. These effects are usually reversible.

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.

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.

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).

There is limited clinical experience with moderate hepatic impairment. Therefore, sparsentan should be used with caution in these patients.

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.

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 itraconazole (strong CYP3A inhibitor) increased sparsentan C_max by 1.3-fold and AUC_0-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 C_max by 1.4-fold and AUC_0-inf by 1.7-fold. Co-administration with a moderate CYP3A inhibitor such as conivaptan, fluconazole and nelfinavir inhibitor should be done with caution.

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). As there is limited clinical experience in patients with severe kidney disease, sparsentan is not recommended in these patients.

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

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.

As hyperkalaemia may occur in patients treated with medicinal products that antagonise the angiotensin II receptor type 1 (AT1R), 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.

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.

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.

Avoid initiation of sparsentan in patients with elevated aminotransferase (>2 × ULN) prior to drug initiation.

Sparsentan should be used with caution in patients with bilateral renal artery stenosis.

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. Sparsentan should not be uptitrated in patients with systolic blood pressure values ≤100 mmHg.

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 with heart failure. Therefore, sparsentan should be used with caution in patients with heart failure.

There are no or limited amount of data from the use of sparsentan in pregnant women. Studies in animals have shown reproductive toxicity.

Sparsentan is contraindicated during pregnancy.

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

Women of childbearing potential

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.

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.

Sparsentan 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. Patients with dizziness, should be advised to refrain from driving or using machines until symptoms have subsided.

Summary of the safety profile The most commonly reported adverse drug reactions (ADRs) were hypotension (9%), hyperkalaemia (7%), dizziness (7%), and oedema peripheral (5%). The most common serious adverse reaction reported was acute kidney injury (1%).

Tabulated list of adverse reactions

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.

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).

Adverse drug reactions observed during clinical trials:

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

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 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.

Hyperkalaemia

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

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.