Iptacopan

12.1 Mechanism of Action Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, generation of downstream effectors, and the amplification of the terminal pathway. In PNH, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement-mediated IVH. In IgAN, the deposition of galactose deficient IgA1 (Gd-IgA1) containing immune complexes in the kidney locally activates the alternative complement pathway which is thought to contribute to the pathogenesis of IgAN. By binding to Factor B, iptacopan inhibits the alternative pathway. In C3G, overactivation of the alternative complement pathway leads to C3 cleavage within the glomeruli resulting in C3 deposition and inflammation, which are thought to contribute to the pathogenesis of C3G. By binding to Factor B, iptacopan inhibits the alternative pathway.

1 INDICATIONS AND USAGE FABHALTA is a complement factor B inhibitor, indicated for: the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). ( 1.1 ) the reduction of 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. ( 1.2 ) This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether FABHALTA 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. the treatment of adults with complement 3 glomerulopathy (C3G), to reduce proteinuria. ( 1.3 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria FABHALTA is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). 1.2 Immunoglobulin A Nephropathy FABHALTA 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 reduction of proteinuria. It has not been established whether FABHALTA 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. 1.3 Complement 3 Glomerulopathy FABHALTA is indicated for the treatment of adults with complement 3 glomerulopathy (C3G), to reduce proteinuria.

