Novartis reports Phase IIIB data shows Fabhalta improves hemoglobin in PNH patients switching from anti-C5 therapy; APPULSE-PNH study demonstrates efficacy after 24 weeks of treatment

• In the Phase IIIB APPULSE-PNH study, oral Fabhalta^® (iptacopan) improved the average hemoglobin (Hb) level versus baseline in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who were switched from anti-C5 therapies (Hb ≥10g/dL following treatment with eculizumab or ravulizumab)^1,2
  
  
• PNH is a rare, chronic and serious complement-mediated blood disorder, characterized by hemolysis, anemia, thrombosis and other symptoms, and patients are often treated with anti-C5 therapies^3-5
  
  
• Findings from APPULSE-PNH build on the Phase III program showing the efficacy and safety of Fabhalta in adults with PNH¹, which is approved in the US, EU, Japan and China^6-9

Basel, December 6, 2024 – Novartis today announced positive topline results from APPULSE-PNH, a Phase IIIB study evaluating the efficacy and safety of twice-daily oral monotherapy Fabhalta^® (iptacopan) in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who were switched from anti-C5 therapies (Hb ≥10g/dL following treatment with eculizumab or ravulizumab)¹. After 24 weeks of treatment with Fabhalta, the average Hb level improved versus baseline¹.

“These new results add to the body of evidence reinforcing that Fabhalta can benefit both patients previously treated with anti-C5 therapies studied in the APPULSE-PNH and APPLY-PNH trials and complement-inhibitor naïve patients studied in the APPOINT-PNH trial,” said Antonio Risitano, M.D., Ph.D., Chair of the International PNH Interest Group and Head of the Hematology and Hematopoietic Transplant Unit, Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria at the AORN San Giuseppe Moscati, Avellino, Italy, and APPULSE-PNH trial lead investigator. “Treatment goals for patients with PNH have greatly evolved, and we can now aim to resolve signs and symptoms of disease in most patients. It is promising to see this evolution, and we will continue to make progress to best support these patients.”

In the study, the safety profile of Fabhalta monotherapy was consistent with previously reported data^1,10.

“Across multiple clinical trials, Fabhalta has consistently shown clinically meaningful benefits for patients with PNH, and the APPULSE-PNH trial is a compelling addition to this body of evidence," said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. “These data reinforce our confidence in Fabhalta, the first and only oral monotherapy currently available for the treatment of adults with PNH, to provide meaningful hemoglobin improvement, regardless of previous treatment experience.”

Data will be presented at an upcoming medical meeting in 2025. Fabhalta was recently granted accelerated approval by the US Food and Drug Administration (FDA) for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, and development is ongoing in multiple complement-mediated diseases^6,11.

About APPULSE-PNH
APPULSE-PNH (NCT05630001) is a Phase IIIB multicenter, single-arm, open-label study to evaluate the efficacy and safety of twice-daily oral Fabhalta^® (iptacopan) monotherapy (200mg) in adults with PNH who were switched from anti-C5 therapies (eculizumab or ravulizumab)². The trial enrolled 52 participants who received Fabhalta for 24 weeks².

Participants enrolled were required to be on a stable regimen with anti-C5 therapies (eculizumab or ravulizumab) for at least 6 months prior to screening with average hemoglobin (Hb) ≥10g/dL and no red blood cell transfusions in this period^2,12. The primary endpoint is change from baseline Hb levels after 24 weeks of treatment with Fabhalta^2,12.

About paroxysmal nocturnal hemoglobinuria (PNH)
PNH is a rare, chronic and serious complement-mediated blood disorder¹³. People with PNH have an acquired mutation in some of their hematopoietic stem cells (which are located in the bone marrow and can grow and develop into red blood cells [RBCs], white blood cells and platelets) that causes them to produce RBCs that are susceptible to premature destruction by the complement system^4,13. This leads to intravascular hemolysis (destruction of RBCs within blood vessels) and extravascular hemolysis (destruction of RBCs mostly in the spleen and liver), which cause anemia (low levels of circulating RBCs), thrombosis (formation of blood clots), fatigue and other debilitating symptoms^4,13.
   
It is estimated that approximately 10-20 people per million worldwide live with PNH¹³. Although PNH can develop at any age, it is often diagnosed in people between 30-40 years old^14,15.

PNH has a significant unmet need not addressed by anti-C5 therapies (eculizumab or ravulizumab). Anti-C5 therapies (eculizumab or ravulizumab) are commonly administered every 2-8 weeks as intravenous infusions, and treatment visits (including journey, waiting, infusion and recovery time) can take approximately 4 to 5 hours⁵. Despite treatment with anti-C5 therapies, a large proportion of people with PNH remain anemic, and some dependent on blood transfusions^3,4,16-20.

About Fabhalta^® (iptacopan) 
Fabhalta (iptacopan) is an oral, Factor B inhibitor of the alternative complement pathway¹².

Fabhalta, discovered at Novartis, received approval by the FDA in December 2023 for the treatment of adults with PNH and by the European Medicines Agency (EMA) in May 2024 for the treatment of adults with PNH with hemolytic anemia^6,7. In August 2024, Fabhalta was granted accelerated approval by the US Food and Drug Administration (FDA) for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, and development is ongoing in multiple complement-mediated diseases^6,11. Fabhalta is being studied in a broad range of rare kidney diseases, including C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and lupus nephritis (LN). Studies are ongoing to evaluate the safety and efficacy profiles in these investigational indications and support potential regulatory submissions.

Disclaimer
This media update contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this media update, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this media update will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this media update as of this date and does not undertake any obligation to update any forward-looking statements contained in this media update as a result of new information, future events or otherwise.

