FILSPARI

1 INDICATIONS AND USAGE FILSPARI is an endothelin and angiotensin II receptor antagonist indicated: • To slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression ( 1.1 , 12.1 , 14.1 ). • To reduce proteinuria in adult and pediatric patients aged 8 years and older with focal segmental glomerulosclerosis (FSGS) without nephrotic syndrome ( 1.2 , 12.1 , 14.2 ). 1.1 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 [see Clinical Pharmacology ( 12.1 ), Clinical Studies ( 14.1 )]. 1.2 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 [see Clinical Pharmacology ( 12.1 ), Clinical Studies ( 14.2 )].

2 DOSAGE AND ADMINISTRATION • Prior to initiating treatment with FILSPARI, discontinue use of renin- angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) ( 2.1 , 4 , 7.1 ). • IgAN (Adult Patients): Initiate treatment with FILSPARI at 200 mg orally once daily. After 14 days, increase to 400 mg once daily, as tolerated. ( 2.4 ) • FSGS (Adult and Pediatric Patients 8 years and older): • Greater than 50 kg: Initiate treatment with FILSPARI at 400 mg orally once daily. After 14 days, increase to 800 mg once daily, as tolerated ( 2.4 ). • 50 kg and less: Initiate treatment with FILSPARI at 200 mg orally once daily. After 14 days, increase to 400mg once daily, as tolerated ( 2.4 ). • When resuming FILSPARI after interruption, consider re-titration ( 2.4 ). • Instruct patients to swallow tablets whole with water prior to the morning or evening meal ( 2.5 ). • For patients who are unable to swallow whole tablets, FILSPARI may be crushed and mixed with water immediately before administration ( 2.5 , 12.3 ). 2.1 General Considerations Prior to initiating treatment with FILSPARI, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . 2.2 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 [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.1 )]. 2.3 Pregnancy Testing Exclude pregnancy before initiating treatment with FILSPARI [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 , 8.3 )]. 2.4 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 [see Dosage and Administration ( 2.5 ) and Drug Interactions ( 7.2 )]. Table 1: Recommended FILSPARI Dosing in Patients with IgAN and in Patients with FSGS Indication Starting Dose (orally once daily for 14 days and increase to recommended dose, as tolerated) Recommended Dose (orally once daily) IgAN (Adult Patients) 200 mg 400 mg FSGS (Adults and Pediatric Patients 8 Years and Older) Patients weighing greater than 50 kg 400 mg 800 mg Patients weighing less than or equal to 50 kg 200 mg 400 mg 2.5 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 [see Clinical Pharmacology ( 12.3 )]. 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. 2.6 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 an…

5 WARNINGS AND PRECAUTIONS • Hypotension ( 5.4 ) • Acute Kidney Injury ( 5.5 ) • Hyperkalemia ( 5.6 ) • Fluid Retention ( 5.7 ) 5.1 Hepatotoxicity Elevations in ALT or AST of at least 3-fold ULN have been observed in up to 3.5% of FILSPARI-treated patients, including cases confirmed with rechallenge [see Adverse Reactions ( 6.1 )] . While no concurrent elevations in bilirubin greater than 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 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 ( 2.6 )] . 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 , 2.6 )] . Avoid initiation of FILSPARI in patients with elevated aminotransferases (greater than 3-times ULN) 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 , 2.6 ), and Warnings and Precautions ( 5.2 )]. 5.2 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 [see Warnings and Precautions ( 5.1 )]. 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 , 2.6 ), Warnings and Precautions ( 5.1 )]. • Pharmacies that dispense FILSPARI must be certified with the FILSPARI REMS and must dispense only to patients who are authorized to receive FILSPARI. Further information is available at www.filsparirems.com or 1-833-513-1325. 5.3 Embryo-Fetal Toxicity Based on data from animal reproduction studies, FILSPARI may cause fetal harm when administered to a pregnant patient and is contraindicated for use during pregnancy. The available human data for endothelin receptor antagonists do not establish the presence or absence of fetal harm related to the use of FILSPARI. Counsel patients who can become pregnant of the potential risk to a fetus. Exclude pregnancy before initiating treatment with FILSPARI. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment, during treatment, and for two weeks after discontinuation of treatment with FILSPARI. Advise pre-pubertal females and/or their guardian(s) of the fetal risk and the need to use effective contraception once they reach reproductive potential. When pregnancy is detected, discontinue FILSPARI as soon as possible [see Dosage and Administration ( 2.3 ), Contraindications ( 4 ), Use in Specific Populations ( 8.1 , 8.3 )] . 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 clinical trials, 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 …

4 CONTRAINDICATIONS Use of FILSPARI is contraindicated in patients who are pregnant [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 )] . Do not co-administer FILSPARI with ARBs, ERAs, or aliskiren [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.1 )]. • Pregnancy ( 4 ). • Concomitant use with angiotensin receptor blockers (ARBs), ERAs, or aliskiren ( 4 ).

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…

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 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 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.

6 ADVERSE REACTIONS 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 ( 5.3 )] • 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 )] Most common adverse reactions in patients with IgAN (≥5%) are hyperkalemia, hypotension (including orthostatic hypotension), peripheral edema, dizziness, anemia, and acute kidney injury ( 6.1 ). Most common adverse reactions in patients with FSGS (≥5%) are peripheral edema, hypotension (including orthostatic hypotension), hyperkalemia, dizziness, and anemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Travere Therapeutics at 1-877-659-5518 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 . Table 3: Adverse Reactions Reported in 2% or More of Subjects with IgAN Treated with FILSPARI (PROTECT) 1 Includes related terms. 2 Elevations in ALT or AST greater than 3-fold ULN. FILSPARI (N = 202) n (%) Irbesartan (N = 202) n (%) Hyperkalemia 1 34 (17) 27 (13) Hypotension (including orthostatic hypotension) 33 (16) 13 (6) Peripheral edema 1 33 (16) 29 (14) Dizziness 1 32 (16) 14 (7) Anemia 16 (8) 9 (4) Acute kidney injury 12 (6) 5 (2) Transaminase elevations 2 7 (3.5) 8 (4.0) FSGS The safety of FILSPARI was evaluated in DUPLEX ( NCT03493685 ), a randomized, double-blind, active-controlled clinical study in adult and pediatric patients with FSGS [see Clinical Trials ( 14.2 )] . The data below reflects FILSPARI exposure in adult (n=168) and pediatric patients 9 years and older (n=16) with FSGS who received FILSPARI at the recommended dosing regimens for a median duration of 108 weeks The most common adverse reactions reported in adult and pediatric patients 9 years of age and older are presented in Table 4 . Table 4: Adverse Reactions Reported in 2% or More of Subjects with FSGS Treated with FILSPARI (Overall DUPLEX Population) 1 Includes related terms. 2 Elevations in ALT or AST greater than 3-fold ULN. FILSPARI (N=184) n (%) Irbesartan (N = 187) n (%) Peripheral edema 1 42 (23) 45 (24) Hypotension (including orthostatic hypotension) 38 (21) 25 (13) Hyperkalemia 1 37 (20) 21 (11) Dizziness 1 25 (14) 21 (11) Anemia 24 (13) 10 (5) Acute kidney injury 8 (4) 13 (7) Transaminase elevations 2 7 (4) 5 (3) Laboratory Tests 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 compared to the irbesartan arm (19% vs 13% in PROTECT; 45% vs 18% in DUPLEX). 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.