Filspari Drug Information

Immunoglobulin A Nephropathy FILSPARI is indicated to slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression.

Focal Segmental Glomerulosclerosis FILSPARI is indicated to reduce proteinuria in adult and pediatric patients aged 8 years and older with focal segmental glomerulosclerosis (FSGS) without nephrotic syndrome.

General Considerations Prior to initiating treatment with FILSPARI, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs).

Monitoring

Initiate treatment with FILSPARI only after measuring aminotransferase levels and total bilirubin. Avoid initiation in patients with elevated aminotransferases greater than 3 times ULN. Continue required monitoring every 3 months during treatment with FILSPARI.

Pregnancy Testing

Exclude pregnancy before initiating treatment with FILSPARI.

Recommended Dosage

The recommended dosing of FILSPARI in patients with IgAN and in patients with FSGS is described in Table 1. When resuming treatment with FILSPARI in patients with IgAN or FSGS after an interruption, consider initiating at 50% of the recommended dose and titrating to the recommended dose after 14 days.

Administration •

Instruct patient to swallow tablets whole with water prior to the morning or evening meal. • For patients who are unable to swallow whole tablets FILSPARI may be crushed and suspended in water immediately before administration prior to the morning or evening meal. Administration of FILSPARI with other liquids has not been studied and is not recommended. • Preparation and Administration of FILSPARI Suspension in Water: 1. Crush the FILSPARI tablet in a clean pill crusher or mortar and pestle. 2.

Suspend the crushed tablet in half cup of water and mix. 3. Orally administer the entire prepared suspension immediately. If any portion of the tablet is left in the cup, add little more water to the cup, swirl and swallow immediately. 4.

Do not store suspension for later use. Take dose before the same meal each day. • If a dose is missed, take the next dose at the regularly scheduled time. Do not take double or extra doses.

Dosage Adjustment for Aminotransferase Elevations

If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2. Do not resume treatment in patients who have experienced clinical symptoms of hepatotoxicity or in patients whose hepatic enzyme levels and bilirubin have not returned to pretreatment levels. Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations Greater Than 3 Times ULN ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; ULN = upper limit of normal.

ALT/AST levels Treatment and monitoring recommendations Greater than 3 times and less than or equal to 8 times ULN Confirm elevation with a repeat measure. Close monitoring is required in these patients. Greater than 8 times ULN Stop treatment permanently if no other cause found.

Dosage Modification for Concomitant Use with Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors with FILSPARI. If a strong CYP3A inhibitor cannot be avoided, interrupt treatment with FILSPARI.

Clinical Trials Experience

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. IgAN The safety of FILSPARI was evaluated in PROTECT ( NCT03762850 ), a 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 110 weeks.

The most common adverse reactions are presented in Table 3. 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 or DUPLEX clinical studies.

Renin-Angiotensin System Inhibitors and ERAs

Do not coadminister FILSPARI with ARBs, ERAs, or aliskiren. Combined use of these agents is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure).

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.

Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors. No FILSPARI dose adjustment is needed. Sparsentan is a CYP3A substrate.

Concomitant use with a strong CYP3A inhibitor increases sparsentan C max and AUC, which may increase the risk of FILSPARI adverse reactions.

Strong CYP3A Inducers

Avoid concomitant use with a strong CYP3A inducer. Concomitant use with a strong CYP3A inducer decreases sparsentan C max and AUC, which may reduce FILSPARI efficacy.

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. These effects are usually reversible.

CYP2B6, 2C9, and 2C19 Substrates Monitor for efficacy of concurrently administered CYP2B6, 2C9, and 2C19 substrates and consider dosage adjustment in accordance with the Prescribing Information. Sparsentan is a weak inducer of CYP2B6 and 2C9, and a moderate inducer of 2C19. Sparsentan decreases exposure of these substrates, which may reduce efficacy related to these substrates.

P-gp Substrates Monitor for adverse reactions and consider dose reduction of P-gp substrates with narrow therapeutic indices when co-administered with FILSPARI. FILSPARI is a weak P-gp inhibitor. Co-administration of FILSPARI may increase plasma concentrations of P-gp substrate drugs.

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.

Pregnancy Risk Summary Based on data from animal reproductive toxicity studies, FILSPARI may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy. 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. Available data from postmarketing reports and published literature over decades of use with ERA in the same class as FILSPARI have not identified an increased risk of fetal harm; however, these data are limited.

Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. 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 (AT 1 ) 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. An increase in a 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.

Pediatric Use The safety and effectiveness of FILSPARI for reducing proteinuria in FSGS have been established in pediatric patients aged 8 years and older. Use of FILSPARI for this indication is supported by evidence from an adequate and well-controlled trial that enrolled 35 pediatric patients aged 9 years and older. The safety and effectiveness of FILSPARI in pediatric patients less than 8 years of age with FSGS have not been established.

• Use of FILSPARI is contraindicated in patients who are pregnant. Do not co-administer FILSPARI with ARBs, ERAs, or aliskiren.
• Pregnancy.
• Concomitant use with angiotensin receptor blockers (ARBs), ERAs, or aliskiren.

There is no experience with overdose with FILSPARI. Sparsentan has been given in doses up to 1600 mg/day in healthy volunteers, or up to 800 mg/day in patients. Overdose of FILSPARI may result in decreased blood pressure.

In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because sparsentan is highly protein-bound.