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References

1. Novartis. Data on file.
2. Clinicaltrials.gov. NCT05630001. Single Arm, Open Label Trial With Iptacopan Treatment for 24 Weeks, in Patients on Stable Regimen of Anti-C5 Who Switch to Iptacopan. (APPULSE). Available from: https://clinicaltrials.gov/study/NCT05630001 Accessed October, 2024.
3. McKinley CE, Richards SJ, Munir T, et al. Extravascular Hemolysis Due to C3-Loading in Patients with PNH Treated with Eculizumab: Defining the Clinical Syndrome. Blood. 2017;130(Supplement 1):3471.
4. Dingli D, Matos JE, Lehrhaupt K, et al. The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey. Ann Hematol. 2022;101(2):251-263.
5. Levy AR, Dysart L, Patel Y, et al. Comparison of Lost Productivity Due to Eculizumab and Ravulizumab Treatments for Paroxysmal Nocturnal Hemoglobinuria in France, Germany, Italy, Russia, Spain, the United Kingdom, and the United States. Blood. 2019;134(Supplement_1):4803.
6. Fabhalta^®. US FDA Prescribing information. East Hanover, NJ:Novartis Pharmaceuticals Corp; 2024. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218276s001lbl.pdfThis indication is approved under accelerated approval based on reduction of HIGHLIGHTS OF PRESCRIBING INFORMATION proteinuria. It has not been established whether FABHALTA slows kidney These highlights do not include all the information needed to use function decline in patients with IgAN. Continued approval for this indication FABHALTA safely and effectively. See full prescribing information for may be contingent upon verification and description of clinical benefit in a FABHALTA. confirmatory clinical trial. FABHALTA® (iptacopan) capsules, for oral use Initial U.S. Approval: 2023 ------------------------DOSAGE AND ADMINISTRATION---------------------- 200 mg orally twice daily with or without food. (2.2) WARNING: SERIOUS INFECTIONS CAUSED BY ---------------------DOSAGE FORMS AND STRENGTHS---------------------- ENCAPSULATED BACTERIA Capsules: 200 mg (3) See full prescribing information for complete boxed warning. -------------------------------CONTRAINDICATIONS------------------------------ FABHALTA increases the risk of serious and life-threatening • Serious hypersensitivity to iptacopan or any of the excipients. (4) infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae • Initiation in patients with unresolved serious infection caused by type b. encapsulated bacteria. (4) • Complete or update vaccination for encapsulated bacteria at least ------------------------WARNINGS AND PRECAUTIONS----------------------- 2 weeks prior to the first dose of FABHALTA, unless the risks of • Monitoring of PNH Manifestations After FABHALTA Discontinuation: delaying FABHALTA outweigh the risk of developing a serious Monitor for signs of hemolysis after discontinuation. (5.3) infection. Comply with the most current Advisory Committee on • Hyperlipidemia: Monitor serum lipid parameters periodically during Immunization Practices (ACIP) recommendations for vaccinations treatment and initiate cholesterol-lowering medication, if indicated. (5.4) against encapsulated bacteria in patients receiving a complement inhibitor. (5.1) -------------------------------ADVERSE REACTIONS------------------------------ • Patients receiving FABHALTA are at increased risk for invasive • Most common adverse reactions in adults with PNH (incidence ≥ 10%) disease caused by encapsulated bacteria, even if they develop were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial antibodies following vaccination. Monitor patients for early signs infection, viral infection, nausea and rash. (6.1) and symptoms of serious infections and evaluate immediately if • Most common adverse reactions in adults with IgAN (incidence ≥ 5%) infection is suspected. (5.1) were upper respiratory tract infection, lipid disorder, and abdominal pain. FABHALTA is available only through a restricted program under a (6.1) Risk Evaluation and Mitigation Strategy (REMS) called FABHALTA To report SUSPECTED ADVERSE REACTIONS, contact Novartis REMS. (5.2) Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA- ----------------------------RECENT MAJOR CHANGES-------------------------- 1088 or www.fda.gov/medwatch. Indications and Usage (1.2) 08/2024 -------------------------------DRUG INTERACTIONS------------------------------ Dosage and Administration (2.1) 03/2024 • CYP2C8 inducers (e.g., rifampin): May decrease iptacopan exposure. Monitor for loss of efficacy. (7.1) -----------------------------INDICATIONS AND USAGE-------------------------- • Strong CYP2C8 inhibitors (e.g., gemfibrozil): May increase iptacopan FABHALTA is a complement factor B inhibitor, indicated for: exposure. Coadministration not recommended. (7.2) • the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). (1.1) -----------------------------USE IN SPECIFIC POPULATIONS------------------ • the reduction of proteinuria in adults with primary immunoglobulin A • Severe hepatic impairment: Use not recommended. (8.7) nephropathy (IgAN) at risk of rapid disease progression, generally a See 17 for PATIENT COUNSELING INFORMATION and Medication urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g. (1.2) Guide. Revised: 08/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA 1 INDICATIONS AND USAGE 8 USE IN SPECIFIC POPULATIONS 1.1 Paroxysmal Nocturnal Hemoglobinuria 8.1 Pregnancy 1.2 Immunoglobulin A Nephropathy 8.2 Lactation 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use 2.1 Recommended Vaccination and Prophylaxis for Encapsulated 8.5 Geriatric Use Bacterial Infections 8.7 Hepatic Impairment 2.2 Recommended Dosage 11 DESCRIPTION 2.3 PNH Patients Switching From Anti-C5 (eculizumab, 12 CLINICAL PHARMACOLOGY ravulizumab) to FABHALTA 12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics 4 CONTRAINDICATIONS 12.3 Pharmacokinetics 5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY 5.1 Serious Infections Caused by Encapsulated Bacteria 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.2 FABHALTA REMS 14 CLINICAL STUDIES 5.3 Monitoring of PNH Manifestations After FABHALTA 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) Discontinuation 14.2 Immunoglobulin A Nephropathy (IgAN) 5.4 Hyperlipidemia 16 HOW SUPPLIED/STORAGE AND HANDLING 6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS *Sections or subsections omitted from the full prescribing information are not 7.1 listed. CYP2C8 Inducers 7.2 Strong CYP2C8 Inhibitors Reference ID: 5426117 FULL PRESCRIBING INFORMATION WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA FABHALTA, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b [see Warnings and Precautions (5.1)]. Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. • Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of FABHALTA, unless the risks of delaying therapy with 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. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by encapsulated bacteria. • 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. Because of the risk of serious infections caused by encapsulated bacteria, FABHALTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the FABHALTA REMS [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 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. 2 DOSAGE AND ADMINISTRATION 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)]. Reference ID: 5426117 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. 3 DOSAGE FORMS AND STRENGTHS Capsules: 200 mg of iptacopan in pale yellow, opaque, hard gelatin capsules imprinted with “LNP200” on the body and “NVR” on the cap. 4 CONTRAINDICATIONS FABHALTA is contraindicated: • in patients with serious hypersensitivity to iptacopan or any of the excipients. • for initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Caused by Encapsulated Bacteria FABHALTA, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type b. Life- threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of FABHALTA treatment is contraindicated in patients with unresolved serious infections caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of FABHALTA, according to the current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with FABHALTA. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including FABHALTA. The benefits and risks of treatment with FABHALTA, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria. Reference ID: 5426117 Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of FABHALTA in patients who are undergoing treatment for serious infections, depending on the risks of interrupting treatment in the disease being treated. FABHALTA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)]. 5.2 FABHALTA REMS FABHALTA is available only through a restricted program under a REMS called FABHALTA REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1)]. Notable requirements of the FABHALTA REMS include the following: • Prescribers must enroll in the REMS. • Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria. • Prescribers must provide patients with the REMS educational materials. • Prescribers must assess patient vaccination status for vaccines against encapsulated bacteria and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of FABHALTA. • Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with vaccines against encapsulated bacteria according to current ACIP recommendations at least two weeks prior to the first dose of FABHALTA. • Pharmacies that dispense FABHALTA must be certified in the FABHALTA REMS and must verify prescribers are certified. • Patients must receive counseling from the prescriber about the need to receive vaccinations against encapsulated bacteria per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the early signs and symptoms of serious infections. • Patients must be instructed to carry the Patient Safety Card with them at all times during treatment and for 2 weeks following the last dose of FABHALTA. Further information is available by telephone: 1-833-99FABHA (1-833-993-2242) or online at www.FABHALTA-REMS.com. 5.3 Monitoring of PNH Manifestations After FABHALTA Discontinuation In PNH patients, after discontinuing treatment with FABHALTA, closely monitor patients for at least 2 weeks after the last dose for signs and symptoms of hemolysis. These signs include elevated lactate dehydrogenase (LDH) levels along with a sudden decrease in hemoglobin or PNH clone size, fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (such as thrombosis, stroke and myocardial infarction), dysphagia, or erectile dysfunction. If discontinuation of FABHALTA is necessary, consider alternative therapy. If hemolysis occurs after discontinuation of FABHALTA, consider restarting treatment with FABHALTA, if appropriate, or initiating another treatment for PNH. 5.4 Hyperlipidemia FABHALTA may increase total cholesterol, LDL-cholesterol, and serum triglycerides [see Adverse Reactions (6.1)]. Of the 54 FABHALTA-treated patients who had a normal total cholesterol level at baseline in APPLY-PNH, 43% developed Grade 1 hypercholesterolemia during the randomized treatment period. One FABHALTA- Reference ID: 5426117 treated patient in APPLY-PNH experienced increased total cholesterol that worsened to Grade 2 from Grade 1 at baseline. Of the 34 FABHALTA-treated patients who had a normal cholesterol level at baseline in APPOINT-PNH, 24% developed Grade 1 hypercholesterolemia during the core treatment period. Of the 60 FABHALTA-treated patients who had LDL-cholesterol ≤ 130 mg/dL at baseline in APPLY-PNH, 17% developed LDL-cholesterol > 130-160 mg/dL, 8% developed LDL-cholesterol > 160-190 mg/dL, and 7% developed LDL-cholesterol > 190 mg/dL during the randomized treatment period. Of the 36 FABHALTA- treated patients who had LDL-cholesterol ≤ 130 mg/dL at baseline in APPOINT-PNH, 11% developed LDL- cholesterol > 130-160 mg/dL and 3% developed LDL-cholesterol > 160-190 mg/dL. Of the 52 patients with normal triglyceride levels at baseline in APPLY-PNH, 23% developed Grade 1 elevated triglycerides during the randomized treatment period. Three FABHALTA-treated patients in APPLY-PNH experienced an increase in triglycerides from Grade 1 to Grade 2. Of the 37 FABHALTA-treated patients who had a normal triglyceride level at baseline in APPOINT-PNH, 27% developed Grade 1 elevated triglycerides in the core treatment period. Of the 102 FABHALTA-treated patients in APPLY-PNH and APPOINT-PNH, two patients required cholesterol-lowering medications. Monitor serum lipid parameters periodically during treatment with FABHALTA and initiate cholesterol- lowering medication, if indicated. 6 ADVERSE REACTIONS The following clinically significant adverse reaction is 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)]. 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. Reference ID: 5426117 Table 1: Adverse Reactions Reported in > 5% of Patients Treated with FABHALTA in APPLY-PNH or APPOINT-PNH Studies (24-Week Treatment Period) Adverse reactions APPLY-PNH APPOINT-PNH FABHALTA Anti-C5 FABHALTA (N = 62) (Eculizumab or (N = 40) n (%) Ravulizumab) n (%) (N = 35) n (%) Headachea 12 (19) 1 (3) 11 (28) Nasopharyngitisb 10 (16) 6 (17) 6 (15) Diarrhea 9 (15) 2 (6) 3 (8) Abdominal paina 9 (15) 1 (3) 3 (8) Bacterial infectionc 7 (11) 4 (11) 2 (5) Nausea 6 (10) 1 (3) 2 (5) Viral infectiond 6 (10) 11 (31) 7 (18) Arthralgia 5 (8) 1 (3) 0 Thrombocytopeniaa 4 (6) 0 0 Dizziness 4 (6) 0 1 (3) Systemic hypertensiona 4 (6) 0 0 Lipid disordere 4 (6) 0 3 (8) Rashf 2 (3) 0 4 (10) aIncludes similar terms. bNasopharyngitis contains: rhinitis allergic, upper respiratory tract infection, pharyngitis, rhinitis. cBacterial 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. dViral infection contains: COVID-19, herpes zoster, oral herpes, nasal herpes, influenza A virus test positive, influenza. eLipid disorder contains: dyslipidemia, blood cholesterol increased, low density lipoprotein increased, hypercholesterolemia, blood triglycerides increased, hyperlipidemia. fRash contains: dermatitis allergic, acne, erythema multiforme, rash maculo-papular, rash erythematous. 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 double-blind clinical study in adults with IgAN (eGFR ≥ 20 mL /min/1.73 m2 at baseline). Reference ID: 5426117 The data below reflect FABHALTA exposure in 235 patients with IgAN (eGFR ≥ 20 mL/min/1.73 m2 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 % of patients treated with FABHALTA and were ≥ 2% higher in frequency than placebo. All of these adverse reactions were mild or moderate in severity. Table 2: Adverse Reactions Reported in ≥ 3% of Adult Patients with IgAN (eGFR≥ 20 mL /min/1.73 m2) Treated with FABHALTA and ≥ 2% Higher in Frequency Than Placebo in APPLAUSE-IgAN Adverse reaction FABHALTA Placebo (N = 235) (N = 235) n (%) n (%) Upper respiratory tract 20 (9) 16 (7) infection Lipid disorder1 15 (6) 10 (4) Abdominal pain1 15 (6) 5 (2) Nausea 8 (3) 2 (1) Dizziness 7 (3) 2 (1) 1 Includes similar terms. 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 drug- associated 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 and IgAN 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). Reference ID: 5426117 The estimated background risk of major birth defects and miscarriage for the indicated populations 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. IgAN in pregnancy is associated with adverse maternal outcomes, including increased rates of cesarean section, pregnancy-induced hypertension, pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including stillbirth and low birth weight. 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. 8.2 Lactation Risk Summary There are no data on the presence of iptacopan or its metabolites 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 or IgAN 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. There were 8 IgAN patients 65 years of age and older in APPLAUSE-IgAN [see Clinical Studies (14)]. Of the total number of FABHALTA-treated patients, 3 (2.4%) were 65 years of age and older. Clinical studies of FABHALTA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Reference ID: 5426117 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. O HO O (S) (S) N HCl O H2O N H Iptacopan hydrochloride monohydrate is a white or almost white to pale purplish-pink powder. FABHALTA is supplied as hard gelatin capsules for oral administration. The capsules are packaged in high- density polyethylene (HDPE) bottles with induction seals and child resistant caps. Each FABHALTA capsule contains 200 mg iptacopan (provided as 225.8 mg iptacopan hydrochloride monohydrate) and the capsule shell contains the following inactive ingredients: gelatin, red ferric oxide, titanium dioxide, yellow ferric oxide. The black printing ink contains ferrosoferric oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. 12 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 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 effect of the alternative pathway. 12.2 Pharmacodynamics Inhibition of the alternative complement pathway biomarkers, the 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 Reference ID: 5426117 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 the 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. In IgAN patients receiving 200 mg twice daily, the in vitro alternative pathway assay, plasma Bb, plasma soluble C5b-9 (also known as MAC), and urine soluble C5b-9 decreased from baseline by 85.2%, 17.5%, 19.5% and 96.5%, respectively, on the first observation at Month 9. 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 concentrations. After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L. Elimination The terminal half-life (t1/2) of iptacopan at steady state is approximately 25 hours after administration of FABHALTA 200 mg twice daily. The apparent clearance of iptacopan at steady state is 8 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. Reference ID: 5426117 Excretion In a human study, following a single 100 mg oral dose of [14C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 72% in the feces and 25% in the urine, for a total mean excretion of >96% of the dose. Specifically, 18% of the dose was excreted as parent iptacopan in the urine, and 17% 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 There were no clinically significant differences in the exposure of FABHALTA between patients with an eGFR in the range of 25 to <90 mL/min compared to those with normal eGFR. No data are currently available in patients on dialysis. 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 48%, 58% and 271% 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. 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 approximately 9-times the MRHD based on AUC. In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeat- dose toxicity studies with oral administration in dogs at doses ≥ 2-times the MRHD based on AUC, with no clear effects on sperm numbers, morphology, or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre- and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to approximately 11-times the MRHD based on AUC. Reference ID: 5426117 14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) APPLY-PNH: Anti-C5 Treatment Experienced Patients With PNH The efficacy of FABHALTA administered orally in adults with PNH was evaluated in a multi-center, open- label, 24-week, active comparator-controlled trial (APPLY-PNH; NCT04558918). The study enrolled adults with PNH and residual anemia (hemoglobin < 10 g/dL) despite previous treatment with a stable regimen of anti-C5 treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization. Ninety-seven patients were randomized in an 8:5 ratio to switch to FABHALTA 200 mg orally twice daily (n = 62) or to continue anti-C5 treatment (US-approved and non-US-approved eculizumab product n = 23 or US- approved and non-US-approved ravulizumab product n = 12) throughout the duration of the 24-week randomized controlled period. Randomization was stratified based on prior anti-C5 treatment and transfusion history within the last 6 months. Following completion of the 24-week randomized controlled period, all patients were eligible to enroll in a 24-week treatment extension period and receive FABHALTA monotherapy. Subsequently, patients were eligible to enter a separate long-term extension study. Patients were required to be vaccinated against Neisseria meningitidis and recommended to be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to the first dose of study medication. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 3). The mean time on prior anti-C5 treatment was 3.8 and 4.2 years for the FABHALTA and anti-C5 groups, respectively. The baseline mean PNH RBC clone size (Type II + III) was 64.6% for the FABHALTA group and 57.4% for the anti-C5 group. Table 3: Patient Baseline Demographics and Characteristics in APPLY-PNH Parameters Statistics FABHALTA Anti-C5 (n = 62) (Eculizumab or Ravulizumab) (n = 35) Age (years) Mean (SD) 51.7 (16.9) 49.8 (16.7) min, max 22, 84 20, 82 Sex Female n (%) 43 (69.4) 24 (68.6) Race White n (%) 48 (77.4) 26 (74.3) Asian n (%) 12 (19.4) 7 (20.0) Black or African American n (%) 2 (3.2) 2 (5.7) Ethnicity Not Hispanic or Latino n (%) 51 (82.3) 27 (77.1) Hispanic or Latino n (%) 8 (12.9) 2 (5.7) Not reported/unknown n (%) 3 (4.8) 6 (17.1) Hemoglobin level (g/dL) Mean (SD) 8.9 (0.7) 8.9 (0.9) LDH level (U/L) Mean (SD) 269 (70) 273 (85) Absolute reticulocyte count (ARC) (109/L) Mean (SD) 193 (84) 191 (81) Reference ID: 5426117 At least one transfusion in 6 months prior to randomization n (%) 35 (56.5) 21 (60.0) History of MAVEs n (%) 12 (19.4) 10 (28.6) Disease duration (years) Mean (SD) 11.9 (9.8) 13.5 (10.9) Abbreviations: LDH, lactate dehydrogenase; MAVEs, major adverse vascular events (includes thrombosis, stroke and myocardial infarction); SD, standard deviation. Efficacy was established based on demonstration of superiority of switching to FABHALTA compared to continuing on anti-C5 therapy in achieving hematological response after 24 weeks of treatment, without a need for transfusion, by assessing the proportion of patients demonstrating: 1) sustained increase of ≥ 2 g/dL in hemoglobin levels from baseline (hemoglobin improvement) and 2) sustained hemoglobin levels ≥ 12 g/dL. Additional efficacy endpoints included transfusion avoidance, change from baseline in hemoglobin levels and change from baseline in absolute reticulocyte counts. The efficacy results from the APPLY-PNH trial are provided in Table 4. Reference ID: 5426117 Table 4: Efficacy Results for the 24-week Randomized Treatment Period for APPLY-PNH Endpoints FABHALTA Anti-C5 Difference (N = 62) (Eculizumab or (95% CI) Ravulizumab) p-value (N = 35) Primary endpoints Patients with sustained increase of 51/62 0/35 hemoglobin levels ≥ 2 g/dLa from baseline in the absence of transfusions Response rate (%) 82.3 0 81.5b (95% CI) (70.5, 90.8) (0, 10.0) (71.6, 91.4) < 0.0001 Patients with sustained hemoglobin 42/62 0/35 level ≥ 12 g/dLa in the absence of transfusions Response rate (%) 67.7 0 66.6b (95% CI) (54.7, 79.1) (0, 10.0) (54.6, 78.6) < 0.0001 Secondary endpoints Patients avoiding transfusionc,d 59/62 16/35 Transfusion avoidance rate (%) 95.2 45.7 49.5b (95% CI) (86.5, 99.0) (28.8, 63.4) (32.5, 66.6) < 0.0001 Hemoglobin change from baseline 3.6 -0.1 3.7 (g/dL) (adjusted meane,f) (3.3, 3.9) (-0.5, 0.3) (3.2, 4.1) (95% CI) < 0.0001 Absolute reticulocyte count change -116 0 -116 from baseline (109/L) (adjusted meane) (-127, -105) (-13, 14) (-132, -100) (95% CI) < 0.0001 Abbreviations: RR, rate ratio. aAssessed between Day 126 and 168. bAdjusted difference in proportion. cAssessed between Day 14 and 168. dTransfusion avoidance is defined as absence of administration of packed-red blood cell transfusions between Day 14 and 168. eAdjusted mean assessed between Day 126 and 168. fExcludes values within 30 days post-transfusion. APPOINT-PNH: Complement Inhibitor Naïve Patients with PNH Study APPOINT-PNH (NCT04820530) is a single arm study in adults with PNH who were not previously treated with a complement inhibitor. This study enrolled a total of 40 adults with PNH (RBC clone size ≥ 10%), hemoglobin < 10 g/dL, and LDH > 1.5 times upper limit of normal (ULN). All 40 patients received FABHALTA 200 mg orally twice daily during the 24-week open-label core treatment period. Subsequently, patients were eligible to enroll in a 24-week treatment extension period and continue to receive FABHALTA, followed by a separate long-term extension study. The mean age of the patients was 42.1 years and 42.5% were female. The mean disease duration was 4.7 years. The baseline mean PNH RBC clone size (Type II + III) was 42.7%, mean baseline hemoglobin was 8.2 g/dL, and approximately 70% of patients required a transfusion in the 6 months prior to treatment. The baseline mean Reference ID: 5426117 LDH level was 1,699 U/L and the mean absolute reticulocyte count was 154 X 109/L. About 13% of patients had a history of MAVEs. No patients discontinued from the core treatment period of the study. In total, 77.5% (95% CI: 61.5%, 89.2%) of patients (31/40) achieved a sustained increase (between Day 126 and Day 168) in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of RBC transfusions, based on central laboratory hemoglobin values. In a sensitivity analysis, 87.5% (95% CI: 73.2%, 95.8%) of patients (35/40) achieved a sustained increase (between Day 126 and Day 168) in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of RBC transfusions, including local laboratory hemoglobin values when central laboratory hemoglobin values were not available. 14.2 Immunoglobulin A Nephropathy (IgAN) The effect of FABHALTA was evaluated in a multicenter, randomized, double-blind study (APPLAUSE-IgAN, NCT04578834) in adults with biopsy-proven IgAN, eGFR ≥ 20 mL/min/1.73 m2, and urine protein-to- creatinine ratio (UPCR) ≥1 g/g on a stable dose of maximally-tolerated renin-angiotensin system (RAS) inhibitor therapy with or without a stable dose of an SGLT2 inhibitor. Patients with other glomerulopathies or those who had been recently treated with systemic immunosuppressants were excluded. Patients were included in either the Main Study Population (eGFR ≥ 30 mL/min/1.73 m2) or the Severe Renal Impairment population (eGFR ≥ 20 and <30 mL/min/1.73 m2). Within each group, patients were randomized (1:1) to either FABHALTA 200 mg or placebo twice daily. Rescue immunosuppressive treatment could be initiated per investigator discretion during the trial. Patients were required to be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae and were recommended to be vaccinated against Haemophilus influenzae type b. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to first dosing. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered. The efficacy analysis was based on the first 250 patients with an eGFR ≥ 30 mL/min/1.73 m2 (Main Study Population), who had completed or discontinued the study prior to the Month 9 visit. At baseline, the mean age of these patients was 39 years (range 18 to 74 years); 52% were male, 44% White, 54% Asian, and < 1% Black or African American; the mean eGFR was 64 mL/min/1.73 m2; the geometric mean UPCR (sampled from a 24- hr urine collection) was 2.0 g/g, and 12% had a UPCR ≥3.5 g/g. At baseline, 99% of patients were treated with an ACEi or ARB and 13% were on an SGLT2i. Approximately 59% had a history of hypertension, 6% had a history of type 2 diabetes, and 75% had hematuria based on urine dipstick. The primary endpoint was the percent reduction in UPCR (sampled from a 24-hr urine collection) at Month 9 relative to baseline (see Table 5). The mean percent change from baseline in UPCR over time is shown in Figure 1. Table 5: Percent Reduction in UPCR at Month 9 in APPLAUSE-IgAN FABHALTA Placebo (N=125) (N=125) Geometric mean of UPCR, g/g Baseline 1.9 (n=125) 2.0 (n=125) Month 9 1.0 (n= 119) 1.7 (n=110) % reduction in UPCR at Month 9 relative to 44% 9% baseline (95% CI)a (36%, 51%) (-5%, 21%) FABHALTA versus placebo: % reduction in 38% UPCR at Month 9 relative to baseline (95% CI)a (26%, 49%) p-valueb <0.0001 Reference ID: 5426117 a Percent reduction in UPCR was obtained from the adjusted geometric mean ratios where the log transformed ratio to baseline in UPCR (sampled from 24hr urine collection) was analyzed using an MMRM; Values after taking rescue immunosuppressive treatment for IgAN were imputed to reflect disease worsening. Rescue immunosuppressive treatment for IgAN was initiated in 0 and 7 (5.6%) patients in the FABHALTA and placebo group up to Month 9, respectively. b One-sided p-value statistically significant at the 0.005 level. Abbreviations: CI, confidence interval; IgAN, immunoglobulin A nephropathy; MMRM, mixed model of repeated measures; N, number of subjects in each group; n, number of subjects with available data at the time of analysis; UPCR, urine protein-to-creatinine ratio Figure 1: Geometric Mean Percent Change from Baseline in UPCR by Visit in APPLAUSE-IgAN 10 ,,-._, - - - FABHALTA - .... - PLACEBO I >u-< *l.{) 0 .°....'_ ,, Cl) s::: _ _ _ _ _ _ _ _ _ _ -9 (-2~ 5) Q) -10 t/l .".0' .0... . -20 Cl) ..:..:.:. ]" ' -30 Cl) 00 s::: .."c': u -40 * -44 (-51, -36) --0 Cl) "' -50 ::, i -60 FABN= 125 ll5 llS PBON= 125 ll2 106 Baseline Week 26 Week 39 Visi t Adjusted % change relative to baseline in UPCR were obtained by analyzing the log transformed ratio to baseline in UPCR using an MMRM as described in Table 5. N represents the number of subjects with values non-missing/not imputed as per the intercurrent event handling strategy by visit and treatment group. Abbreviations: CI, confidence interval; FAB, FABHALTA; MMRM, mixed model repeated measures; N, number of subjects in each group; PBO, placebo; UPCR, urine protein-to-creatinine ratio The treatment effect on UPCR at Month 9 was consistent across all subgroups including age, sex, race, baseline disease characteristics (such as baseline eGFR and proteinuria levels), and the use of SGLT2i. 16 HOW SUPPLIED/STORAGE AND HANDLING 200 mg capsules: pale yellow opaque hard capsules, imprinted with “LNP200” on one half and “NVR” on the other half, packaged in a high-density polyethylene (HDPE) bottle with induction seal and child-resistant cap. Each bottle contains 60 capsules (NDC 0078-1189-20). Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Reference ID: 5426117 17 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 to 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 [see Warnings and Precautions (5.1)]. Inform patients that vaccination may not prevent serious infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1)]: • 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 [see Warnings and Precautions (5.2)]. 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 Reference ID: 5426117 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, visit www.FABHALTA.com or call 1-888-669-6682. © Novartis Reference ID: 5426117 MEDICATION GUIDE FABHALTA® (fab hal tah) (iptacopan) capsules, for oral use What is the most important information I should know about FABHALTA? FABHALTA is a medicine that affects part of your immune system. FABHALTA may lower the ability of your immune system to fight infections. • FABHALTA increases your chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. These serious infections may quickly become life-threatening or fatal if not recognized and treated early. o You must complete or update your vaccinations against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before your first dose of FABHALTA. o If you have not completed your vaccinations and FABHALTA must be started right away, you should receive the required vaccinations as soon as possible. o If you have not been vaccinated and FABHALTA must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. o If you have been vaccinated against these bacteria in the past, you might need additional vaccinations before starting FABHALTA. Your healthcare provider will decide if you need additional vaccinations. o Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you have any of these signs and symptoms of a serious infection:  fever with or without shivers or chills  fever and a rash  fever with chest pain and cough  fever with breathlessness or fast breathing  fever with high heart rate  headache with nausea or vomiting  headache and fever  headache with stiff neck or stiff back  confusion  body aches with flu-like symptoms  clammy skin  eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 2 weeks after your last dose of FABHALTA. Your risk of serious infections may continue for a few weeks after your last dose of FABHALTA. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. FABHALTA is only available through a program called the FABHALTA Risk Evaluation and Mitigation Strategy (REMS). Before you can take FABHALTA, your healthcare provider must: • enroll in the FABHALTA REMS program • counsel you about the risk of serious infections caused by certain bacteria • give you information about the symptoms of serious infections • make sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start FABHALTA right away and you are not up to date on your vaccinations • give you a Patient Safety Card about your risk of serious infections, as discussed above For more information about side effects, see “What are the possible side effects of FABHALTA?” What is FABHALTA? FABHALTA is a prescription medicine used to: • treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH). • reduce levels of protein in the urine (proteinuria) in adults with a kidney disease called primary immunoglobulin A nephropathy (IgAN), who are at risk of their disease progressing quickly. It is not known if FABHALTA is safe and effective in children with PNH or IgAN. Who should not take FABHALTA? Do not take FABHALTA if you: • are allergic to iptacopan or any of the ingredients in FABHALTA. See the end of this Medication Guide for a complete list of ingredients in FABHALTA. Reference ID: 5426117 • have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b when you are starting FABHALTA treatment. Before you take FABHALTA, tell your healthcare provider about all of your medical conditions, including if you: • have an infection or fever • have liver problems • are pregnant or plan to become pregnant. It is not known if FABHALTA will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if FABHALTA passes into your breast milk. You should not breastfeed during treatment and for 5 days after your final dose of FABHALTA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking FABHALTA with certain other medicines may affect the way FABHALTA works and may cause side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take FABHALTA? • Take FABHALTA exactly as your healthcare provider tells you. Do not change the dose or stop taking FABHALTA unless your healthcare provider tells you. • Take 1 FABHALTA capsule 2 times each day, with or without food. • Swallow the capsules whole. Do not open, break, or chew capsules. • If you miss a dose or doses of FABHALTA, take 1 dose of FABHALTA as soon as you remember, even if it is almost time to take your next scheduled dose, and then take your next dose of FABHALTA at your regularly scheduled time. For people with PNH: • If you are changing treatment from eculizumab to FABHALTA, you should take your starting dose of FABHALTA no later than 1 week after your last dose of eculizumab. • If you are changing treatment from ravulizumab to FABHALTA, you should take your starting dose of FABHALTA no later than 6 weeks after your last dose of ravulizumab. • If you stop taking FABHALTA, your healthcare provider will need to monitor you closely for at least 2 weeks after stopping FABHALTA. Stopping treatment with FABHALTA may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to breakdown of red blood cells include: o decreased hemoglobin level in your blood o tiredness o blood in your urine o pain in the stomach (abdomen) o shortness of breath o blood clots, stroke, and heart attack o trouble swallowing o erectile dysfunction • It is important you take FABHALTA exactly as your healthcare provider tells you to lower the possibility of breakdown of red blood cells due to PNH. What are the possible side effects of FABHALTA? FABHALTA may cause serious side effects, including: • See “What is the most important information I should know about FABHALTA?” • Increased cholesterol and triglyceride (lipid) levels in your blood. Your healthcare provider will do blood tests to check your cholesterol and triglycerides during treatment with FABHALTA. Your healthcare provider may start you on a medicine to lower your cholesterol if needed. The most common side effects of FABHALTA in adults include: • headache • pain in the stomach (abdomen) • nasal congestion, runny nose, cough, sneezing, and sore • infections (bacterial and viral) throat (nasopharyngitis) • nausea • diarrhea • rash Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of FABHALTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store FABHALTA? Reference ID: 5426117 • Store FABHALTA capsules at room temperature between 68°F to 77°F (20°C to 25°C). • The FABHALTA container contains a child resistant cap. Keep FABHALTA and all medicines out of the reach of children. General information about the safe and effective use of FABHALTA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FABHALTA for a condition for which it was not prescribed. Do not give FABHALTA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about FABHALTA that is written for health professionals. What are the ingredients in FABHALTA? Active ingredient: iptacopan Inactive ingredients: the capsule shell contains gelatin, red ferric oxide, titanium dioxide, yellow ferric oxide. The black printing ink contains ferrosoferric oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 © Novartis For more information, go to www.FABHALTA.com or call 1-888-669-6682. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 08/2024 Reference ID: 5426117 Accessed November 2024.
7. Fabhalta^®. EMA Summary of Product Characteristics. Novartis Europharm Limited; 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/fabhalta-epar-product-information_en.pdfANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT FABHALTA 200 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains iptacopan hydrochloride monohydrate equivalent to 200 mg iptacopan. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule (capsule) Size 0 pale yellow, opaque hard capsule (21.2 to 22.2 mm) with “LNP200” on the body and “NVR” on the cap, containing white or almost white to pale purplish-pink powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications FABHALTA is indicated as monotherapy in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who have haemolytic anaemia. 4.2 Posology and method of administration Posology The recommended dose is 200 mg taken orally twice daily. Healthcare professionals should advise patients with PNH about the importance of adherence to the dosing schedule in order to minimise the risk of haemolysis (see section 4.4). If a dose or doses are missed, the patient should be advised to take one dose as soon as possible (even if it is shortly before the next scheduled dose) and then to resume the regular dosing schedule. Patients with several consecutive missed doses should be monitored for potential signs and symptoms of haemolysis. PNH is a disease that requires chronic treatment. Discontinuation of this medicinal product is not recommended unless clinically indicated (see section 4.4). Patients switching from anti-C5 (eculizumab, ravulizumab) or other PNH therapies to iptacopan To reduce the potential risk of haemolysis with abrupt treatment discontinuation: • For patients switching from eculizumab, iptacopan should be initiated no later than 1 week after the last dose of eculizumab. • For patients switching from ravulizumab, iptacopan should be initiated no later than 6 weeks after the last dose of ravulizumab. Switches from complement inhibitors other than eculizumab and ravulizumab have not been studied. 2 Special populations Elderly No dose adjustment is required for patients 65 years of age and older (see section 5.2). Renal impairment No dose adjustment is required in patients with mild (estimated glomerular filtration rate [eGFR] between 60 and <90 ml/min) or moderate (eGFR between 30 and <60 ml/min) renal impairment. No data are currently available in patients with severe renal impairment or on dialysis and no dose recommendations can be given (see section 5.2). Hepatic impairment The use of iptacopan 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 section 5.2). Paediatric population The safety and efficacy of iptacopan in children aged below 18 years have not been established. No data are available. Method of administration For oral use. This medicinal product may be taken with or without food (see section 5.2). 4.3 Contraindications • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Patients who are not currently vaccinated against Neisseria meningitidis and Streptococcus pneumoniae, unless the risk of delaying treatment outweighs the risk of developing an infection from these encapsulated bacteria (see section 4.4). • Patients with unresolved infection caused by encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae or Haemophilus influenzae type B, at treatment initiation. 