DRUG INTERACTIONS-

 • CYP2C8 inducers (e.g., rifampin): May decrease iptacopan exposure. Monitor for loss of efficacy.

 • Strong CYP2C8 inhibitors (e.g., gemfibrozil): May increase iptacopan exposure. Coadministration not recommended. 

BRIEF SUMMARY

IPTACOPAN- (Dec 2023)

Indn-       To treat paroxymal nocturnal hemoglobinuria   

Comp-         Capsules: 200 mg    200 mg orally twice daily with or without food.

ADR-     Most common adverse reactions in adults with PNH (incidence = 10%) were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea and rash

CI-     • Serious hypersensitivity to iptacopan or any of the excipients.

• Initiation in patients with unresolved serious infection caused by encapsulated bacteria.

WARNINGS AND PRECAUTIONS-

 • Monitoring of PNH Manifestations After FABHALTA Discontinuation: Monitor for signs of hemolysis after discontinuation.

• Hyperlipidemia: Monitor serum lipid parameters periodically during treatment and initiate cholesterol-lowering medication, if indicate

Pat Infm-

Serious Infections Caused by Encapsulated Bacteria-                             

Advise patients of the risk of serious infection.

Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of FABHALTA or receive antibacterial drug prophylaxis if FABHALTA treatment must be initiated immediately and they have not been previously vaccinated.

Inform patients of the requirement to be revaccinated according to current ACIP recommendations for encapsulated bacteria while on FABHALTA therapy.

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 53

Name-          FABHALTA

Active ingedient-       Iptacopan 

Indication              To treat paroxymal nocturnal hemoglobinuria                                   

Date  of approval       12/05/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                 FABHALTA safely and effectively.

See full prescribing information for FABHALTA. FABHALTA® (iptacopan) capsules, for oral use

Initial U.S. Approval: 2023

WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA -

See full prescribing information for complete boxed warning.

FABHALTA increases the risk of serious and life-threatening infections caused by encapsulated bacteria, including Streptococcus pneumoniae,

Neisseria meningitidis, and Haemophilus influenzae type B.

• Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of FABHALTA, unless the risks of delaying FABHALTA outweigh the risk of developing a serious infection.

Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor.

 • Patients receiving FABHALTA are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected.

 FABHALTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called FABHALTA REMS.

INDICATIONS AND USAGE-

 FABHALTA is a complement factor B inhibitor, indicated for the

ADVERSE REACTIONS-

 Most common adverse reactions in adults with PNH (incidence = 10%) were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea and rash.

CONTRAINDICATIONS-

 • Serious hypersensitivity to iptacopan or any of the excipients.

• Initiation in patients with unresolved serious infection caused by encapsulated bacteria.

WARNINGS AND PRECAUTIONS-

 • Monitoring of PNH Manifestations After FABHALTA Discontinuation: Monitor for signs of hemolysis after discontinuation.

• Hyperlipidemia: Monitor serum lipid parameters periodically during treatment and initiate cholesterol-lowering medication, if indicated. 

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) -----------------------------USE IN SPECIFIC POPULATIONS------------------ • Severe renal impairment: Use not recommended. (8.6) • Severe hepatic impairment: Use not recommended. (8.7

DOSAGE AND ADMINISTRATION-

 200 mg orally twice daily with or without food.

DOSAGE FORMS AND STRENGTHS-

 Capsules: 200 mg 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).\

Serious Infections Caused by Encapsulated Bacteria-                                          Advise patients of the risk of serious infection.

Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of FABHALTA or receive antibacterial drug prophylaxis if FABHALTA treatment must be initiated immediately and they have not been previously vaccinated.

Inform patients of the requirement to be revaccinated according to current ACIP recommendations for encapsulated bacteria while on FABHALTA therapy.

