Atrasentan

1 INDICATIONS AND USAGE VANRAFIA is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 g/g. This indication is approved under accelerated approval based on a reduction of proteinuria [see Clinical Studies (14.1)] . It has not been established whether VANRAFIA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. VANRAFIA is an endothelin receptor antagonist indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 g/g. ( 1 ) This indication is approved under accelerated approval based on a reduction of proteinuria. It has not been established whether VANRAFIA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. ( 1 )

2 DOSAGE AND ADMINISTRATION 0.75 mg orally once daily with or without food ( 2.2 ) 2.1 Pregnancy Testing Exclude pregnancy before initiating VANRAFIA [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)] . 2.2 Recommended Dosage The recommended dose of VANRAFIA is 0.75 mg administered orally once daily with or without food [see Clinical Pharmacology (12.3)] . Swallow tablets whole. Do not cut, crush, or chew. If a dose or doses are missed, take the prescribed dose at the next scheduled time. Do not double the dose to make up for a missed dose.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Embryo-fetal Toxicity [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Fluid Retention [see Warnings and Precautions (5.3)] Decreased Sperm Counts [see Warnings and Precautions (5.4)] Most common adverse reactions (incidence ≥ 5%) were peripheral edema and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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. The safety of VANRAFIA was evaluated in ALIGN (NCT04573478), a randomized, double-blind, placebo controlled clinical study in 403 adults with IgAN [see Clinical Studies (14.1)] . The median duration of treatment was 47 weeks (range: 0 to 128 weeks). The most common adverse reactions (≥ 5%) with VANRAFIA were peripheral edema and anemia. Table 1 describes the adverse reactions that occurred in ≥ 2% of patients treated with VANRAFIA and higher than placebo in the ALIGN study. Table 1: Adverse Reactions Reported in ≥ 2% of Adult Patients with IgAN Treated with VANRAFIA and Higher than Placebo in ALIGN * Includes related terms ** Elevations in ALT or AST > 3-fold upper limit of normal (ULN) Adverse Reaction VANRAFIA (N = 201) n (%) Placebo (N = 202) n (%) Peripheral edema* 21 (10%) 14 (7%) Anemia* 12 (6%) 2 (1%) Liver transaminase elevation** 4 (2%) 2 (1%) Laboratory Tests and Vital Signs Hemoglobin Decrease At Week 36, the mean change in hemoglobin from baseline for those patients receiving VANRAFIA in the ALIGN study was -0.7 g/dL compared to -0.2 g/dL for those receiving placebo. The incidence of a hemoglobin decrease > 2 g/dL compared to baseline and below the lower limit of normal was greater for the VANRAFIA arm (12%) compared to the placebo arm (4%). These decreases are thought to be in part due to hemodilution. There were no treatment discontinuations due to anemia or hemoglobin decrease in the ALIGN study. Blood Pressure Decrease At Week 36, the mean change from baseline in systolic and diastolic blood pressure (BP) for patients receiving VANRAFIA in the ALIGN study was -4 mmHg and -4 mmHg, respectively, compared to +3 mmHg and +2 mmHg, respectively, in patients receiving placebo. Hypotension observed in VANRAFIA treated patients was mild or moderate in severity, rarely symptomatic, and did not necessitate treatment discontinuation.

12.3 Pharmacokinetics Atrasentan area under the time concentration curve (AUC) is dose proportional across the 0.35 mg to 30 mg (0.47 to 40 times the approved recommended dosage) dose range. Atrasentan steady state plasma concentrations are reached within 7 days with 2- to 3-fold accumulation. Absorption Atrasentan time to peak plasma concentration (T max ) is approximately 0.5 hour. Effect of Food No clinically significant differences in atrasentan pharmacokinetics were observed following administration with a high-fat meal (800 to 1000 Kcal, > 50% fat) in healthy subjects. Distribution Atrasentan steady-state apparent (oral) volume of distribution (Vd/F) is 1180 L. Atrasentan is > 99% bound to human plasma proteins, in vitro. Elimination Atrasentan effective half-life is approximately 24 to 41 hours with an apparent (oral) clearance (CL/F) of 19 L/h. Metabolism Atrasentan is extensively metabolized by CYP3A and multiple uridine 5'-diphospho-glucuronosyltransferases (UGTs) with approximately half via CYP3A and the remaining half via glucuronidation by multiple UGTs. Excretion After a single dose of radiolabeled atrasentan 10 mg to healthy subjects, approximately 86% of the dose was recovered in feces (5.5% as parent atrasentan). Renal excretion was minimal, with < 4% recovered in urine (negligible amounts of parent atrasentan). Specific Populations No clinically significant differences in the pharmacokinetics of atrasentan were observed based on age (19 to 77 years), sex, race, mild to severe renal impairment (eGFR 15 to 90 mL/min/1.73 m 2 , estimated by CKD-EPI), or mild to moderate hepatic impairment (Child-Pugh class A or B). The effect of severe hepatic impairment (Child-Pugh class C) or end-stage renal disease (eGFR < 15 mL/min/1.73 m 2 ) on atrasentan pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong and moderate CYP3A inducers : Atrasentan C trough decreased by 90% following coadministration of a single dose of 10 mg VANRAFIA with rifampin (strong CYP3A inducer). OATP1B1/1B3 inhibitors : Atrasentan C max was 4.3 times as high and AUC was 3.8 times as high following coadministration of a single dose of 0.75 mg VANRAFIA with cyclosporine (OATP1B1/1B3 inhibitor). Strong CYP3A inhibitors : Atrasentan AUC increased by 90% following coadministration of a single dose of 10 mg VANRAFIA with ketoconazole (strong CYP3A inhibitor). Other Drugs : No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate), losartan (CYP2C9 and CYP3A4 substrate) or fexofenadine (P-gp substrate) were observed or expected when used concomitantly with VANRAFIA. In Vitro Studies CYP450 Enzymes : Atrasentan is a CYP3A substrate. Atrasentan inhibits in vitro CYP3A, CYP2B6, CYP2C8 and CYP2C9 and induces CYP3A and CYP2B6, but is not expected to cause clinically significant interactions with these CYP450 enzymes in the liver. Atrasentan does not inhibit CYP1A2, CYP2C19, or CYP2D6 and is not an inducer of CYP1A2. Transporter Systems : Atrasentan is a substrate of P-gp and OATP1B1/1B3 but not a substrate of BCRP, MRP2/4, NTCP, OCT1, or OATP2B1. Atrasentan inhibits P-gp, OATP1B1, and OATP1B3, but not expected to cause clinically significant interactions. Atrasentan does not inhibit MRP, NTCP, OCT, OAT1, MATE1, or MATE2K.