4.4 Special warnings and precautions for use Serious infections caused by encapsulated bacteria The use of complement inhibitors, such as iptacopan, may predispose individuals to serious, life- threatening or fatal infections caused by encapsulated bacteria. To reduce the risk of infection, all patients must be vaccinated against encapsulated bacteria, including Neisseria meningitidis and Streptococcus pneumoniae. It is recommended to vaccinate patients against Haemophilus influenzae type B if vaccine is available. Healthcare professionals should refer to local vaccination guideline recommendations. Vaccines should be administered at least 2 weeks prior to administration of the first dose of iptacopan. If treatment must be initiated prior to vaccination, patients should be vaccinated as soon as possible and provided with antibacterial prophylaxis until 2 weeks after vaccine administration. If necessary, patients may be revaccinated in accordance with local vaccination guideline recommendations. Vaccination reduces, but does not eliminate, the risk of serious infection. Serious infection may rapidly become life-threatening or fatal if not recognised and treated early. Patients should be informed of and monitored for early signs and symptoms of serious infection. Patients should be 3 immediately evaluated and treated if infection is suspected. The use of iptacopan during treatment of serious infection may be considered following an assessment of the risks and benefits (see section 4.8). PNH laboratory monitoring Patients with PNH receiving iptacopan should be monitored regularly for signs and symptoms of haemolysis, including measuring lactate dehydrogenase (LDH) levels. Monitoring of PNH manifestations after treatment discontinuation If treatment must be discontinued, patients should be closely monitored for signs and symptoms of haemolysis for at least 2 weeks after the last dose. These signs and symptoms include, but are not limited to, elevated LDH levels along with sudden decrease in haemoglobin or PNH clone size, fatigue, haemoglobinuria, abdominal pain, dyspnoea, dysphagia, erectile dysfunction, or major adverse vascular events (MAVEs), including venous or arterial thrombosis. If treatment discontinuation is necessary, alternative therapy should be considered. If haemolysis occurs after discontinuation of iptacopan, restarting treatment should be considered. Co-administration with other medicinal products Concomitant use of iptacopan with strong inducers of CYP2C8, UGT1A1, PgP, BCRP and OATP1B1/3 has not been studied clinically; therefore, concomitant use is not recommended due to the potential for reduced efficacy of iptacopan (see section 4.5). If an alternative concomitant medicinal product cannot be identified, patients should be monitored for potential signs and symptoms of haemolysis. Educational materials All physicians who intend to prescribe FABHALTA must ensure they have received and are familiar with the physician educational materials. Physicians must explain and discuss the benefits and risks of FABHALTA therapy with the patient and provide them with the patient information pack. The patient should be instructed to seek prompt medical care if they experience any sign or symptom of serious infection or serious haemolysis following treatment discontinuation. 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicinal products on iptacopan Strong inducers of CYP2C8, UGT1A1, PgP, BCRP and OATP1B1/3 Although concomitant administration of iptacopan with strong inducers of CYP2C8, UGT1A1, PgP, BCRP and OATP1B1/3, such as rifampicin, has not been studied clinically, concomitant use with iptacopan is not recommended due to the potential for reduced efficacy of iptacopan (see section 4.4). Effects of iptacopan on other medicinal products CYP3A4 substrates In vitro data showed iptacopan has potential for induction of CYP3A4 and may decrease the exposure of sensitive CYP3A4 substrates. The concomitant use of iptacopan and sensitive CYP3A4 substrates has not been studied clinically. Caution should be exercised if co-administration of iptacopan with sensitive CYP3A4 substrates is required, especially for those with a narrow therapeutic index (e.g. carbamazepine, ciclosporin, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus). CYP2C8 substrates In vitro data showed iptacopan has potential for time-dependent inhibition of CYP2C8 and may increase the exposure of sensitive CYP2C8 substrates, such as repaglinide, dasabuvir or paclitaxel. 4 The concomitant use of iptacopan and sensitive CYP2C8 substrates has not been studied clinically. Caution should be exercised if co-administration of iptacopan with sensitive CYP2C8 substrates is required. 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data from the use of iptacopan in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at exposures between 2- and 8-fold the human exposure at the maximum recommended human dose (MRHD) (see section 5.3). PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, as well as adverse foetal outcomes, including foetal death and premature delivery. The use of iptacopan in pregnant women or women planning to become pregnant may only be considered following a careful assessment of the risk and benefits, if necessary. Breast-feeding It is unknown whether iptacopan is excreted in human milk. There are no data on the effects of iptacopan on the breast-fed newborn/infant or on milk production. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from FABHALTA therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effect of iptacopan on human fertility. Available non-clinical data do not suggest an effect of iptacopan treatment on fertility (see section 5.3). 4.7 Effects on ability to drive and use machines FABHALTA has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions were upper respiratory tract infection (18.9%), headache (18.3%) and diarrhoea (11.0%). The most commonly reported serious adverse reaction was urinary tract infection (1.2%). Tabulated list of adverse reactions Table 1 shows the adverse reactions observed in the clinical studies with iptacopan in patients with PNH. Adverse reactions are listed by MedDRA system organ class (SOC) and frequency, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000) or very rare (<1/10 000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 5 Table 1 Adverse reactions System Organ Class Frequency category Adverse reaction Infections and infestations Upper respiratory tract infection1 Very common Urinary tract infection2 Common Bronchitis3 Common Pneumonia bacterial Uncommon Blood and lymphatic system disorders Platelet count decreased Common Nervous system disorders Headache4 Very common Dizziness Common Gastrointestinal disorders Diarrhoea Very common Abdominal pain5 Common Nausea Common Skin and subcutaneous tissue disorders Urticaria Uncommon Musculoskeletal and connective tissue disorders Arthralgia Common 1 Upper respiratory tract infection includes preferred terms influenza, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 2 Urinary tract infection includes preferred terms urinary tract infection and cystitis escherichia. 3 Bronchitis includes preferred terms bronchitis, bronchitis haemophilus and bronchitis bacterial. 4 Headache includes preferred terms headache and head discomfort. 5 Abdominal pain includes preferred terms abdominal pain, abdominal pain upper, abdominal tenderness and abdominal discomfort. Description of selected adverse reactions Platelet count decreased Decrease in platelet count events was reported in 12/164 (7%) patients with PNH. Of these, 5 patients had events of mild severity, 5 had moderate events and 2 had severe events. Patients with severe events had concurrent anti-platelet antibodies or idiopathic bone marrow aplasia with pre-existing thrombocytopenia. The events started within the first 2 months of iptacopan treatment in 7/12 patients, and after a longer exposure (111 to 951 days) in 5/12 patients. At the cut-off date, 7 (58%) patients had recovered or events were resolving and iptacopan treatment was continued throughout in all patients. Infections In PNH clinical studies 1/164 (0.6%) PNH patients reported serious bacterial pneumonia while receiving treatment with iptacopan; the patient had been vaccinated against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B and recovered following treatment with antibiotics while continuing treatment with iptacopan. Blood cholesterol and blood pressure increases In patients treated with iptacopan 200 mg twice a day in PNH clinical studies, mean increases from baseline of approximately 0.7 mmol/l were seen at month 6 for total cholesterol and LDL-cholesterol. The mean values remained within the normal ranges. Increases in blood pressure, particularly diastolic blood pressure (DBP), were observed (mean increase 4.7 mmHg at month 6). The mean DBP did not exceed 80 mmHg. Total cholesterol, LDL-C and DBP increases correlated with increases in haemoglobin (improvement in anaemia) in patients with PNH (see section 5.1). 6 Heart rate decrease In patients treated with iptacopan 200 mg twice a day in PNH clinical studies, a mean decrease in heart rate of approximately 5 bpm was seen at month 6 (mean of 68 bpm). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose During clinical studies, a few patients took up to 800 mg iptacopan daily and this was well tolerated. In healthy volunteers, the highest dose was 1 200 mg administered as a single dose and this was well tolerated. General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, complement inhibitors, ATC code: L04AJ08 Mechanism of action Iptacopan is a proximal complement inhibitor that targets Factor B (FB) to selectively inhibit the alternative pathway. Inhibition of FB in the alternative pathway of the complement cascade prevents the activation of C3 convertase and the subsequent formation of C5 convertase to control both C3- mediated extravascular haemolysis (EVH) and terminal complement-mediated intravascular haemolysis (IVH). Pharmacodynamic effects The onset of inhibition of the alternative complement pathway, measured using an ex vivo alternative pathway assay, Bb levels (fragment b of Factor B) and plasma levels of C5b-9, was ≤2 hours after a single iptacopan dose in healthy volunteers. A comparable effect of iptacopan was observed in patients with PNH previously exposed to anti-C5 agents and treatment-naïve patients. In treatment-naïve PNH patients, iptacopan 200 mg twice daily reduced LDH by >60% compared to baseline after 12 weeks and maintained the effect through to the end of the study. 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 exposure of the 200 mg twice daily dose), showed no effect on cardiac repolarisation or QT interval. 7 Clinical efficacy and safety The efficacy and safety of iptacopan in adult patients with PNH were evaluated in two multicentre, open-label, 24-week phase III studies: an active comparator-controlled study (APPLY-PNH) and a single-arm study (APPOINT-PNH). APPLY-PNH: anti-C5 treatment experienced patients with PNH APPLY-PNH enrolled adult PNH patients (RBC clone size ≥10%) with residual anaemia (haemoglobin <10 g/dl) despite previous treatment with a stable regimen of anti-C5 treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomisation. Patients (N=97) were randomised in 8:5 ratio either to receive iptacopan 200 mg orally twice daily (N=62) or to continue anti-C5 treatment (eculizumab N=23; or ravulizumab N=12) throughout the duration of the 24-week randomised controlled period (RCP). Randomisation was stratified based on prior anti-C5 treatment and transfusion history within the last 6 months. Demographics and baseline disease characteristics were generally well balanced between treatment groups. At baseline, patients had a mean (standard deviation [SD]) age of 51.7 (16.9) years (range 22- 84) and 49.8 (16.7) years (range 20-82) in the iptacopan and anti-C5 groups, respectively and 69% of patients were female in both groups. The mean (SD) haemoglobin was 8.9 (0.7) g/dl and 8.9 (0.9) g/dl, in the iptacopan and anti-C5 group, respectively. Fifty-seven percent (iptacopan group) and 60% (anti- C5 group) of patients received at least one transfusion in the 6 months prior to randomisation. Amongst those, the mean (SD) number of transfusions was 3.1 (2.6) and 4.0 (4.3) in the iptacopan and anti-C5 group, respectively. The mean (SD) LDH level was 269.1 (70.1) U/l in the iptacopan group and 272.7 (84.8) U/l in the anti-C5 group. The mean (SD) absolute reticulocyte count was 193.2 (83.6) 109/l in the iptacopan group and 190.6 (80.9) 109/l in the anti-C5 group. The mean (SD) total PNH RBC clone size (Type II + III) was 64.6% (27.5%) in the iptacopan group and 57.4% (29.7%) in the anti-C5 group. During the RCP, 1 patient in the iptacopan group discontinued treatment due to pregnancy; no patients in the anti-C5 group discontinued. Efficacy was based on two primary endpoints to demonstrate superiority of iptacopan to anti-C5 in achieving haematological response after 24 weeks of treatment, without a need for transfusion, by assessing the proportion of patients demonstrating: 1) sustained increase of ≥2 g/dl in haemoglobin levels from baseline (haemoglobin improvement) and/or 2) sustained haemoglobin levels ≥12 g/dl. Iptacopan demonstrated superiority to anti-C5 therapy for the two primary endpoints, as well as for several secondary endpoints including transfusion avoidance, changes from baseline in haemoglobin levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, absolute reticulocyte counts (ARCs) and annualised rate of clinical breakthrough haemolysis (see Table 2). The treatment effect of iptacopan on haemoglobin was seen as early as day 7 and sustained during the study (see Figure 1). 8 Table 2 Efficacy results for the 24-week randomised treatment period in APPLY-PNH Endpoints Iptacopan Anti-C5 Difference (N=62) (N=35) (95% CI) p-value Primary endpoints Number of patients achieving 51/60b 0/35b haemoglobin improvement (sustained increase of haemoglobin levels ≥2 g/dl from baselinea in the absence of transfusions) Response ratec (%) 82.3 2.0 80.2 (71.2, 87.6) <0.0001 Number of patients achieving sustained 42/60b 0/35b haemoglobin level ≥12 g/dla in the absence of transfusions Response ratec (%) 68.8 1.8 67.0 (56.4, 76.9) <0.0001 Secondary endpoints Number of patients avoiding transfusiond,e 59/62b 14/35b Transfusion avoidance ratec (%) 94.8 25.9 68.9 (51.4, 83.9) <0.0001 Haemoglobin level change from baseline 3.60 -0.06 3.66 (g/dl) (adjusted meanf) (3.20, 4.12) <0.0001 FACIT-Fatigue score change from 8.59 0.31 8.29 baseline (adjusted meang) (5.28, 11.29) <0.0001 Clinical breakthrough haemolysish,i, % 3.2 (2/62) 17.1 (6/35) (n/N) Annualised rate of clinical breakthrough 0.07 0.67 RR=0.10 haemolysis (0.02, 0.61) 0.01 Absolute reticulocyte count change from -115.8 0.3 -116.2 baseline (109/l) (adjusted meang) (-132.0, -100.3) <0.0001 LDH ratio to baseline (adjusted geometric 0.96 0.98 Ratio = 0.99 meang) (0.89, 1.10) 0.84 MAVEsh % 1.6 0 (n/N) (1/62) Annualised rate of MAVEsh 0.03 0 0.03 (-0.03, 0.10) 0.32 RR: rate ratio; LDH: lactate dehydrogenase; MAVEs: major adverse vascular events a,d,h Assessed between days 126 and 168(a), 14 and 168(d), 1 and 168(h). b Based on observed data among evaluable patients. (In 2 patients with partially missing central haemoglobin data between days 126 and 168, the haematological response could not be established unequivocally. The haematological response was derived using multiple imputation. These patients did not discontinue.) c Response rate reflects the model estimated proportion. e Transfusion avoidance is defined as absence of administration of packed red blood cell transfusions between days 14 and 168 or meeting the criteria for transfusion between days 14 and 168. f,g Adjusted mean assessed between days 126 and 168, values within 30 days after transfusion were excluded(f)/included(g) in the analysis. i Clinical breakthrough haemolysis is defined as meeting clinical criteria (either decrease of haemoglobin level ≥2 g/dl compared to the last assessment or within 15 days, or signs or symptoms of gross haemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs and symptoms) and laboratory criteria (LDH >1.5 x ULN and increased as compared to the last 2 assessments). 9 Figure 1 Mean haemoglobin level* (g/dl) during 24-week randomised treatment period in APPLY-PNH 12 g/dl Baseline Day 7 Day 14 Day 28 Day 42 Day 56 Day 84 Day 112 Day 126 Day 140 Day 154 Day 168 Visit Anti-C5 Iptacopan *Note: The figure includes all haemoglobin data collected in the study, including those values within 30 days after RBC transfusion. APPOINT-PNH: Complement inhibitor-naïve study APPOINT-PNH was a single-arm study in 40 adult PNH patients (RBC clone size ≥10%) with haemoglobin <10 g/dl and LDH >1.5 x ULN who were not previously treated with a complement inhibitor. All 40 patients received iptacopan 200 mg orally twice daily during the 24-week open-label core treatment period. At baseline, patients had a mean (SD) age of 42.1 (15.9) years (range 18-81) and 43% were female. The mean (SD) haemoglobin was 8.2 (1.1) g/dl. Seventy percent of patients received at least one transfusion in the 6 months prior to treatment. Amongst those the mean (SD) number of transfusions was 3.1 (2.1). The mean (SD) LDH level was 1 698.8 (683.3) U/l, and the mean (SD) absolute reticulocyte count was 154.3 (63.7) 109/l. The mean (SD) total PNH RBC clone size (Type II + III) was 42.7% (21.2%). No patients discontinued from the core treatment period of the study. Efficacy was based on the primary endpoint assessing the effect of iptacopan treatment on the proportion of patients achieving haemoglobin improvement (sustained increase of ≥2 g/dl in haemoglobin levels from baseline, without a need for RBC transfusion, after 24 weeks). See Table 3 for detailed efficacy results and see Figure 2 for the mean LDH level change during the 24-week core treatment period. 10 Mean haemoglobin level (SD) g/dl Table 3 Efficacy results for the 24-week core treatment period in APPOINT-PNH Endpoints Iptacopan (N=40) 95% CI Primary endpoint Number of patients achieving haemoglobin improvement (sustained 31/33b increase of haemoglobin levels ≥2 g/dl from baselinea in the absence of transfusions) Response ratec (%) 92.2 (82.5, 100.0)d Secondary endpoints Number of patients achieving sustained haemoglobin level ≥12 g/dla in the 19/33b absence of transfusions Response ratec (%) 62.8 (47.5, 77.5) Number of patients avoiding transfusione,f 40/40b Transfusion avoidance ratec (%) 97.6 (92.5, 100.0) Haemoglobin level change from baseline (g/dl) +4.3 (adjusted meang) (3.9, 4.7) Clinical breakthrough haemolysisi,j, % (n/N) 0/40 Annualised rate of clinical breakthrough haemolysis 0.0 (0.0, 0.2) Absolute reticulocyte count change from baseline (109/l) -82.5 (adjusted meanh) (-89.3, -75.6) LDH percent change from baseline -83.6 (adjusted meanh) (-84.9, -82.1) Percentage of patients with MAVEsj 0.0 a,e,j Assessed between days 126 and 168(a), 14 and 168(e), 1 and 168(j). b Based on observed data among evaluable patients. (In 7 patients with partially missing central haemoglobin data between days 126 and 168, the haematological response could not be established unequivocally. The haematological response was derived using multiple imputation. These patients did not discontinue.) c Response rate reflects the model estimated proportion. d The threshold for demonstration of benefit was 15%, representing the rate that would have been expected on anti-C5 treatment. f Transfusion avoidance is defined as absence of administration of packed red blood cell transfusions between days 14 and 168 or meeting the criteria for transfusion between days 14 and 168. g,h Adjusted mean assessed between days 126 and 168, values within 30 days after transfusion were excluded(g)/included(h) in the analysis. i Clinical breakthrough haemolysis defined as meeting clinical criteria (either decrease of haemoglobin level ≥2 g/dl compared to the latest assessment or within 15 days; or signs or symptoms of gross haemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs and symptoms) and laboratory criteria (LDH >1.5 x ULN and increased as compared to the last 2 assessments). 11 Figure 2 Mean LDH level (U/l) during 24-week core treatment period in APPOINT-PNH 375 U/l (1.5 x ULN) Visits Treatment: Iptacopan Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with FABHALTA in one or more subsets of the paediatric population in PNH (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties 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). In healthy volunteers, steady-state Cmax,ss (geo-mean (%CV)) was 4 020 ng/ml (23.8%) and AUCtau,ss was 25 400 ng*hr/ml (15.2%). Inter- and intra-subject variability in iptacopan pharmacokinetics is low to moderate. Results from a food-effect study with a high-fat high-calorie meal in healthy volunteers indicated that Cmax and area under the curve (AUC) of iptacopan were not affected by food. Therefore, iptacopan may be taken with or without food. Distribution Iptacopan showed concentration-dependent plasma protein binding due to binding to the target FB in the systemic circulation. Iptacopan was 75 to 93% protein bound in vitro at the relevant clinical plasma concentrations. After administration of iptacopan 200 mg twice daily, the geo-mean apparent volume of distribution at steady state was approximately 265 litres. Biotransformation 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 with a small contribution from CYP2D6. Direct glucuronidation (by UGT1A1, UGT1A3 and UGT1A8) is a minor pathway. In plasma, iptacopan was the major component, accounting for 83% of the AUC0-48 h. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the AUC0-48 h. Iptacopan metabolites are not considered pharmacologically active. Elimination In a study in healthy volunteers, following a single 100 mg oral dose of [14C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the faeces and 24.8% in the urine. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine and 16.8% in faeces. The 12 Mean LDH level (SD) U/l apparent clearance (CL/F) after administration of iptacopan 200 mg twice daily at steady state is 7 960 ml/min. The half-life (t½) of iptacopan at steady state is approximately 25 hours after administration of iptacopan 200 mg twice daily. Linearity/non-linearity At doses between 25 and 100 mg twice daily, the pharmacokinetics of iptacopan were overall less than dose proportional. However, oral doses of 100 mg and 200 mg were approximately dose proportional. Non-linearity was primarily attributed to the saturable binding of iptacopan to its target FB in plasma. Drug interactions A dedicated interaction study in which iptacopan was co‑administered with other medicinal products was conducted in healthy volunteers and did not demonstrate any clinically relevant interactions. Iptacopan as a substrate CYP2C8 inhibitors When iptacopan is co‑administered with clopidogrel (a moderate CYP2C8 inhibitor), the iptacopan Cmax and the AUC increased by 5% and 36%, respectively. OATP1B1/OATP1B3 inhibitors When iptacopan is co‑administered with ciclosporin (a strong OATP 1B1/1B3 inhibitor, and a PgP and BCRP inhibitor), the iptacopan Cmax and AUC increased by 41% and 50%, respectively. Iptacopan as an inhibitor PgP substrates In the presence of iptacopan, the Cmax of digoxin (a PgP substrate) increased by 8% while its AUC was unchanged. OATP substrates In the presence of iptacopan, the Cmax and AUC of rosuvastatin (an OATP substrate) remained unchanged. Special populations A population pharmacokinetic (PK) analysis was conducted on data from 234 patients. Age (18 to 84 years), body weight, eGFR, race and gender did not significantly influence iptacopan PK. Studies that included Asian subjects showed that the PK of iptacopan were similar to Caucasian (white) subjects. Renal impairment The effect of renal impairment on the clearance of iptacopan was assessed using a population PK analysis. There were no clinically relevant differences in the clearance of iptacopan between patients with normal renal function and patients with mild (eGFR between 60 and 90 ml/min) or moderate (eGFR between 30 and 60 ml/min) renal impairment and no dose adjustment is required (see section 4.2). Patients with severe renal impairment or on dialysis have not been studied. Hepatic impairment Based on a study in subjects with mild (Child-Pugh A, n=8), moderate (Child-Pugh B, n=8) or severe (Child-Pugh C, n=6) hepatic impairment, a negligible effect on the total systemic exposure of iptacopan was observed compared to subjects with normal hepatic function. Unbound iptacopan Cmax increased 1.4-, 1.7- and 2.1-fold, and unbound iptacopan AUCinf increased by 1.5-, 1.6- and 3.7-fold in subjects with mild, moderate and severe hepatic impairment, respectively (see section 4.2). 13 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Reproductive toxicity In oral dose animal fertility studies, iptacopan did not impact fertility in male rats up to the highest dose tested (750 mg/kg/day), which corresponds to 6-fold the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and hypospermatogenesis) were observed in repeated dose toxicity studies after oral administration in rats and dogs at doses >3- fold the MRHD based on AUC, with no apparent effects on sperm numbers, morphology or motility, or fertility. In the female fertility and early embryonic developmental study in rats, iptacopan-related findings were limited to increased pre-and post-implantation losses and, consequently, decreased numbers of live embryos only at the highest dose of 1 000 mg/kg/day orally, which corresponds to ~5-fold the MRHD based on total AUC. The dose of 300 mg/kg/day is the no-observed-adverse-effect level (NOAEL) which corresponds to ~2-fold the MRHD based on AUC. Animal reproduction studies in rats and rabbits demonstrated that oral administration of iptacopan during organogenesis did not induce adverse embryo or foetal toxicity up to the highest doses, which correspond to 5-fold (for rats) and 8-fold (for rabbits) the MRHD of 200 mg twice daily based on AUC. In the pre- and postnatal development study in rats, with iptacopan administered orally to females during gestation, parturition and lactation (from gestational day 6 to lactation day 21), there were no adverse effects on pregnant dams or offspring up to the highest dose tested of 1 000 mg/kg/day (estimated 5-fold the MRHD based on AUC). Repeated dose toxicity In the chronic toxicity study, one male dog at the highest dose level (margin to clinical exposure near 20-fold), was sacrificed 103 days after completed iptacopan administration due to irreversible non- regenerative severe anaemia associated with bone marrow fibrosis. During the treatment phase, haematology findings indicating inflammation and dyserythropoiesis were observed. No mechanism for the observed findings has been identified and a relation to treatment cannot be excluded. Mutagenicity and carcinogenicity Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays. Carcinogenicity studies conducted with iptacopan in mice and rats via oral administration did not identify any carcinogenic potential. The highest doses of iptacopan studied in mice (1 000 mg/kg/day) and rats (750 mg/kg/day) were approximately 4- and 12-fold the MRHD based on AUC, respectively. Phototoxicity In vitro and in vivo phototoxicity tests were equivocal. In the in vivo phototoxicity study, with iptacopan at doses between 100 and 1 000 mg/kg (equivalent to 38-fold the human total Cmax at the MRHD), some mice showed a non-dose-response pattern of transient minimal erythema, scabs and dryness and slight increase in average ear weight subsequent to irradiation. 14 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule shell Gelatin Red iron oxide (E172) Titanium dioxide (E171) Yellow iron oxide (E172) Printing ink Black iron oxide (E172) Concentrated ammonia solution (E527) Potassium hydroxide (E525) Propylene glycol (E1520) Shellac (E904) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container FABHALTA is supplied in PVC/PE/PVDC blisters with aluminium foil backing. Packs containing 28 or 56 hard capsules. Multipacks containing 168 (3 packs of 56) hard capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 15 8. MARKETING AUTHORISATION NUMBER(S) EU/1/24/1802/001-003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17 May 2024 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu. 16 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 17 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Novartis Pharmaceutical Manufacturing LLC Verovškova Ulica 57 1000 Ljubljana Slovenia Novartis Pharma GmbH Roonstrasse 25 90429 Nuremberg Germany Novartis Farmacéutica S.A. Gran Via De Les Corts Catalanes 764 08013 Barcelona Spain Novartis Pharma GmbH Sophie-Germain-Strasse 10 90443 Nuremberg Germany The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. 18 An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures Prior to launch of FABHALTA in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority (NCA). The educational programme is aimed at providing healthcare professionals (HCPs) and patients/caregivers with educational information on the following safety areas of interest: • Infections caused by encapsulated bacteria • Serious haemolysis following discontinuation of iptacopan The MAH shall ensure that in each Member State where FABHALTA is marketed, all HCPs and patients/caregivers who are expected to prescribe or use FABHALTA have access to/are provided with the following educational package: • Physician educational material • Patient information pack Physician educational material: o The Summary of Product Characteristics o Guide for healthcare professionals • The Guide for healthcare professionals shall contain the following key messages: o FABHALTA may increase the risk of serious infections with encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. o Ensure patients are vaccinated against N. meningitidis and S. pneumoniae before starting treatment, and/or receive antibiotic prophylaxis until 2 weeks after vaccination. o Recommend vaccination against H. influenzae to patients where vaccines are available. o Ensure that FABHALTA is only dispensed after a written confirmation that the patient has received vaccination against N. meningitidis and S. pneumoniae, in accordance with current national vaccination guidelines, and/or is receiving prophylactic antibiotic. o Ensure prescribers or pharmacists receive annual reminders of mandatory revaccinations in accordance with current national vaccination guidelines (including N. meningitidis, S. pneumoniae, and, if appropriate, H. influenzae) o Monitor patients for signs and symptoms of sepsis, meningitis or pneumonia, such as: fever with or without shivers or chills, headache and a fever, 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 with a stiff neck or stiff back, confusion, body aches with flu-like symptoms, clammy skin, eyes sensitive to light. If bacterial infection is suspected, treat with antibiotics immediately. o Discontinuation of FABHALTA may increase the risk of serious haemolysis, therefore advice on adherence to the dosing schedule is important, as is close monitoring for signs of haemolysis following treatment discontinuation. If discontinuation of FABHALTA is necessary, alternative therapy should be considered. If haemolysis occurs after discontinuation of FABHALTA, restarting FABHALTA treatment should be considered. Possible signs and symptoms you 19 need to look out for are: elevated lactate dehydrogenase (LDH) levels along with sudden decrease in haemoglobin or PNH clone size, fatigue, haemoglobinuria, abdominal pain, dyspnoea, dysphagia, erectile dysfunction or major adverse vascular events including thrombosis. o Details about the PASS and how to enter patients, if applicable. The patient information pack: o Package leaflet o Patient/caregiver guide o Patient safety card • The Patient/caregiver guide shall contain the following key messages: o Treatment with FABHALTA may increase the risk of serious infections. o Doctors will inform you about which vaccinations are required prior to treatment and/or the need to receive antibiotic prophylaxis. o Signs and symptoms of serious infection are: fever with or without shivers or chills, headache and a fever, 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 with a stiff neck or stiff back, confusion, body aches with flu-like symptoms, clammy skin, eyes sensitive to light. o Contact your doctor in case you experience any of the signs and symptoms above and seek immediate medical care at the nearest medical centre. o Discontinuation of FABHALTA may increase the risk of serious breakdown of red blood cells (haemolysis). It is important that you adhere to the scheduled treatment regimen. Possible signs and symptoms you need to look out for are: fatigue, blood in the urine, abdominal pain, shortness of breath, difficulty swallowing, erectile dysfunction or major adverse vascular events including thrombosis. o Tell your doctor before discontinuing FABHALTA. o If you miss a dose, take it as soon as you can, even if it is close to the next dose. o You will receive a patient safety card and will need to carry it with you and tell any treating healthcare professional that you are being treated with FABHALTA. o If you have any adverse reactions, including infections or serious haemolysis, it is important that you report them immediately. o You will be informed of the details to enroll in the PASS. • Patient Safety Card: o Statement that the patient is receiving FABHALTA. o Signs and symptoms of serious infection caused by encapsulated bacteria and warning to seek immediate treatment with antibiotics if bacterial infection is suspected. o Contact details where a healthcare professional can receive further information. • System for Controlled Access: o The MAH shall ensure that in each Member State where FABHALTA is marketed, a system aimed to control access beyond the level of routine risk minimisation measures is in place. The following requirement needs to be fulfilled before the product is dispensed: o Submission of written confirmation of the patient’s vaccination against N. meningitidis and S. pneumoniae infections and/or receipt of prophylactic antibiotic according to national guidelines. • Annual reminder of mandatory revaccinations: o The MAH shall send to prescribers or pharmacists who prescribe/dispense FABHALTA an annual reminder in order that the prescriber/pharmacist checks if a revaccination (booster vaccination) against N. meningitidis and S. pneumoniae infections is required for their patients on treatment with FABHALTA, in accordance with current national vaccination guidelines. 20 ANNEX III LABELLING AND PACKAGE LEAFLET 21 A. LABELLING 22 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF PACK CONTAINING 28 HARD CAPSULES 1. NAME OF THE MEDICINAL PRODUCT FABHALTA 200 mg hard capsules iptacopan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains iptacopan hydrochloride monohydrate equivalent to 200 mg iptacopan. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 28 capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 23 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/24/1802/001 28 hard capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE FABHALTA 200 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 24 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF PACK CONTAINING 28 HARD CAPSULES 1. NAME OF THE MEDICINAL PRODUCT FABHALTA 200 mg hard capsules iptacopan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains iptacopan hydrochloride monohydrate equivalent to 200 mg iptacopan. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 14 capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use ‘QR code to be included’ www.fabhalta.eu Scan me 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 25 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/24/1802/001 28 hard capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE FABHALTA 200 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 26 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF PACK CONTAINING 56 HARD CAPSULES 1. NAME OF THE MEDICINAL PRODUCT FABHALTA 200 mg hard capsules iptacopan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains iptacopan hydrochloride monohydrate equivalent to 200 mg iptacopan. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 56 capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use ‘QR code to be included’ www.fabhalta.eu Scan me 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 27 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/24/1802/002 56 hard capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE FABHALTA 200 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 28 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT FABHALTA 200 mg hard capsules iptacopan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains iptacopan hydrochloride monohydrate equivalent to 200 mg iptacopan. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule Multipack: 168 (3 x 56) capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 29 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/24/1802/003 168 (3 x 56) hard capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE FABHALTA 200 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 30 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT FABHALTA 200 mg hard capsules iptacopan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains iptacopan hydrochloride monohydrate equivalent to 200 mg iptacopan. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 56 capsules Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use ‘QR code to be included’ www.fabhalta.eu Scan me 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 31 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/24/1802/003 168 (3 x 56) hard capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE FABHALTA 200 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 32 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT FABHALTA 200 mg capsules iptacopan 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Mon. Tue. Wed. Thu. Fri. Sat. Sun. 33 B. PACKAGE LEAFLET 34 Package leaflet: Information for the patient FABHALTA 200 mg hard capsules iptacopan This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What FABHALTA is and what it is used for 2. What you need to know before you take FABHALTA 3. How to take FABHALTA 4. Possible side effects 5. How to store FABHALTA 6. Contents of the pack and other information 1. What FABHALTA is and what it is used for FABHALTA contains the active substance iptacopan, which belongs to a group of medicines called complement inhibitors. FABHALTA is used on its own in adults to treat paroxysmal nocturnal haemoglobinuria (PNH), a disease in which the immune system (the body’s natural defence system) attacks and damages red blood cells. FABHALTA is used in adults who have anaemia (low levels of red blood cells) due to the breakdown of their red blood cells. The active substance in FABHALTA, iptacopan, targets a protein called Factor B, which is involved in a part of the body’s immune system called the “complement system”. In patients with PNH, the complement system is overactive, causing the destruction and breakdown of the red blood cells, which can lead to anaemia, tiredness, difficulty in functioning, pain, pain in the stomach (abdomen), dark urine, shortness of breath, difficulty swallowing, impotence and blood clots. By attaching to and blocking the Factor B protein, iptacopan can stop the complement system from attacking the red blood cells. This medicine has been shown to increase the number of red blood cells and thus may improve symptoms of anaemia. 2. What you need to know before you take FABHALTA Do not take FABHALTA - if you are allergic to iptacopan or any of the other ingredients of this medicine (listed in section 6). - if you have not been vaccinated against Neisseria meningitidis and Streptococcus pneumoniae, unless your doctor decides that urgent treatment with FABHALTA is needed. 35 - if you have an infection caused by a type of bacteria called encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae or Haemophilus influenzae type B, before starting FABHALTA treatment. Warnings and precautions Serious infection caused by encapsulated bacteria FABHALTA may increase your risk of infection caused by encapsulated bacteria, including Neisseria meningitidis (bacteria that cause meningococcal disease, including serious infection of the linings of the brain and of the blood) and Streptococcus pneumoniae (bacteria causing pneumococcal disease, including infection of the lungs, ears and blood). Talk to your doctor before you start FABHALTA to be sure that you receive vaccination against Neisseria meningitidis and Streptococcus pneumoniae. You may also receive vaccination against Haemophilus influenzae type B if this is available in your country. Even if you have had these vaccinations in the past, you might still need to be revaccinated before starting FABHALTA. These vaccinations should be given at least 2 weeks before starting FABHALTA. If this is not possible, you will be vaccinated as soon as possible after you start FABHALTA and your doctor will prescribe antibiotics for you to use until 2 weeks after you have been vaccinated to reduce the risk of infection. You should be aware that vaccination reduces the risk of serious infections but may not prevent all serious infections. You should be closely monitored by your doctor for symptoms of infection. Tell your doctor immediately if you get any of the following symptoms of serious infection during treatment with FABHALTA: - fever with or without shivers or chills - headache and a fever - fever and a rash - fever with chest pain and cough - fever with breathlessness/fast breathing - fever with high heart rate - headache with feeling sick (nausea) or vomiting - headache with stiff neck or stiff back - confusion - body aches with flu-like symptoms - clammy skin - eyes sensitive to light Children and adolescents Do not give FABHALTA to children or adolescents below 18 years of age. No data are available on the safety and effectiveness of FABHALTA in this age group. Other medicines and FABHALTA Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines, including medicines obtained without a prescription. In particular: Tell your doctor or pharmacist if you are using certain medicines because they may stop FABHALTA from working properly: - certain medicines used to treat bacterial infections – such as rifampicin Tell your doctor or pharmacist if you are using any of the following medicines because FABHALTA may stop these medicines from working properly: - certain medicines used to treat epilepsy – such as carbamazepine - certain medicines used to prevent organ rejection after an organ transplant – such as ciclosporin, sirolimus, tacrolimus - certain medicines used to treat migraines – such as ergotamine 36 - certain medicines used to treat chronic pain – such as fentanyl - certain medicines used to control involuntary movements or sounds – such as pimozide - certain medicines used to treat an abnormal heart rhythm – such as quinidine - certain medicines used to treat type 2 diabetes – such as repaglinide - certain medicines used to treat hepatitis C infection – such as dasabuvir - certain medicines used to treat cancer – such as paclitaxel Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. You should also tell your doctor if you become pregnant during treatment with FABHALTA. Your doctor will discuss with you the potential risks of taking FABHALTA during pregnancy or breast-feeding. Your doctor will decide whether you should take FABHALTA while you are pregnant only after a careful risk-benefit assessment. It is unkown whether iptacopan, the active substance in FABHALTA, passes into human milk and may affect the breast-fed newborn/infant. Your doctor will decide whether you should stop breast-feeding or stop FABHALTA treatment, taking into account the benefit of breast-feeding for your baby and the benefit of treatment for yourself. Driving and using machines This medicine has no or negligible influence on the ability to drive and use machines. 