Inform patients that vaccination may not prevent serious infection and to seek immediate medical attention if the following signs or symptoms occur

 • fever with or without shivers or chills                                                                                 • fever and a rash                                                                                                                 • fever with chest pain and cough                                                                                        • fever with breathlessness/fast breathing                                                                            • fever with high heart rate                                                                                                    • headache with nausea or vomiting                                                                                     • headache and a fever                                                                                                        • headache with a stiff neck or stiff back                                                                                 • confusion                                                                                                                           • body aches with flu-like symptoms                                                                                     • clammy skin                                                                                                                       • eyes sensitive to light Inform patients that they will be given a Patient

Safety Card for FABHALTA that they should carry with them at all times during and for 2 weeks following treatment with FABHALTA.

This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation.

FABHALTA REMS FABHALTA is available only through a restricted program called FABHALTA REMS 

Inform the patient of the following notable requirements:                                                         • Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria.                                                                                                         

• Patients must receive written educational materials about this risk.                                   

 • Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 weeks following treatment with FABHALTA.                                             

 • Patients must be instructed to complete or update vaccines against encapsulated bacteria per ACIP recommendations as directed by the prescriber prior to treatment with FABHALTA.                                                                                                                         

 • Patients must receive antibiotics as directed by the prescriber if they are not up to date on vaccinations against encapsulated bacteria and have to start FABHALTA right away. Importance of Adherence to Dosing Schedule Inform patients with PNH of the importance of taking FABHALTA as prescribed in order to minimize the risk of hemolysis.

Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH if FABHALTA is discontinued and that they should be monitored by their healthcare providers for at least 2 weeks following discontinuation of FABHALTA.

Inform patients who discontinue FABHALTA to keep the Patient Safety Card with them for 2 weeks after the last dose of FABHALTA.

The increased risk of serious infection may continue for a few weeks after the last dose of FABHALTA.

Hyperlipidemia-                                                                                                                Inform patients that FABHALTA may increase their cholesterol and triglycerides and that monitoring of these parameters will be needed periodically during treatment.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 For more information,

CLINICAL PHARMACOLOGY 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 complementmediated IVH. 12.2 Pharmacodynamics Inhibition of the alternative complement pathway biomarkers, in vitro alternative pathway assay and plasma Bb (fragment Bb of Factor B), started approximately 2 hours after a single iptacopan dose in healthy volunteers. In PNH patients receiving concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 54.1% and 56.1%, respectively, on the first observation on Day 8. In treatment naïve PNH patients, these same biomarkers decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with FABHALTA 200 mg twice daily. In PNH patients on concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the mean PNH red blood cell (RBC) clone size was 54.8% at baseline and increased to 89.2% after 13 weeks; the proportion of PNH Type II + III RBCs with C3 deposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment naïve PNH patients, the mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks; there were negligible PNH Type II + III RBCs with C3 deposition in this population due to the predominance of IVH. Iptacopan reduces serum LDH levels. In PNH patients previously treated with eculizumab, all patients treated with FABHALTA 200 mg twice daily achieved a reduction of LDH levels to < 1.5 times upper limit of normal (ULN) at 13 weeks. In treatment naïve PNH patients, FABHALTA 200 mg twice daily reduced LDH by > 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years. Cardiac Electrophysiology In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the MRHD) showed no effect on cardiac repolarization or QT interval. 12.3 Pharmacokinetics Absorption Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post dose. At the recommended dosing regimen of 200 mg twice daily, steady state is achieved in approximately 5 days with minor accumulation (1.4-fold). Effect of Food Based on a food-effect study in healthy volunteers, a high-fat meal did not affect the exposure of iptacopan to a clinically meaningful degree. Distribution Iptacopan showed concentration-dependent plasma protein binding due to binding to the target Factor B in the systemic circulation. Iptacopan was 75% to 93% protein bound in vitro at the relevant clinical plasma Reference ID: 5288334 concentrations. After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L. Elimination The half-life (t1/2) of iptacopan at steady state is approximately 25 hours after administration of FABHALTA 200 mg twice daily. The clearance of iptacopan at steady state is 7.96 L/h after administration of FABHALTA 200 mg twice daily. Metabolism Metabolism is a predominant elimination pathway for iptacopan with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan undergoes Phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan was the major component, accounting for 83% of the drug related species. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the drug related species. Iptacopan metabolites are not pharmacologically active. Excretion In a human study, following a single 100 mg oral dose of [14C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the feces and 24.8% in the urine, for a total mean excretion of >96% of the dose. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine, and 16.8% of the dose was excreted as parent iptacopan in feces. Linearity/Non-linearity At doses between 25 mg and 200 mg twice daily, iptacopan was overall less than dose proportional. However, oral doses of 100 mg and 200 mg were approximately dose proportional. Specific Populations A population pharmacokinetic (PK) analysis was conducted on iptacopan data from 234 patients. Age, body weight, race, and gender did not have a clinically significant effect on iptacopan PK. Patients with Renal Impairment The effect of renal impairment on the exposure of iptacopan was assessed using a population pharmacokinetic analysis. Renal function was estimated as eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. There were no clinically relevant differences in the exposure of iptacopan between patients with normal renal function compared to patients with mild (eGFR 60 to < 90 mL/min/1.73 m2 ) or moderate (eGFR 30 to < 60 mL/min/1.73 m2 ) renal impairment. The population pharmacokinetic analysis did not include a sufficient number of patients with severe renal impairment with or without hemodialysis. Patients with Hepatic Impairment In a study in subjects with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe hepatic impairment (Child-Pugh class C), there was a negligible effect of hepatic impairment on the total (bound+unbound) exposure of iptacopan. However, unbound iptacopan AUCinf increased by 1.5, 1.6, and 3.7-fold in patients with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function. Drug Interaction Studies Based on a clinical drug interaction study in healthy volunteers, iptacopan exposure did not change to a clinically relevant degree when coadministered with clopidogrel (a moderate CYP2C8 inhibitor) or cyclosporine (a P-gp, BCRP, and OATP 1B1/1B3 inhibitor). The exposure of digoxin (a P-gp substrate) and rosuvastatin (an OATP substrate) did not change to a clinically relevant degree when coadministered with iptacopan. Reference ID: 5288334