2 DOSAGE AND ADMINISTRATION 200 mg orally twice daily with or without food. ( 2.2 ) 2.1 Recommended Vaccination and Prophylaxis for Encapsulated Bacterial Infections Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y and B) , according to current ACIP recommendations at least 2 weeks prior to initiation of FABHALTA [see Warnings and Precautions (5.1)] . If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccines for Streptococcus pneumoniae and Neisseria meningitidis according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible [see Warnings and Precautions (5.1)] . Healthcare providers who prescribe FABHALTA must enroll in the FABHALTA REMS [see Warnings and Precautions (5.2)] . 2.2 Recommended Dosage The recommended dosage of FABHALTA is 200 mg orally twice daily without regard to food. Swallow capsules whole. Do not open, break, or chew capsules. If a dose or doses are missed, advise the patient to take one dose of FABHALTA as soon as possible (even if it is soon before the next scheduled dose) and then to resume the regular dosing schedule. 2.3 PNH Patients Switching From Anti-C5 (eculizumab, ravulizumab) to FABHALTA To reduce the potential risk of hemolysis with abrupt discontinuation of other PNH therapies: For patients switching from eculizumab, initiate FABHALTA no later than 1 week after the last dose of eculizumab. For patients switching from ravulizumab, initiate FABHALTA no later than 6 weeks after the last dose of ravulizumab. There is no available information regarding the timeframe for initiation of FABHALTA after other PNH therapies.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections Caused by Encapsulated Bacteria [see Warnings and Precautions (5.1)] . Hyperlipidemia [see Warnings and Precautions (5.4)] . Most common adverse reactions in adults with PNH (incidence ≥ 10%) were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea and rash. ( 6.1 ) Most common adverse reactions in adults with IgAN (incidence ≥ 5%) were upper respiratory tract infection, lipid disorder, and abdominal pain. ( 6.1 ) Most common adverse reactions in adults with C3G (incidence ≥ 10%) were nasopharyngitis and viral infections. ( 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. Paroxysmal Nocturnal Hemoglobinuria (PNH) The data described below reflects the exposure in adults with PNH who received FABHALTA (n = 62) or anti-C5 treatment (US-approved and non-US-approved eculizumab product or US-approved and non-US-approved ravulizumab product, n = 35) in APPLY-PNH [NCT04558918] and adults who received FABHALTA (n = 40) in APPOINT-PNH [NCT04820530] at the recommended dosing regimen for 24 weeks. In APPLY-PNH, serious adverse reactions were reported in 2 (3%) patients with PNH receiving FABHALTA. Serious adverse reactions included pyelonephritis, urinary tract infection and COVID-19. In APPOINT-PNH, serious adverse reactions were reported in 2 (5%) patients with PNH receiving FABHALTA. Serious adverse reactions included COVID-19 and bacterial pneumonia. The most common adverse reactions (≥ 10%) with FABHALTA were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash. Table 1 describes the adverse reactions that occurred in > 5% of patients treated with FABHALTA in the APPLY-PNH or APPOINT-PNH studies. Table 1: Adverse Reactions Reported in > 5% of Patients Treated with FABHALTA in APPLY-PNH or APPOINT-PNH Studies (24-Week Treatment Period) a Includes similar terms. b Nasopharyngitis contains: rhinitis allergic, upper respiratory tract infection, pharyngitis, rhinitis. c Bacterial infection contains: pyelonephritis, urinary tract infection, bronchitis bacterial, bronchitis haemophilus, cholecystitis, folliculitis, cellulitis, arthritis bacterial, sepsis, klebsiella infection, staphylococcal infection, Pseudomonas infection, hordeolum, pneumonia bacterial. d Viral infection contains: COVID-19, herpes zoster, oral herpes, nasal herpes, influenza A virus test positive, influenza. e Lipid disorder contains: dyslipidemia, blood cholesterol increased, low density lipoprotein increased, hypercholesterolemia, blood triglycerides increased, hyperlipidemia. f Rash contains: dermatitis allergic, acne, erythema multiforme, rash maculo-papular, rash erythematous. Adverse reactions APPLY-PNH APPOINT-PNH FABHALTA (N = 62) n (%) Anti-C5 (Eculizumab or Ravulizumab) (N = 35) n (%) FABHALTA (N = 40) n (%) Headache a 12 (19) 1 (3) 11 (28) Nasopharyngitis b 10 (16) 6 (17) 6 (15) Diarrhea 9 (15) 2 (6) 3 (8) Abdominal pain a 9 (15) 1 (3) 3 (8) Bacterial infection c 7 (11) 4 (11) 2 (5) Nausea 6 (10) 1 (3) 2 (5) Viral infection d 6 (10) 11 (31) 7 (18) Arthralgia 5 (8) 1 (3) 0 Thrombocytopenia a 4 (6) 0 0 Dizziness 4 (6) 0 1 (3) Systemic hypertension a 4 (6) 0 0 Lipid disorder e 4 (6) 0 3 (8) Rash f 2 (3) 0 4 (10) Clinically relevant adverse reactions reported in less than or equal to 5% of patients includes urticaria in one patient (3%) in APPOINT-PNH. Description of Select Adverse Reactions (graded per NCI CTCAE Version 4.03 unless noted otherwise) Platelet Count Decreased Of the 37 FABHALTA-treated patients who had normal platelet counts at baseline in APPLY-PNH, 43% experienced any Grade thrombocytopenia during the randomized treatment period. Three FABHALTA-treated patients in APPLY-PNH experienced decreased platelets that worsened to Grade ≥ 3 from baseline (one patient with normal platelets that worsened to Grade 4, one patient with baseline Grade 1 that worsened to Grade 4, and one patient with baseline Grade 3 that worsened to Grade 4). Immunoglobulin A Nephropathy (IgAN) The safety of FABHALTA was evaluated in APPLAUSE-IgAN, a randomized placebo-controlled, double-blind clinical study in adults with IgAN (eGFR ≥ 20 mL /min/1.73 m 2 at baseline). The data below reflect FABHALTA exposure in 235 patients with IgAN (eGFR ≥ 20 mL/min/1.73 m 2 at baseline) with a median duration of 43 weeks (up to 104 weeks) in APPLAUSE-IgAN. Table 2 describes the adverse reactions that occurred in ≥ 3 %

7 DRUG INTERACTIONS CYP2C8 inducers (e.g., rifampin): May decrease iptacopan exposure. Monitor for loss of efficacy. ( 7.1 ) Strong CYP2C8 inhibitors (e.g., gemfibrozil): May increase iptacopan exposure. Coadministration not recommended. ( 7.2 ) 7.1 CYP2C8 Inducers Concomitant use of CYP2C8 inducers (e.g., rifampin) may decrease iptacopan exposure, which may result in loss of or reduced efficacy of FABHALTA. Monitor the clinical response and discontinue use of the CYP2C8 inducer if loss of efficacy of FABHALTA is evident. 7.2 Strong CYP2C8 Inhibitors Concomitant use of strong CYP2C8 inhibitors (e.g., gemfibrozil) may increase iptacopan exposure, which may result in an increased risk for adverse reactions with FABHALTA. Coadministration with a strong CYP2C8 inhibitor is not recommended.