3. How to take FABHALTA Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Do not exceed the prescribed dose. The recommended dose is 200 mg (one capsule) to be taken by mouth twice daily (once in the morning and once in the evening). Swallow the FABHALTA capsule with a glass of water. Taking FABHALTA at the same time each day will help you to remember when to take your medicine. It is important that you take FABHALTA according to your doctor’s instructions to reduce the risk of breakdown of red blood cells due to PNH. FABHALTA with food FABHALTA can be taken with or without food. Switching from other PNH medicines to FABHALTA If you are switching from any other PNH medicine, ask your doctor when to start taking FABHALTA. How long to take FABHALTA PNH is a lifelong condition and it is expected that you will need to use FABHALTA for a long time. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect. If you have questions about how long you will need to take FABHALTA, talk to your doctor. 37 If you take more FABHALTA than you should If you have accidently taken too many capsules or if someone else accidentally takes your medicine, talk to your doctor immediately. If you forget to take FABHALTA If you miss a dose or doses, take one dose of FABHALTA as soon as you remember (even if it is shortly before the next scheduled dose), then take the next dose at the usual time. If you miss several doses in a row, contact your doctor who may decide to monitor you for any signs of the breakdown of red blood cells (see section “If you stop taking FABHALTA” below). If you stop taking FABHALTA Stopping your treatment with FABHALTA can make your condition worse. Do not stop taking FABHALTA without talking to your doctor first. If your doctor decides to stop your treatment with this medicine, you will be monitored closely for at least 2 weeks after stopping treatment for any signs of the breakdown of red blood cells. Your doctor may prescribe a different PNH medicine or restart your FABHALTA treatment. Symptoms or problems that can happen due to breakdown of red blood cells include: - low levels of haemoglobin in your blood, as seen in blood tests - tiredness - blood in the urine - pain in the stomach (abdomen) - shortness of breath - trouble swallowing - erectile dysfunction (impotence) - blood clots (thrombosis) If you experience any of these after stopping treatment, contact your doctor. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects The most commonly reported serious side effect is urinary tract infection. If you experience any of the symptoms of serious infection listed under “Serious infection caused by encapsulated bacteria” in section 2 of this leaflet, you should immediately inform your doctor. Other side effects Very common (may affect more than 1 in 10 people) - infections of the nose and throat (upper respiratory tract infection) - headache - diarrhoea Common (may affect up to 1 in 10 people) - persistent cough or irritation of the airways (bronchitis) - low levels of platelets (which help the blood clot) in the blood (thrombocytopenia), which may cause you to bleed or bruise more easily - dizziness - pain in the stomach (abdomen) 38 - feeling sick (nausea) - joint pain (arthralgia) Uncommon (may affect up to 1 in 100 people) - lung infection, which can cause chest pain, cough and fever - itchy rash (urticaria) Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store FABHALTA Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister after “EXP”. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What FABHALTA contains - The active substance is iptacopan. - The other ingredients are: - Capsule shell: gelatin, red iron oxide (E172), titanium dioxide (E171), yellow iron oxide (E172) - Printing ink: black iron oxide (E172), concentrated ammonia solution (E527), potassium hydroxide (E525), propylene glycol (E1520), Shellac (E904) What FABHALTA looks like and contents of the pack Pale yellow, opaque hard capsules, with “LNP200” on the body and “NVR” on the cap, containing white or almost white to pale purplish-pink powder. The capsule size is approximately 21 to 22 mm. FABHALTA is supplied in PVC/PE/PVDC blisters with aluminium foil backing. FABHALTA is available in - packs containing 28 or 56 hard capsules and in - multipacks comprising 3 cartons, each containing 56 capsules. Not all pack sizes may be marketed. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 39 Manufacturer Novartis Pharmaceutical Manufacturing LLC Verovškova Ulica 57 1000 Ljubljana Slovenia Novartis Pharma GmbH Roonstrasse 25 90429 Nuremberg Germany Novartis Farmacéutica S.A. Gran Via De Les Corts Catalanes 764 08013 Barcelona Spain Novartis Pharma GmbH Sophie-Germain-Strasse 10 90443 Nuremberg Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Lietuva Novartis Pharma N.V. SIA Novartis Baltics Lietuvos filialas Tél/Tel: +32 2 246 16 11 Tel: +370 5 269 16 50 България Luxembourg/Luxemburg Novartis Bulgaria EOOD Novartis Pharma N.V. Тел.: +359 2 489 98 28 Tél/Tel: +32 2 246 16 11 Česká republika Magyarország Novartis s.r.o. Novartis Hungária Kft. Tel: +420 225 775 111 Tel.: +36 1 457 65 00 Danmark Malta Novartis Healthcare A/S Novartis Pharma Services Inc. Tlf.: +45 39 16 84 00 Tel: +356 2122 2872 Deutschland Nederland Novartis Pharma GmbH Novartis Pharma B.V. Tel: +49 911 273 0 Tel: +31 88 04 52 111 Eesti Norge SIA Novartis Baltics Eesti filiaal Novartis Norge AS Tel: +372 66 30 810 Tlf: +47 23 05 20 00 Ελλάδα Österreich Novartis (Hellas) A.E.B.E. Novartis Pharma GmbH Τηλ: +30 210 281 17 12 Tel: +43 1 86 6570 España Polska Novartis Farmacéutica, S.A. Novartis Poland Sp. z o.o. Tel: +34 93 306 42 00 Tel.: +48 22 375 4888 40 France Portugal Novartis Pharma S.A.S. Novartis Farma - Produtos Farmacêuticos, S.A. Tél: +33 1 55 47 66 00 Tel: +351 21 000 8600 Hrvatska România Novartis Hrvatska d.o.o. Novartis Pharma Services Romania SRL Tel. +385 1 6274 220 Tel: +40 21 31299 01 Ireland Slovenija Novartis Ireland Limited Novartis Pharma Services Inc. Tel: +353 1 260 12 55 Tel: +386 1 300 75 50 Ísland Slovenská republika Vistor hf. Novartis Slovakia s.r.o. Sími: +354 535 7000 Tel: +421 2 5542 5439 Italia Suomi/Finland Novartis Farma S.p.A. Novartis Finland Oy Tel: +39 02 96 54 1 Puh/Tel: +358 (0)10 6133 200 Κύπρος Sverige Novartis Pharma Services Inc. Novartis Sverige AB Τηλ: +357 22 690 690 Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: https://www.ema.europa.eu. 41 Accessed November 2024.
8. Fabhalta^®. PMDA Drug Information Sheet. Novartis Pharma KK; 2024. Available from: https://www.pmda.go.jp/files/000271929.pdfPharmaceuticals and Medical Devices Safety Information No. 414 November 2024 Table of Contents 1. Suspected Adverse Reactions to Influenza Vaccines in the 2023 Season ............................................................................. 5 2. Revision of PRECAUTIONS for Non-steroidal Anti- inflammatory Drugs Regarding Myocardial Infarction and Cerebrovascular Disorder ........................................................ 10 3. Revisions of PRECAUTIONS (No.354) ................................... 13 Aspirin (preparations indicated for antipyresis/analgesia/anti-inflammation) (and 17 others) .............................................................................................. 13 4. List of Products Subject to Early Post-marketing Phase Vigilance..................................... 23 This Pharmaceuticals and Medical Devices Safety Access to the latest safety information is available via Information (PMDSI) publication is issued reflective of the PMDA Medi-navi. safety information collected by the Ministry of Health, Labour and Welfare (MHLW). It is intended to The PMDA Medi-navi is an e-mail mailing list service facilitate safer use of pharmaceuticals and medical that serves to provide essential safety information devices by healthcare providers. The PMDSI is released by the MHLW and PMDA. Subscribing to the available on the Pharmaceuticals and Medical Medi-navi will allow you to receive this information on Devices Agency (PMDA) web page the day of its release. (https://www.pmda.go.jp/english/safety/info- This service is available only in Japanese. services/drugs/medical-safety-information/0002.html) and on the MHLW website (https://www.mhlw.go.jp/, only in Japanese). Register Available information is listed here here Published by Pharmaceutical Safety Division, Ministry of Health, Labour and Welfare Pharmaceutical Safety Bureau, Ministry of Health, Labour and Welfare 1-2-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-8916 Japan This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 1 - Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 Ministry of Health, Labour and Welfare Pharmaceutical Safety Bureau, Japan [ Outline of Information ] No. Subject Measures Outline of Information Page This section describes the status of instances of suspected adverse reactions to influenza vaccines reported from October 1, 2023 through March 31, 2024 (hereinafter referred to as the “2023 season”). Medical institutions are required to report to the MHLW when they encounter symptoms from influenza vaccines that they decide meet the Suspected Adverse Reaction Reporting Criteria regardless of causality. Reports by medical institutions, together with those by the marketing authorization holders Suspected Adverse (MAHs), are compiled and evaluated by the Reactions to Influenza PMDA. For serious cases, including fatal 1 cases, the PMDA performs causality 5 Vaccines in the 2023 assessment and/or considers the necessity Season of safety measures in consultation with experts. Joint meetings of the Side Effect Subcommittee of the Immunization and Vaccine Section Meeting in the Health Science Council and the Subcommittee on Drug Safety of the Committee on Drug Safety in the Pharmaceutical Affairs Council are convened periodically for the purpose of investigating and reviewing these reports of suspected adverse reactions to influenza vaccines and to discuss the necessity of safety measures. NSAIDs are used for antipyretic, analgesic, and anti-inflammatory purposes in various diseases as prescription drugs, guidance- mandatory drugs, and over-the-counter drugs. For the risk of myocardial infarction and Revision of cerebrovascular disorder in patients treated PRECAUTIONS for Non- with NSAIDs for which systemic effects are steroidal Anti- expected, a pharmacoepidemiological study inflammatory Drugs was conducted using the National Database 2 of Health Insurance Claims and Specific 10 (NSAIDs) Regarding P Health Checkups of Japan (hereinafter Myocardial Infarction and referred to as the "NDB"). Cerebrovascular As a result of reviewing the results of the Disorder NDB study including the opinions of expert advisors, the MHLW determined that it was necessary to take safety measures and instructed the MAHs to revise the PRECAUTIONS on October 8,2024. The details of the review are described in this section. rations indicated for 3 Revisions of Aspirin (prepa P antipyresis/analgesia/anti-inflammation) 13 PRECAUTIONS (No.354) (and 17 others) List of Products Subject List of products subject to Early Post- 4 to Early Post-marketing marketing Phase Vigilance as of September 23 Phase Vigilance 30, 2024 E: Distribution of Dear Healthcare Professional Letters of Emergency Communications, R: Distribution of Dear This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 2 - Healthcare Professional Letters of Rapid Communications, P: Revision of PRECAUTIONS, C: Case Reports Reporting of safety information such as adverse reactions to the Minister of Health, Labour and Welfare is a duty of healthcare professionals. If healthcare professionals such as physicians, dentists, and pharmacists detect adverse reactions, infections, or malfunctions associated with drugs, medical devices, or regenerative medical products, please report them to the Minister of Health, Labour and Welfare directly or through the marketing authorization holder. As healthcare professionals, drugstore and pharmacy personnel are also required to report adverse reactions, etc. Please utilize the Report Reception Site for reporting. (This service is available only in Japanese.) https://www.pmda.go.jp/safety/reports/hcp/0002.html This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 3 - Abbreviations ADEM Acute Disseminated Encephalomyelitis ADR Adverse Drug Reaction AGEP Acute Generalised Exanthematous Pustulosis CI Confidence Interval DIDPC Department of Infectious Disease Prevention and Control EPPV Early Post-marketing Phase Vigilance FDA Food and Drug Administration JCS Japanese Circulation Society MAH Marketing Authorization Holder MHLW Ministry of Health, Labour and Welfare National Database of Health Insurance Claims and Specific Health NDB Checkups of Japan NSAIDs Non-steroidal Anti-inflammatory Drugs OTC Over-the-Counter PMDA Pharmaceuticals and Medical Devices Agency Act on Securing Quality, Efficacy and Safety of Pharmaceuticals PMD Act and Medical Devices PSB Pharmaceutical Safety Bureau PSD Pharmaceutical Safety Division PV Law Preventive Vaccination Law RS virus Respiratory Syncytial virus SOC System Organ Class This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 4 - 1 Suspected Adverse Reactions to Influenza Vaccines in the 2023 Season 1. Introduction This section describes the status of instances of suspected adverse reactions to influenza vaccines reported from October 1, 2023 through March 31, 2024 (hereinafter referred to as the “2023 season”). Medical institutions are required to report to the MHLW when they encounter symptoms from influenza vaccines that they decide meet the Suspected Adverse Reaction Reporting Criteria regardless of causality. Reports by medical institutions, together with those by the marketing authorization holders (MAHs), are compiled and evaluated by the PMDA. For serious cases, including fatal cases, the PMDA performs causality assessment and/or considers the necessity of safety measures in consultation with experts. Joint meetings of the Side Effect Subcommittee of the Immunization and Vaccine Section Meeting in the Health Science Council and the Subcommittee on Drug Safety of the Committee on Drug Safety in the Pharmaceutical Affairs Council (hereinafter referred to as the “Joint Meeting”) are convened periodically for the purpose of investigating and reviewing these reports of suspected adverse reactions to influenza vaccines and to discuss the necessity of safety measures1)2). 2. Reports of suspected adverse reactions to influenza vaccines (2023 season) (1) Numbers and frequencies of suspected adverse reactions reported Table 1 shows the numbers of reported suspected adverse reactions to the influenza vaccines and frequencies calculated from the estimated numbers of vaccinated persons based on the number of vaccines distributed to medical institutions. Table 1 Numbers of suspected adverse reactions reported and estimated number of vaccinated persons Reports by MAHs Reports by medical institutions** (serious reports)* Estimated Number of serious cases Number of serious cases number of reported (frequency) reported (frequency) vaccinated Number of Number of persons reports Number of patient (number of (frequency) patient mortalities mortalities vaccinations) reported reported 49,058,485 24 3 75 43 7 (as of March (0.000049%) (0.0000061%) (0.00015%) (0.00009%) (0.0000143%) 31, 2024) * Reports by the MAHs were on cases determined to be “serious” under Article 68-10, Paragraph 1 of the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (PMD Act). Reports by the MAHs may duplicate some cases reported by medical institutions, and such duplicated cases are included in the number for reports by medical institutions. ** Reports by medical institutions were submitted under Article 12, Paragraph 1 of the Preventive Vaccination Law (PV Law) or Article 68-10, Paragraph 2 of the PMD Act. (2) Reports of suspected adverse reactions by sex and age group The numbers of reported suspected adverse reactions to influenza vaccines are shown by sex and age group in Table 2 and Table 3, respectively. This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 5 - Table 2 Number of reports by sex Number of Reports Number of reports Sex by MAHs by medical institutions (serious cases) Male 16 35 Female 7 40 Unknown 1 0 Total 24 75 Table 3 Number of reports by age group Number of Reports by Number of reports by medical institutions MAHs Number of serious cases Number of serious cases reported reported er of Number of Age group Numb Number of patient reports patient mortalities mortalities reported reported 0 - 9 3 0 28 16 0 10 - 19 1 0 3 2 0 20 - 29 2 0 3 1 0 30 - 39 1 0 4 1 0 40 - 49 1 0 7 5 0 50 - 59 2 0 6 2 0 60 - 69 2 0 3 2 0 70 - 79 4 0 11 6 1 80 or older 5 1 10 8 6 Unknown 3 2 0 0 0 Total 24 3 75 43 7 (3) Details of reported symptoms Suspected adverse reactions to influenza vaccines reported during the 2023 season are outlined by System Organ Class (SOC) in the right-hand side columns of Table 4. A total of 10 cases of post-vaccination deaths were reported for this season. Among them, 9 cases excluding 1 case under investigation were evaluated by experts. The assessment by experts determined that the causality between the vaccination and death could not be assessed due to lack of information for these cases. A total of 5 cases Note 1) of possible Guillain-Barré syndrome or acute disseminated encephalomyelitis (ADEM) were reported for this season. The assessment by experts determined that a causal relationship between the respective diseases and vaccination was reasonably possible for 1 case. A total of 8 cases Note 2) were reported as possible anaphylaxis. Experts concluded that 3 cases (including 2 serious cases) were assessed as Level 3 or higher anaphylaxis using the Brighton Criteria. Regarding the number of reports from the MAHs by manufacturing lot, no distinct increases in the number of cases reported as possible anaphylaxis were attributed to any of the specific lots. At the Joint Meeting held in July 2024, it was concluded that there were no new concerns This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 6 - regarding the safety of the vaccines, including other reported symptoms than anaphylaxis, with no safety measures such as revision of package inserts required at present, but reporting of suspected adverse reactions and their details should be carefully monitored. Note 1) Cases reported with the symptom name “Guillain-Barré syndrome” or “ acute disseminated encephalomyelitis” Note 2) Cases reported with the symptom name “anaphylactic reaction,” “anaphylactic shock,” “anaphylactoid reaction” Table 4 Comparison of the number of suspected adverse reaction reports between the 2022 and 2023 seasons (by SOC) 2022 season† 2023 season†† Reports by Reports by Reports by Reports by medical medical MAHs MAHs SOC of symptom institutions institutions (serious (serious (serious (serious cases) cases) cases) cases) Gastrointestinal disorders 3 4 1 5 General disorders and 13 12 8 16 administration site conditions Infections and infestations 1 7 2 8 Haepatobiliary disorders 0 1 1 1 Eye disorders 2 0 1 6 Musculoskeletal and connective 1 3 5 2 tissue disorders Blood and lymphatic system 0 4 1 5 disorders Vascular disorders 0 5 1 3 Respiratory, thoracic and 1 9 