Sparsentan

7 DRUG INTERACTIONS • Strong CYP3A inhibitors: Avoid concomitant use. Increased sparsentan exposure ( 2.7 , 7.2 , 12.3 ). • Moderate CYP3A inhibitors: Monitor adverse reactions. Increased sparsentan exposure ( 7.2 , 12.3 ). • Strong CYP3A inducers: Avoid concomitant use. Decreased sparsentan exposure ( 7.3 , 12.3 ). • Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase (COX-2) inhibitors: Monitor for signs of worsening renal function. Increased risk of kidney injury ( 7.4 ). • CYP2B6, 2C9, and 2C19 substrates: Monitor for substrate efficacy. Decreased exposure of these substrates ( 7.5 , 12.3 ).

• P-gp substrates: Monitor for adverse reactions of P-gp substrates with narrow therapeutic indices. Increased exposure to substrates ( 7.6 , 12.3 ). • Agents Increasing Serum Potassium: Increased risk of hyperkalemia, monitor serum potassium frequently ( 5.6 , 7.7 ).

7.1 Renin-Angiotensin System 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 ( 2.4 , 2.7 ), 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 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.

7.5 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 [see Clinical Pharmacology ( 12.3 )] , which may reduce efficacy related to these substrates.

7.6 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 [see Clinical Pharmacology ( 12.3 )] .

7.7 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 )] .

8.1 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 [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. 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. In pregnant rabbits, oral administration of sparsentan throughout organogenesis at doses of 2.5, 10…