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays. Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to ~9-times the MRHD based on AUC. In a fertility stud

7 DRUG INTERACTIONS 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from clinical trials with FABHALTA use in pregnant women are insufficient to identify a drugassociated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations). The use of FABHALTA in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4 to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data In an embryo-fetal development study in rats, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4- times the MRHD based on AUC. In an embryo-fetal development study in rabbits, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 450 mg/kg/day, which corresponds to 6-times the MRHD based on AUC. In a pre- and postnatal development study in rats, oral administration of iptacopan during gestation, parturition, and lactation did not cause adverse effects in offspring when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. Reference ID: 5288334 8.2 Lactation Risk Summary There are no data on the presence of iptacopan or its metabolite in either human or animal milk, the effects on the breastfed child or on milk production. Since many medicinal products are secreted into human milk, and because of the potential for serious adverse reactions in a breastfed child, breastfeeding should be discontinued during treatment and for 5 days after the final dose. 8.4 Pediatric Use Safety and effectiveness in pediatric patients with PNH have not been established. 8.5 Geriatric Use There were 29 PNH patients 65 years of age and older in APPLY-PNH and APPOINT-PNH [see Clinical Studies (14)]. Of the total number of FABHALTA-treated patients during the 24-week treatment period in these studies, 21 (20.6%) were 65 years of age and older, while 7 (6.9%) were 75 years of age and older. Clinical studies of FABHALTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Renal Impairment The use of FABHALTA is not recommended in patients with severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 ) with or without hemodialysis. No dose adjustment is required in patients with mild (eGFR 60 to < 90 mL/min/1.73 m2 ) or moderate (eGFR 30 to < 60 mL/min/1.73 m2 ) renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The use of FABHALTA is not recommended in patients with severe hepatic impairment (Child-Pugh class C). No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment [see Clinical Pharmacology (12.3)].

11 DESCRIPTION FABHALTA contains iptacopan, a complement Factor B inhibitor. The molecular weight of iptacopan hydrochloride monohydrate is approximately 477 g/mol. The chemical name is (2S,4S)-2-(4-Carboxyphenyl)-4- ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-1-ium chloride-water (1/1). The molecular formula is C25H30N2O4·HCl H2O. The structure is shown below.