2 3 mediastinal disorders Injury, poisoning and procedural 1 1 0 0 complications Cardiac disorders 1 6 2 6 Nervous system disorder 8 23 6 15 Renal and urinary disorders 3 1 1 3 Mental disorder 0 1 1 0 Metabolic and nutritional 0 3 0 1 disorders Endocrine disorders 1 1 0 1 Skin and subcutaneous tissue 5 4 0 4 disorders Immune system disorders 4 5 2 7 Investigations 0 9 4 3 Total 44 99 38 89 † Reported from October 1, 2022 to September 30, 2023 †† Reported from October 1, 2023 to March 31, 2024 3. Future safety measures As detailed in the “Reporting Suspected Adverse Reactions for Routine Vaccination, etc.” notification3), medical institutions are urged to promptly report when they encounter symptoms that they believe meet the Suspected Adverse Reaction Reporting Criteria even if the causality is This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 7 - unclear. In addition to the conventional reporting by fax, electronic reporting is available through the website since April 1, 2021. [Report Reception Site (electronic report system)] https://www.pmda.go.jp/safety/reports/hcp/0002.html (only in Japanese) The MHLW/PMDA will continue their efforts to gather information concerning the safety of influenza vaccines including suspected adverse reaction reports, etc. and to implement safety measures based on such information. Continued cooperation is requested in alerting vaccine recipients to adverse reactions and reporting them when suspected. [References] 1) MHLW: The Side Effect Subcommittee of the Immunization and Vaccine Section Meeting in the Health Science Council (the 102nd meeting) and the 2024 Subcommittee on Drug Safety of the Committee on Drug Safety in the Pharmaceutical Affairs Council (the 4th meeting) (Joint Meeting) •Material 2-29 Reports of Suspected Adverse Reactions to Influenza Vaccines https://www.mhlw.go.jp/content/11120000/001280878.pdf (only in Japanese) •Material 2-34 List of reports of fatal cases after vaccination https://www.mhlw.go.jp/content/11120000/001280826.pdf (only in Japanese) 2) MHLW: The Side Effect Subcommittee of the Immunization and Vaccine Section Meeting in the Health Science Council (the 101st meeting) and the 2024 Subcommittee on Drug Safety of the Committee on Drug Safety in the Pharmaceutical Affairs Council (the 1st meeting) (Joint Meeting) •Material 2-31 List of reports of fatal cases after vaccination https://www.mhlw.go.jp/content/11120000/001244848.pdf (only in Japanese) 3) “Partial Amendment of Reporting Suspected Adverse Reactions for Routine Vaccinations, etc.” dated August 8, 2024, Joint DIDPC Notification No.0808-5 and PSB Notification No.0808-1 by the Director of the Department of Infectious Disease Prevention and Control and the Director- General of the Pharmaceutical Safety Bureau, Ministry of Health, Labor and Welfare https://www.mhlw.go.jp/bunya/kenkou/kekkaku- kansenshou20/hukuhannou_houkoku/kanrentuuti.html (only in Japanese) Report form https://www.mhlw.go.jp/bunya/kenkou/kekkaku- kansenshou20/hukuhannou_houkoku/dl/r04youshiki_02.pdf (only in Japanese) Entry instructions https://www.mhlw.go.jp/bunya/kenkou/kekkaku- kansenshou20/hukuhannou_houkoku/dl/r04youshiki_03.pdf (only in Japanese) Report entry application (National Institute of Infectious Diseases) http://www.nih.go.jp/niid/ja/vaccine-j/6366-vaers-app.html (only in Japanese) This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 8 - Reference: Suspected Adverse Reaction Reporting Criteria Symptoms Time to onset after inoculation Anaphylaxis 4 hours Hepatic impairment 28 days Interstitial pneumonia 28 days Acute disseminated encephalomyelitis (ADEM) 28 days Acute generalised exanthematous pustulosis (AGEP) 28 days Guillain-Barré syndrome 28 days Convulsion 7 days Vasculitis 28 days Thrombocytopenic purpura 28 days Optic neuritis 28 days Myelitis 28 days Asthmatic attack 24 hours Nephrotic syndrome 28 days Encephalitis or encephalopathy 28 days Oculomucocutaneous syndrome 28 days Other reactions Time frame in which the event (symptoms suspected to be associated with the vaccination was considered by the physician and either (1) requiring hospital admission or (2) resulting in, to be associated with the or associated with a risk of death or persistent incapacity) vaccination Except for “other reactions,” any event occurring within the specified time frame is subject to mandatory reporting to the MHLW regardless of causality under the PV Law and related rules. Adverse reactions or infections associated with voluntary vaccinations should be reported when reporting is considered necessary to prevent the occurrence and spread of health hazards. Refer to the following for specific cases subject to reporting. Adverse reactions and infections for which causality with vaccinations is unclear may also be subject to reporting. (1) Death (2) Disability (3) Events that may result in death (4) Events that may result in disability (5) Symptoms that require admission or prolonged hospitalization at medical institutions for treatment [excluding events in (3) and (4)] (6) Serious events corresponding to those in items (1) to (5) (7) Congenital diseases or anomalies in the next generation (8) Onset of infections suspected of being caused by use of the applicable pharmaceutical (9) Onset of unknown events which are not mild and could not be predicted based on the package insert, other than those listed in (1) to (8) This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 9 - 2 Revision of PRECAUTIONS for Non-steroidal Anti-inflammatory Drugs Regarding Myocardial Infarction and Cerebrovascular Disorder 1. Introduction Non-steroidal anti-inflammatory drugs (hereinafter referred to as "NSAIDs") are used for antipyretic, analgesic, and anti-inflammatory purposes in various diseases as prescription drugs, guidance-mandatory drugs, and over-the-counter drugs. To clarify the risk of myocardial infarction and cerebrovascular disorder in patients treated with NSAIDs for which systemic effects are expected, a pharmacoepidemiological study (hereinafter referred to as the "NDB study") was conducted using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (hereinafter referred to as "NDB"). As a result of reviewing the results of the NDB study including the opinions of expert advisors, the MHLW determined that it was necessary to call attention to myocardial infarction and cerebrovascular disorder in administration of NSAIDs for which systemic effects are expected, and instructed the MAHs to revise the PRECAUTIONS on October 8, 2024. The details of the review are described in this section. 2. Background In Europe and the United States, the product labeling includes precautions on the risk of myocardial infarction and cerebrovascular disorder as a class effect of NSAIDs excluding aspirin, based on the results of pharmacoepidemiological studies, etc. In Japan, precautions were included in the electronic package inserts for only some of the NSAIDs (celecoxib and diclofenac sodium), for which cases of myocardial infarction and cerebrovascular disorder had been reported, because the risks of myocardial infarction and cerebrovascular disorder had been reported to differ between Japanese and Western populations 1) and reference pharmacoepidemiological studies in Japanese population are limited. Thus, the status of precautions differed among NSAIDs. For this reason, the PMDA conducted the NDB study to clarify the risk of myocardial infarction and cerebrovascular disorder due to NSAIDs for which systemic effects are expected, and reviewed the necessity of taking safety measures for NSAIDs regarding myocardial infarction and cerebrovascular disorder. 3. Details of the review In the NDB study, a case-control study was conducted in patients with chronic diseases such as rheumatoid arthritis and osteoarthritis by matching patients with cardiovascular events (composite outcome of acute coronary syndrome, cerebral infarction, and cerebral haemorrhage) and patients without them using the claims data stored in the NDB between April 1, 2012 and March 31, 2020. The adjusted odds ratio (95% confidence interval) for cardiovascular events in the population who used NSAIDs in the past 14 days (hereinafter referred to as "NSAIDs-treated population") was 1.41 (1.36−1.46) for all NSAIDs in comparison with the population who did not use NSAIDs in the past 180 days (hereinafter referred to as "non-NSAIDs-treated population"), and the adjusted odds ratio (95% CI) for all NSAIDs was 1.24 (1.19−1.28) when aspirin, etc., for which evaluation in the NDB study was considered to be difficult, were excluded. Moreover, the point This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 10 - estimates of the adjusted odds ratios for each NSAID were mostly higher than 1.00 (Figure 1). As a result of evaluation by duration of use of NSAIDs, an increased risk of cardiovascular events was suggested also in the population of short-term use whose duration of use of NSAIDs was less than 30 days. Adjusted Odds Ratio1 2 (95% CI) Adjusted Odds Ratio1 2 3 Results for the use of multiple NSAIDs and those for NSAIDs for which marketing was discontinued or transitional measures were completed are not shown. 1 Estimated using a conditional logistic regression model 2 Adjusted with the matching pairs (age, sex, starting year of follow-up, and history of cardiovascular events) as stratification factors and with hypertension, diabetes mellitus, dyslipidaemia, arrhythmia, antiplatelet drugs, anticoagulant drugs, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, and rheumatoid arthritis as covariates 3 The adjusted odds ratio for aspirin is not shown. 4 Estimated using a contrast method 5 Aspirin and multiple use of NSAIDs Figure 1 Adjusted odds ratios for cardiovascular events in NSAIDs-treated population compared to non-NSAIDs-treated population The adjusted odds ratio (95% confidence interval) for aspirin was remarkably high at 20.47 (19.79−21.18). However, an additional analysis suggested that aspirin may have been prescribed to treat myocardial infarction or cerebrovascular disorder or to prevent the onset of myocardial infarction or cerebrovascular disorder in patients at high risk of onset. Based on this, the PMDA determined that it was not necessary to take safety measures for aspirin regarding myocardial infarction and cerebrovascular disorder at this point for the following reasons: It was considered to be difficult to evaluate the risk of myocardial infarction and cerebrovascular disorder due to aspirin based on the NDB study; no precautions for myocardial infarction and cerebrovascular disorder are included in the product labeling of aspirin in Europe and the United States. For details of the results of the NDB study, please refer to "Evaluation of the risk of cardiovascular events due to non-steroidal anti-inflammatory drugs using NDB." 2) The NDB study was conducted in patients with chronic diseases and did not include salicylic acid preparations, excluding aspirin, pyrazolone preparations, and alminoprofen, which is marketed only as an over-the-counter drug. The PMDA determined that it was not necessary to take safety measures for these drugs regarding myocardial infarction and cerebrovascular disorder at this point for the following reasons, with consideration given to the difficulty in concluding the risk of myocardial infarction and cerebrovascular disorder: There are no literature reports, etc. evaluating This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 11 - the risk of myocardial infarction and cerebrovascular disorder; these preparations are not marketed in Europe and the United States making it impossible to refer to measures taken by the regulatory agencies in Europe and the United States. Based on the above, the MHLW determined that it was necessary to add "myocardial infarction, cerebrovascular disorder" to the Clinically Significant Adverse Reactions section in the electronic package inserts for NSAIDs (excluding some drugs such as aspirin) for which systemic effects are expected, because an increased risk of myocardial infarction and cerebrovascular disorder was suggested. For preparations containing ibuprofen (oral dosage form), preparations containing naproxen, and preparations containing loxoprofen (oral dosage form), which are marketed as guidance-mandatory drugs and/or over-the-counter drugs, the MHLW determined that it was appropriate to add "myocardial infarction, cerebrovascular disorder" to the Consultation section in the package inserts as rare serious adverse reactions, similarly to the prescription drugs of NSAIDs. 4. Closing remark Healthcare professionals are requested to pay sufficient attention to the onset of myocardial infarction and cerebrovascular disorder related to prescription drugs, guidance-mandatory drugs, and over-the-counter drugs of NSAIDs as well as to take appropriate measures when symptoms or signs of myocardial infarction or cerebrovascular disorder are noted during administration of NSAIDs. Especially for guidance-mandatory drugs and over-the-counter drugs of NSAIDs, pharmacists and registered salesclerks are requested to inform consumers that myocardial infarction and cerebrovascular disorder may occur and that they should discontinue the use of the drug and consult a doctor immediately if symptoms indicating adverse reactions occur. [References] 1) JCS 2023 Guideline on the Primary Prevention of Coronary Artery Disease (edited by the Japanese Circulation Society, published on March 10, 2023) 2) Summary of Study Results Using National Database of Health Insurance Claims and Specific Health Checkup of Japan (NDB): https://www.pmda.go.jp/files/000270714.pdf (in Japanese) https://www.pmda.go.jp/files/000270715.pdf (in English) [Reference information] • Revision of PRECAUTIONS (PSB/PSD Notification No. 1008-1 dated October 8, 2024) https://www.pmda.go.jp/files/000271157.pdf (in Japanese) English translation by the PMDA (October 8, 2024) https://www.pmda.go.jp/english/safety/info-services/drugs/revision-of-precautions/0012.html (in English) • Studies conducted by the PMDA https://www.pmda.go.jp/safety/surveillance-analysis/0045.html (only in Japanese) • Food and Drug Administration. 2015. FDA strengthens warnings that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda- strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory • European Medicines Agency. 2012. Assessment report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and cardiovascular risk https://www.ema.europa.eu/en/documents/opinion-any-scientific-matter/assessment-report- article-53-procedure-non-steroidal-anti-inflammatory-drugs-nsaids-cardiovascular-risk_en.pdf This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 12 - 3 Revisions of PRECAUTIONS (No. 354) This section presents details of revisions to the PRECAUTIONS and brand names of drugs that have been revised in accordance with the Notifications dated October 8, 2024. 1 Antipyretics, analgesics and anti-inflammatory agents Aspirin (preparations indicated for antipyresis/analgesia/anti- inflammation) Brand name Aspirin "Maruishi" (Maruishi Pharmaceutical Co., Ltd.) and the others 9. PRECAUTIONS Pregnant women (excluding those within 12 weeks before due date) or CONCERNING women who may be pregnant PATIENTS WITH SPECIFIC If administration is deemed necessary, caution should be exercised BACKGROUNDS such as limiting the drug to the minimum effective use and checking 9.5 Pregnant Women amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors (preparations with expected systemic effects) in their second trimester of pregnancy. 2 Antipyretics, analgesics and anti-inflammatory agents [1] Acemetacin [2] Indometacin (suppositories) [3] Indometacin farnesil [4] Oxaprozin [5] Tiaramide hydrochloride [6] Proglumetacin maleate [7] Meloxicam Brand name [1] Rantudil Kowa Tablets 30 mg (Kowa Company, Ltd.) [2] Inteban Suppositories 25, 50 (Teikoku Seiyaku Co.,Ltd.), and the others [3] Infree Capsules 100 mg, Infree S Capsules 200 mg (Eisai Co., Ltd.) [4] Alvo tablets 100 mg, 200 mg (Taisho Pharmaceutical Co., Ltd.) [5] Solantal Tablets 50 mg, 100 mg (LTL Pharma Co.,Ltd.) [6] Miridacin tablets 90 mg (TAIHO Pharmaceutical Co., Ltd.) [7] Mobic Tablets 5 mg, 10 mg (Nippon Boehringer Ingelheim Co ., Ltd.) and the others 11. ADVERSE Myocardial infarction, cerebrovascular disorder REACTIONS Cardiovascular thromboembolic events including myocardial infarction and cerebrovascular disorder may occur. This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 13 - 11.1 Clinically Significant Adverse Reactions (newly added) 3 Antipyretics, analgesics and anti-inflammatory agents [1] Ampiroxicam [2] Ibuprofen [3] Etodolac [4] Naproxen [5] Piroxicam (oral dosage form) [6] Flurbiprofen (oral dosage form) [7] Flurbiprofen axetil [8] Loxoprofen sodium hydrate (oral dosage form) [9] Lornoxicam Brand name [1] Flucam Capsules 13.5 mg, 27 mg (Pfizer Japan Inc.) [2] Brufen Tablets 100, 200, Brufen Granule 20% (Kaken Pharmaceutical Co., Ltd.), and the others [3] Osteluc Tablets 100, 200 (Aska Pharmaceutical. Co., Ltd.), Hypen Tablets 100 mg, 200 mg (Nippon Shinyaku Co., Ltd.), and the others [4] Naixan Tablets 100 mg (Nipro ES Pharma Co., Ltd.) [5] Baxo Capsule 10, 20 (FUJIFILM Toyama Chemical Co., Ltd.) [6] Froben Tablets 40, Froben Granule 8% (Kaken Pharmaceutical Co., Ltd.) [7] Ropion Intravenous 50 mg (Kaken Pharmaceutical Co., Ltd.) [8] Loxonin Tablets 60 mg, Loxonin Fine Granules 10% (Daiichi Sankyo Co., Ltd.), and the others [9] Lorcam tab. 2 mg, 4 mg (Taisho Pharmaceutical Co., Ltd.), and the others 9. PRECAUTIONS Pregnant women (excluding the third trimester) or women who may be CONCERNING pregnant PATIENTS WITH This drug should be administered only when the therapeutic benefits SPECIFIC are considered to outweigh the risks. If administration is deemed BACKGROUNDS necessary, caution should be exercised such as limiting the drug to the 9.5 Pregnant Women minimum effective use and checking amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors (preparations with expected systemic effects) in their second trimester of pregnancy. 11. ADVERSE Myocardial infarction, cerebrovascular disorder REACTIONS Cardiovascular thromboembolic events including myocardial infarction 11.1 Clinically and cerebrovascular disorder may occur. Significant Adverse Reactions (newly added) This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 14 - 4 Antipyretics, analgesics and anti-inflammatory agents, Agents used for common cold [1] Isopropylantipyrine/acetaminophen/allylisopropylacetylurea/ anhydrous caffeine [2] Salicylamide/acetaminophen/anhydrous caffeine/ chlorpheniramine maleate [3] Salicylamide/acetaminophen/anhydrous caffeine/ promethazine methylenedisalicylate Brand name [1] SG Combination Granules (Shionogi Pharma Co., Ltd.) [2] Pelex combination granule (TAIHO Pharmaceutical Co., Ltd.) [3] PL Combination Granules (Shionogi Pharma Co., Ltd.) and the others 9. PRECAUTIONS Pregnant women or women who may be pregnant should be CONCERNING administered this drug only if the potential therapeutic benefits are PATIENTS WITH considered to outweigh the potential risks. If administration is deemed SPECIFIC necessary, caution should be exercised such as limiting the drug to the BACKGROUNDS minimum effective use and checking amniotic fluid volume and 9.5 Pregnant Women findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors in their second and/or third trimester of pregnancy with a higher risk known in women exposed to the drug in their third trimester. 5 Antipyretics, analgesics and anti-inflammatory agents [1] Ethenzamide [2] Sulpyrine hydrate Brand name [1] Ethenzamide "Yoshida" (Yoshida Pharmaceutical Company Limited) [2] Sulpyrine Injection 250 mg "NP” (Nipro Corporation) and the others 9. PRECAUTIONS Pregnant women or women who may be pregnant CONCERNING This drug should be administered only when the therapeutic benefits PATIENTS WITH are considered to outweigh the risks. If administration is deemed SPECIFIC necessary, caution should be exercised such as limiting the drug to the BACKGROUNDS minimum effective use and checking amniotic fluid volume and 9.5 Pregnant Women findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors in their second and/or third trimester of pregnancy with a higher risk known in women exposed to the drug in their third trimester. 6 Antipyretics, analgesics and anti-inflammatory agents This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 15 - Ketoprofen (injections, suppositories) Brand name Capisten IM 50 mg (Kissei Pharmaceutical Co., Ltd., Ketoprofen Suppositories 50 mg "JG", Ketoprofen Suppositories 75 mg "JG" (Choseido Pharmaceutical Co.,Ltd.), and the others 9. PRECAUTIONS Pregnant women (excluding the third trimester) or women who may CONCERNING be pregnant PATIENTS WITH This drug should be administered only when the therapeutic benefits SPECIFIC are considered to outweigh the risks. If administration is deemed BACKGROUNDS necessary, caution should be exercised such as limiting the drug to the 9.5 Pregnant Women minimum effective use and checking amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. It has been reported that oligohydramnios occurred in pregnant women who had been administered a dermatologic preparation of ketoprofen in their second trimester of pregnancy. In addition, renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors (preparations with expected systemic effects) in their second trimester of pregnancy. 