FILSPARI Film-coated tablet Ref.[107352] Active ingredients: Sparsentan

5.1 Hepatotoxicity

Elevations in ALT or AST of at least 3-fold ULN have been observed in up to 2.5% of FILSPARI-treated patients, including cases confirmed with rechallenge [see Adverse Reactions (6.1)]. While no concurrent elevations in bilirubin >2-times ULN or cases of liver failure were observed in FILSPARI-treated patients in clinical trials, some endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure. To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and monthly for the first 12 months, then every 3 months during treatment [see Dosage and Administration (2.2)].

Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop treatment with FILSPARI and seek medical attention. If aminotransferase levels are abnormal at any time during treatment, interrupt FILSPARI and monitor as recommended [see Dosage and Administration (2.5)].

Consider re-initiation of FILSPARI only when hepatic enzyme levels and bilirubin return to pretreatment values and only in patients who have not experienced clinical symptoms of hepatotoxicity. [see Dosage and Administration (2.2, 2.5)].

Avoid initiation of FILSPARI in patients with elevated aminotransferases (>3x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult and these patients may be at increased risk for serious hepatotoxicity [see Dosage and Administration (2.2, 2.5) and Warnings and Precautions (5.3)].

5.2 Embryo-Fetal Toxicity

Based on data from animal reproduction studies, FILSPARI can cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of treatment with FILSPARI, monthly during treatment and one month after discontinuation of treatment. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].

5.3 FILSPARI REMS

For all patients, FILSPARI is available only through a restricted program under a REMS called the FILSPARI REMS because of the risk of hepatotoxicity and embryo-fetal toxicity [see Contraindications (4), Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.1, 8.3)].

Important requirements of the FILSPARI REMS include the following:

• Prescribers must be certified with the FILSPARI REMS by enrolling and completing training.
• All patients must enroll in the FILSPARI REMS prior to initiating treatment and comply with monitoring requirements [see Dosage and Administration (2.2, 2.5, 2.6), Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.3)].
• Pharmacies that dispense FILSPARI must be certified with the FILSPARI REMS and must dispense only to patients who are authorized to receive FILSPARI.

5.4 Hypotension

Hypotension has been observed in patients treated with ARBs and endothelin receptor antagonists (ERAs) and was observed in clinical studies with FILSPARI. In the PROTECT trial, there was a greater incidence of hypotension-associated adverse events, some serious, including dizziness, in patients treated with FILSPARI compared to irbesartan [see Adverse Reactions (6.1)].

In patients at risk for hypotension, consider eliminating or adjusting other antihypertensive medications and maintaining appropriate volume status.

If hypotension develops, despite elimination or reduction of other antihypertensive medications, consider a dose reduction or dose interruption of FILSPARI. A transient hypotensive response is not a contraindication to further dosing of FILSPARI, which can be given once blood pressure has stabilized.

5.5 Acute Kidney Injury

Monitor kidney function periodically. Drugs that inhibit the renin-angiotensin system can cause acute kidney injury. Patients whose kidney function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute kidney injury on FILSPARI. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in kidney function while on FILSPARI.

5.6 Hyperkalemia

Monitor serum potassium periodically and treat appropriately. Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia. Dosage reduction or discontinuation of FILSPARI may be required [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.7 Fluid Retention

Fluid retention may occur with endothelin receptor antagonists and has been observed in clinical studies with FILSPARI [see Adverse Reactions (6.1)]. FILSPARI has not been evaluated in patients with heart failure.

If clinically significant fluid retention develops, evaluate the patient to determine the cause and the potential need to initiate or modify the dose of diuretic treatment then consider modifying the dose of FILSPARI.

Clinically significant adverse reactions that appear in other sections of the label include:

• Hepatotoxicity [see Warnings and Precautions (5.1)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)]
• Hypotension [see Warnings and Precautions (5.4)]
• Acute Kidney Injury [see Warnings and Precautions (5.5)]
• Hyperkalemia [see Warnings and Precautions (5.6)]
• Fluid Retention [see Warnings and Precautions (5.7)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of FILSPARI was evaluated in PROTECT (NCT03762850), an ongoing, randomized, double-blind, active-controlled clinical study in adults with IgAN.

The data below reflect FILSPARI exposure in 202 patients with a median duration of 73 weeks (up to 110 weeks).

The most common adverse reactions are presented in Table 2.

Table 2. Adverse Reactions¹ Reported in ≥2% in Subjects Treated with FILSPARI:

¹ Data presented include all Treatment-Emergent Adverse Events reported
² Elevations in ALT or AST >3-fold ULN reported as Adverse Events of Interest

Laboratory Tests

Initiation of FILSPARI may cause an initial small decrease in estimated glomerular filtration rate (eGFR) that occurs within the first 4 weeks of starting therapy and then stabilizes.

The incidence of a hemoglobin decrease >2 g/dL compared to baseline and below the lower limit of normal was greater for the FILSPARI arm (11%) compared to the irbesartan arm (5%). This decrease is thought to be in part due to hemodilution. There were no treatment discontinuations due to anemia or hemoglobin decrease in the PROTECT study.

7.1 Renin-Angiotensin System (RAS) Inhibitors and ERAs

Do not coadminister FILSPARI with ARBs, ERAs, or aliskiren [see Dosage and Administration (2.1), Contraindications (4)].

Combined use of these agents is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure).

7.2 Strong and Moderate CYP3A Inhibitors

Avoid concomitant use of FILSPARI with strong CYP3A inhibitors. If a strong CYP3A inhibitor cannot be avoided, interrupt treatment with FILSPARI. When resuming treatment with FILSPARI, consider dose titration [see Dosage and Administration (2.3, 2.6), Clinical Pharmacology (12.3)].

Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors [see Warnings and Precautions (5.4, 5.5, 5.6, 5.7)]. No FILSPARI dose adjustment is needed.

Sparsentan is a CYP3A substrate. Concomitant use with a strong CYP3A inhibitor increases sparsentan C_max and AUC [see Clinical Pharmacology (12.3)], which may increase the risk of FILSPARI adverse reactions.

7.3 Strong CYP3A Inducers

Avoid concomitant use with a strong CYP3A inducer. Sparsentan is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases sparsentan C_max and AUC [see Clinical Pharmacology (12.3)], which may reduce FILSPARI efficacy.

7.4 Antacids and Acid Reducing Agents

Administer FILSPARI 2 hours before or after administration of antacids. Avoid concomitant use of acid reducing agents (histamine H₂ receptor antagonist and PPI proton pump inhibitor) with FILSPARI. Sparsentan exhibits pH-dependent solubility [see Description (11)]. Antacids or acid reducing agents may decrease sparsentan exposure which may reduce FILSPARI efficacy.

7.5 Non-Steroidal Anti-Inflammatory Agents (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors

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 [see Warnings and Precautions (5.5)]. These effects are usually reversible.

7.6 CYP2B6, 2C9, and 2C19 Substrates

Monitor for efficacy of the concurrently administered CYP2B6, 2C9, and 2C19 substrates and consider dosage adjustment in accordance with the Prescribing Information. Sparsentan is an inducer of CYP2B6, 2C9, and 2C19. Sparsentan decreases exposure of these substrates [see Clinical Pharmacology (12.3)], which may reduce efficacy related to these substrates.

7.7 P-gp and BCRP Substrates

Avoid concomitant use of sensitive substrates of P-gp and BCRP with FILSPARI. Sparsentan is an inhibitor of P-gp and BCRP. Sparsentan may increase exposure of these transporter substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

7.8 Agents Increasing Serum Potassium

Monitor serum potassium frequently in patients treated with FILSPARI and other agents that increase serum potassium. Concomitant use of FILSPARI with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that raise serum potassium levels may result in hyperkalemia [see Warnings and Precautions (5.6)].

Risk Summary

Based on data from animal reproductive toxicity studies, FILSPARI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4)]. Available data from reports of pregnancy in clinical trials with FILSPARI are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of sparsentan to pregnant rats throughout organogenesis at 10-times the maximum recommended human dose (MRHD) in mg/day caused teratogenic effects in rats, including craniofacial malformations, skeletal abnormalities, increased embryo-fetal lethality, and reduced fetal weights (see Data). Advise pregnant patients of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In embryo-fetal development studies in pregnant rats and rabbits, teratogenicity and/or developmental toxicity were observed, which were attributed to the antagonism of endothelin type A (ET_A) and angiotensin II type 1 (AT₁) receptors.

In pregnant rats, oral administration of sparsentan throughout organogenesis at doses of 80, 160, and 240 mg/kg/day resulted in dose-dependent teratogenic effects in the form of craniofacial malformations, skeletal abnormalities, increased embryo-fetal lethality, and reduced fetal weights at all doses tested. The area under the curve (AUC) at the lowest dose tested (80 mg/kg/day) was approximately 10 times the AUC at the MRHD of 400 mg/day. In pregnant rabbits, oral administration of sparsentan throughout organogenesis at doses of 2.5, 10 and 40 mg/kg/day resulted in maternal death and abortions at 10 and 40 mg/kg/day which provided exposures approximately 0.1 times and 0.2 times the AUC at the MRHD, respectively. An increase in fetal variation (supernumerary cervical ribs) occurred at the high dose of 40 mg/kg/day.

In the pre- and postnatal development study in rats, oral administration of sparsentan during pregnancy and the lactational period at doses of 5, 20, or 80 mg/kg/day resulted in maternal death, body weight loss/reduced body weight gain, and adverse clinical signs at 80 mg/kg/day. An increase in pup deaths occurred at 80 mg/kg/day (approximately 10 times the AUC at MRHD) during the neonatal period through weaning, and decreased growth occurred at ≥20 mg/kg/day (approximately 2.6 times the AUC at the MRHD) after weaning. The NOAEL for pre- and postnatal development in rats was 5 mg/kg/day, approximately 0.7 times the AUC at the MRHD.

Risk Summary

There are no data on the presence of sparsentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for adverse reactions, such as hypotension in breastfed infants, advise patients not to breastfeed during treatment with FILSPARI.

Based on data from animal reproductive toxicity studies, FILSPARI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4), Use in Specific Populations (8.1)].

Pregnancy Testing

Verify that patients who can become pregnant are not pregnant prior to initiating FILSPARI, monthly during treatment, and one month after discontinuation of treatment. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to their pregnancy and the fetus.

Contraception

Patients who can become pregnant using FILSPARI must use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI to prevent pregnancy [see Warnings and Precautions (5.2)].

The safety and efficacy of FILSPARI in pediatric patients have not been established.

Of the total number of subjects in the PROTECT study of FILSPARI, 15 (7.4%) were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Avoid use of FILSPARI in patients with any hepatic impairment (Child-Pugh class A-C) because of the potential risk of serious liver injury [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].