11. ADVERSE Myocardial infarction, cerebrovascular disorder REACTIONS Cardiovascular thromboembolic events including myocardial infarction 11.1 Clinically and cerebrovascular disorder may occur. Significant Adverse Reactions (newly added) 7 Antipyretics, analgesics and anti-inflammatory agents Zaltoprofen Brand name Soleton Tablets 80 (Nippon Chemiphar Co., Ltd.), Peon tablets 80 (Zeria Pharmaceutical Co., Ltd.), and the others 9. PRECAUTIONS Pregnant women or women who may be pregnant CONCERNING This drug should be administered only if the potential therapeutic PATIENTS WITH benefits are considered to outweigh the potential risks. If SPECIFIC administration is deemed necessary, caution should be exercised such BACKGROUNDS as limiting the drug to the minimum effective use and checking 9.5 Pregnant Women amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors in their second and/or third trimester of pregnancy with a higher risk known in women exposed to the drug in their third trimester. 11. ADVERSE Myocardial infarction, cerebrovascular disorder REACTIONS Cardiovascular thromboembolic events including myocardial infarction 11.1 Clinically and cerebrovascular disorder may occur. Significant Adverse Reactions This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 16 - (newly added) 8 Antipyretics, analgesics and anti-inflammatory agents Dibucaine hydrocholoride/sodium salicylate/calcium bromide Brand name Neo Vitacain Injection 2 mL, 5 mL, Neo Vitacain Injection Syringe 2 mL, 5 mL (VITACAIN PHARMACEUTICAL Co., LTD.), and the others 9. PRECAUTIONS PATIENTS WITH Pregnant women or women who may be pregnant should be SPECIFIC administered this drug only if the potential therapeutic benefits are BACKGROUNDS considered to outweigh the potential risks. If administration is deemed 9.5 Pregnant Women necessary, caution should be exercised such as limiting the drug to the minimum effective use and checking amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in women who had been administered cyclooxygenase inhibitors in their second and/or third trimester of pregnancy with a higher risk known in women exposed to the drug in their third trimester. 9 Antipyretics, analgesics and anti-inflammatory agents Celecoxib Brand name Celecox Tablets 100 mg, 200 mg (Viatris Pharmaceuticals Japan Inc.), and the others 9. PRECAUTIONS Pregnant women (excluding the third trimester) or women who may be CONCERNING pregnant PATIENTS WITH This drug should be administered only when the therapeutic benefits SPECIFIC are considered to outweigh the risks. If administration is deemed BACKGROUNDS necessary, caution should be exercised such as limiting the drug to the 9.5 Pregnant Women minimum effective use and checking amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors (preparations with expected systemic effects) in their second trimester of pregnancy. 10 Antipyretics, analgesics and anti-inflammatory agents [1] Nabumetone [2] Bucolome [3] Mefenamic acid Brand name [1] Relifen Tab. 400 mg (Sanwa Kagaku Kenkyusho Co., Ltd) [2] Paramidin Capsules 300 mg (Aska Pharmaceutical. Co., Ltd.) [3] Pontal Capsules 250 mg, Pontal Powder 50%, Pontal Fine This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 17 - Granules 98.5%, Pontal Syrup 3.25% (Pfizer Japan Inc.) 9. PRECAUTIONS Pregnant women (excluding the third trimester) or women who may be CONCERNING pregnant PATIENTS WITH This drug should be administered only when the therapeutic benefits SPECIFIC are considered to outweigh the risks. If administration is deemed BACKGROUNDS necessary, caution should be exercised such as limiting the drug to the 9.5 Pregnant Women minimum effective use and checking amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors (preparations with expected systemic effects) in their second trimester of pregnancy. 11. ADVERSE Myocardial infarction, cerebrovascular disorder REACTIONS Cardiovascular thromboembolic events including myocardial infarction 11.1 Clinically and cerebrovascular disorder may occur. Significant Adverse Reactions (newly added) 11 Antipyretics, analgesics and anti-inflammatory agents Flufenamate aluminum Brand name Opyrin tab. 125 mg, 250 mg (Taisho Pharmaceutical Co., Ltd.) 9. PRECAUTIONS Pregnant women or women who may be pregnant should be CONCERNING administered this drug only if the potential therapeutic benefits are PATIENTS WITH considered to outweigh the potential risks. If administration is deemed SPECIFIC necessary, caution should be exercised such as limiting the drug to the BACKGROUNDS minimum effective use and checking amniotic fluid volume and 9.5 Pregnant Women findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors in their second and/or third trimester of pregnancy with a higher risk known in women exposed to the drug in their third trimester. 11. ADVERSE Myocardial infarction, cerebrovascular disorder REACTIONS Cardiovascular thromboembolic events including myocardial infarction 11.1 Clinically and cerebrovascular disorder may occur. Significant Adverse Reactions (newly added) 12 Analgesics, anti-itchings, astrigents and anti-inflammatory agents [1] Ibuprofen piconol [2] Indometacin (patches) [3] Diclofenac sodium (dermatologic preparation) This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 18 - [4] Piroxicam (dermatologic preparation) [5] Flurbiprofen (dermatologic preparation) [6] Loxoprofen sodium hydrate (dermatologic preparation) Brand name [1] Vesicum Ointment 5%, Vesicum Cream 5% (Hisamitsu Pharmaceutical Co., Inc.), Staderm Ointment 5%, Staderm Cream 5% (Torii Pharmaceutical Co., Ltd.) [2] Idomethine Kowa Gel 1%, Idomethine Kowa Sol 1%, Idomethine Kowa Cream 1%, Idomethine Kowa Pap (Kowa Company, Ltd.), Inteban Ointment 1%, Inteban Solution for Cutaneous Application, Inteban Cream 1% (Teikoku Seiyaku Co., Ltd.), Inside Pap 70 mg (Hisamitsu Pharmaceutical Co., Inc.), Catlep Pap 70 mg, Catlep Tape 35 mg, 70 mg (Teikoku Seiyaku Co., Ltd.), Intenurse Pap 70 mg (Toko Pharmaceutical industries Co., Ltd.), Aconip PAP 70 mg (Teika Pharmaceutical Co., Ltd.), Hapstar - ID 70 mg (Oishi Koseido Co., Ltd.), Laction Pap 70 mg (Teika Pharmaceutical Co., Ltd.), and the others [3] Voltaren Gel 1%, Voltaren Tape 15 mg, 30 mg, Voltaren Lotion 1% (DOJIN IYAKU-KAKO CO., LTD.), Naboal Gel 1%, Naboal Tape 15 mg, Naboal Tape L 30 mg, Naboal Pap 70 mg, 140 mg (Hisamitsu Pharmaceutical Co., Inc.), and the others [4] Baxo Ointment 0.5% (FUJIFILM Toyama Chemical Co., Ltd.), Feldene Ointment 0.5% (Pfizer Japan Inc.) [5] Zepolas Pap 40 mg, 80 mg, Zepolas Tape 20 mg, 40 mg (Mikasa Seiyaku co., ltd), Adofeed Pap 40 mg (LEAD CHEMICAL Co., Ltd.), Fulruban Pap 40 mg (Taikyo pharmaceutical co., ltd.), Yakuban tape 20 mg, 40 mg, 60 mg (TOKUHON Corporation), and the others [6] Loxonin Pap 100 mg, Loxonin Tape 50 mg, 100mg (LEAD CHEMICAL Co., Ltd.), Loxonin Gel 1% (Daiichi Sankyo Co., Ltd.), and the others 9. PRECAUTIONS Pregnant women or women who may be pregnant should be CONCERNING administered this drug only if the potential therapeutic benefits are PATIENTS WITH considered to outweigh the potential risks. It has been reported that SPECIFIC constriction of the foetal ductus arteriosus occurred in pregnant BACKGROUNDS women who had used cyclooxygenase inhibitors in their second and/or 9.5 Pregnant Women third trimester of pregnancy. In addition, renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. 13 Analgesics, anti-itchings, astrigents and anti-inflammatory agents Indometacin (topical preparations excluding patches) Brand name Idomethine Kowa Gel 1%, Idomethine Kowa Sol 1%, Idomethine Kowa Cream 1%, Idomethine Kowa Pap (Kowa Company, Ltd), Inteban Ointment 1%, Inteban Solution for Cutaneous Application, Inteban Cream 1% (Teikoku Seiyaku Co., Ltd.), Inside Pap 70 mg (Hisamitsu Pharmaceutical Co., Inc.), Catlep Pap 70 mg, Catlep Tape 35 mg, 70 mg (Teikoku Seiyaku Co., Ltd.), Intenurse Pap 70 mg (Toko Pharmaceutical industries Co., Ltd.), Aconip PAP 70 mg (Teika Pharmaceutical Co., Ltd.), Hapstar - ID 70 mg (Oishi Koseido Co., Ltd.), Laction Pap 70 mg (Teika Pharmaceutical Co., Ltd.), and the others 9. PRECAUTIONS Pregnant women or women who may be pregnant should be CONCERNING administered this drug only if the potential therapeutic benefits are This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 19 - PATIENTS WITH considered to outweigh the potential risks. Long-term treatment at a SPECIFIC high dose or with extensive administration should be avoided. It has BACKGROUNDS been reported that constriction of the foetal ductus arteriosus occurred 9.5 Pregnant Women in pregnant women who had used cyclooxygenase inhibitors in their second and/or third trimester of pregnancy. In addition, renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. 14 Analgesics, anti-itchings, astrigents and anti-inflammatory agents Esflurbiprofen/mentha oil Brand name Loqoa tape (Taisho Pharmaceutical Co., Ltd.) 9. PRECAUTIONS Pregnant women (excluding the third trimester) or women who may be CONCERNING pregnant PATIENTS WITH This drug should be administered only when the therapeutic benefits SPECIFIC are considered to outweigh the risks. If administration is deemed BACKGROUNDS necessary, caution should be exercised such as limiting the drug to the 9.5 Pregnant Women minimum effective use and checking amniotic fluid volume and findings suggestive of constriction of the foetal ductus arteriosus with consideration given to the gestational age and duration of administration as necessary. The safety of this drug administered during pregnancy has not been established. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in women who had been administered cyclooxygenase inhibitors (preparations with expected systemic effects) in their second trimester of pregnancy. 11. ADVERSE Myocardial infarction, cerebrovascular disorder REACTIONS Cardiovascular thromboembolic events including myocardial infarction 11.1 Clinically and cerebrovascular disorder may occur. Significant Adverse Reactions (newly added) 15 Analgesics, anti-itchings, astrigents and anti-inflammatory agents Ketoprofen (dermatologic preparation) Brand name Sector Gel 3%, Sector Lotion 3%, Sector Cream 3% (Hisamitsu Pharmaceutical Co., Inc.), Mohrus Pap 30 mg, 60 mg, Mohrus Tape 20 mg, Mohrus Tape L 40 mg, Mohrus Paps XR 120 mg, 240 mg (Hisamitsu Pharmaceutical Co., Inc.), Miltax Pap 30 mg (Nipro Pharma Corporation), and the others 9. PRECAUTIONS Pregnant women (excluding the third trimester) or women who may be CONCERNING pregnant PATIENTS WITH This drug should be administered only when the therapeutic benefits SPECIFIC are considered to outweigh the risks. Caution should be exercised BACKGROUNDS such as limiting the drug to the minimum effective use. It has been 9.5 Pregnant Women reported that oligohydramnios occurred in pregnant women who had used a dermatologic preparation of ketoprofen in their second trimester of pregnancy. In addition, renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 20 - have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had used cyclooxygenase inhibitors (preparations with expected systemic effects) in their second trimester of pregnancy. 16 Analgesics, anti-itchings, astrigents and anti-inflammatory agents, anti-dermoinfectives, emollients (including caustics) [1] Glycol salicylate/l-menthol [2] Methyl salicylate [3] Methyl salicylate/dl-camphor/capsicum extract [4] Methyl salicylate/dl-camphor/l-menthol [5] Methyl salicylate/l-menthol/dl-camphor/glycyrrhetinic acid [6] Felbinac [7] Heparinoid/adrenal extract/salicylic acid [8] Salicylic acid Brand name [1] GS PLASTER C “YUTOKU” (YUTOKU PHARMACEUTICAL IND. Co., LTD.) [2] Methyl Salicylate ”Toho” (Toho Pharmaceutical Co., Ltd.) [3] MS onshippu “TAIHO” (OKAYAMA TAIHO Pharmaceutical Co., Ltd.) and the others [4] MS reishippu “TAIHO” (OKAYAMA TAIHO Pharmaceutical Co., Ltd.) and the others [5] Stickzenol A (Mikasa Seiyaku co., ltd) [6] Napageln Ointment 3%, Napageln Lotion 3%, Napageln Cream 3% (Teikoku Seiyaku Co., Ltd.), Seltouch Pap 70, 140, Seltouch Tape 70 (Teikoku Seiyaku Co., Ltd.), and the others [7] Zestak Cream (Mikasa Seiyaku co., ltd) [8] 5% Salicylic Acid Ointment Toho, 10% Salicylic Acid Ointment Toho (Toho Pharmaceutical Co., Ltd.), and the others 9. PRECAUTIONS Pregnant women or women who may be pregnant should be CONCERNING administered this drug only if the potential therapeutic benefits are PATIENTS WITH considered to outweigh the potential risks. Renal impairment and SPECIFIC decreased urine output in foetuses as well as accompanying BACKGROUNDS oligohydramnios have been reported following use of cyclooxygenase 9.5 Pregnant Women inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred in pregnant women who had been administered cyclooxygenase inhibitors in their second and/or third trimester of pregnancy. 17 Agents affecting metabolism, n.e.c. (not elsewhere classified) Diclofenac etalhyaluronate sodium Brand name Joyclu 30 mg Intra-articular Injection (Seikagaku Corporation) 9. PRECAUTIONS Pregnant women or women who may be pregnant should be CONCERNING administered this drug only if the potential therapeutic benefits are PATIENTS WITH considered to outweigh the potential risks. Renal impairment and SPECIFIC decreased urine output in foetuses as well as accompanying BACKGROUNDS oligohydramnios have been reported following use of cyclooxygenase 9.5 Pregnant Women inhibitors (oral dosage form or suppository) in pregnant women. It has been reported that constriction of the foetal ductus arteriosus occurred This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 21 - in pregnant women who had been administered cyclooxygenase inhibitors in their second and/or third trimester of pregnancy. 18 Cold medicines, Antipyretics and analgesics [1] Preparations containing ibuprofen (OTC drugs) [2] Preparations containing naproxen (guidance-mandatory drugs) [3] Preparations containing loxoprofen sodium hydrate (oral dosage form) (OTC drugs, guidance-mandatory drugs) Brand name [1] Eve-A Tablets (SSP Co., Ltd.) and other OTC drugs, Pabron Ace Pro-X Granules (Taisho Pharmaceutical Co., Ltd.) and other OTC drugs [2] Motrin NX (JNTL Consumer Health K.K.) [3] Loxonin S (Daiichi Sankyo Healthcare Co., Ltd.) and other OTC drugs, Loxonin Common cold medicine (Daiichi Sankyo Healthcare Co., Ltd.) and other guidance-mandatory drugs Consultation If the following symptoms are observed after taking this drug, these (newly added) may be adverse reactions. In such cases, the use of this drug should be immediately discontinued, and a physician, dentist1), pharmacist or registered salesclerk2) should be consulted, presenting them with this document. The following serious symptoms may occur rarely. In such cases, medical attention should be sought immediately. Name of symptoms Symptoms Tight chest pain, difficulty breathing, and Myocardial infarction cold sweat may occur. Some symptoms such as decrease in consciousness/loss of consciousness, Cerebrovascular difficulty in moving unilateral extremities, disorder headache, vomiting, dizziness, difficulty speaking, and speech apraxia may occur suddenly. 1) “Dentist” should be listed only for antipyretics and analgesics. 2) ”Registered salesclerk” should be listed only for preparations containing ibuprofen. This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 22 - ４ List of Products Subject to Early Post-marketing Phase Vigilance Early Post-marketing Phase Vigilance (EPPV) was established in 2001. This unique system for newly-approved drug products refers to any safety assurance activities that are conducted within a period of 6 months just after marketing of a new drug. The MAH responsible for a new drug in the EPPV period is required to collect adverse drug reactions (ADRs) data from all medical institutions where the drug is used and to take safety measures as appropriate. The aim of EPPV is to promote the rational and appropriate use of drugs in medical treatments and to facilitate prompt action for the prevention of serious ADRs. EPPV is specified as a condition of product approval. (As of September 30, 2024) : Products for which EPPV was initiated after September 1, 2024 Nonproprietary name Name of the MAH Date of EPPV initiation Brand name Coronavirus (SARS-CoV-2) RNA Vaccine*1  Meiji Seika Pharma September 30, Kostaive intramuscular injection Co., Ltd. 2024 Brexpiprazole*2  Otsuka Pharmaceutical September 24, Rexulti tablets 1 mg, 2 mg, Rexulti OD tablets Co., Ltd. 2024 0.5 mg, 1 mg, 2 mg Treprostinil*3 Mochida  September 24, Pharmaceutical Co., Treprost Inhalation Solution 1.74 mg 2024 Ltd. Inactivated tissue culture tick-borne encephalitis vaccine  September 13, Ticovac suspension liquid for intramuscular Pfizer Japan Inc. 2024 injection 0.5 mL, Ticovac Junior suspension liquid for intramuscular injection 0.25 mL Freeze-dried human protein C concentrate  Takeda Pharmaceutical September 6, Ceprotin for Intravenous Injection 1000 IU Company Limited 2024 Pneumococcal 20-valent conjugate vaccine adsorbed (mutated diphtheria CRM197  August 30, conjugate)*4 Pfizer Japan Inc. 2024 Prevenar 20 Suspension Liquid for Injection Brivaracetam  August 30, Briviact Tablets 25 mg, 50 mg, Briviact for I.V. UCB Japan Co. Ltd. 2024 injection 25 mg Mepolizumab (genetical recombination)*5  August 28, GlaxoSmithKline K.K. Nucala solution for s.c. injection 100 mg 2024 Maribavir  Takeda Pharmaceutical August 28, Livtencity tablets 200 mg Company Limited 2024 Vilanterol trifenatate/fluticasone furoate  August 23, Relvar 50 Ellipta 14 doses for Pediatric, GlaxoSmithKline K.K. 2024 Relvar 50 Ellipta 30 doses for Pediatric Pirtobrutinib  August 21, Eli Lilly Japan K.K. Jaypirca Tablets 50 mg, 100 mg 2024 This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 23 - Nonproprietary name Name of the MAH Date of EPPV initiation Brand name Zinc histidine hydrate  August 20, Nobelpharma Co., Ltd. Zintus Tablets 50 mg 2024 Momelotinib hydrochloride hydrate  August 15, GlaxoSmithKline K.K. Omjjara Tablets 100 mg, 150 mg, 200 mg 2024 Iptacopan hydrochloride hydrate  August 15, Novartis Pharma K.K. Fabhalta capsules 200 mg 2024 Favipiravir*6  FUJIFILM Toyama August 15, Avigan Tablets 200 mg Chemical Co., Ltd. 2024 Sargramostim (genetical recombination)  July 29, Nobelpharma Co., Ltd. Sargmalin for inhalation 250 µg 2024 Fluciclovine (18F) Injection  Nihon Medi-Physics July 2, Axumin Injection Co., Ltd. 2024 Concizumab (genetical recombination)*7  Novo Nordisk Pharma June 24, Alhemo Subcutaneous Injection 15 mg, 60 Ltd. 2024 mg, 150 mg, 300 mg Vilanterol trifenatate/fluticasone furoate  June 24, GlaxoSmithKline K.K. Relvar 100 Ellipta 14 doses, 30 doses 2024 Zolbetuximab (genetical recombination)  June 12, Astellas Pharma Inc. Vyloy for I.V. infusion 100 mg 2024 Nemolizumab (genetical recombination)*8  June 11, Maruho Co., Ltd. Mitchga Vials 30 mg 2024 Susoctocog alfa (genetical recombination)  Takeda Pharmaceutical June 10, Obizur Intravenous Injection 500 Company Limited 2024 Recombinant respiratory syncytial virus  vaccine*9 May 31, Pfizer Japan Inc. 2024 Abrysvo intramuscular injection Lebrikizumab (genetical recombination)  Ebglyss Subcutaneous Injection Syringes May 31, Eli Lilly Japan K.K. 250 mg, Ebglyss Subcutaneous Injection 2024 Autoinjectors 250 mg Apadamtase alfa (genetical recombination)/  cinaxadamtase alfa (genetical recombination) Takeda Pharmaceutical May 30, Company Limited 2024 Adzynma Intravenous 1500 Cysteamine hydrochloride  Viatris Pharmaceuticals May 30, Cystadrops Ophthalmic Solution 0.38% Japan Inc. 2024 Lonafarnib  May 27, AnGes, Inc. Zokinvy capsules 50 mg, 75 mg 2024 Elranatamab (genetical recombination)  May 22, Pfizer Japan Inc. Elrexfio S.C. Injection 44 mg, 76 mg 2024 Capivasertib  May 22, AstraZeneca K.K. Truqap tablets 160 mg, 200 mg 2024 Nirsevimab (genetical recombination)  Beyfortus 50 mg solution for intramuscular May 22, AstraZeneca K.K. injection in syringe, Beyfortus 100 mg 2024 solution for intramuscular injection in syringe This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 24 - Nonproprietary name Name of the MAH Date of EPPV initiation Brand name Belumosudil mesilate  Meiji Seika Pharma May 22, Rezurock Tablets 200 mg Co., Ltd. 2024 Crovalimab (genetical recombination)  Chugai Pharmaceutical May 22, Piasky for Injection 340 mg Co., Ltd. 2024 Sacubitril valsartan sodium hydrate*10  May 22, Entresto Granules for Pediatric 12.5 mg, Novartis Pharma K.K. 2024 31.25 mg Luspatercept (genetical recombination)  Bristol-Myers Squibb May 20, Reblozyl for S.C. injection 25 mg, 75 mg K.K. 2024 Letermovir*11  May 17, Prevymis Tablets 240 mg, Prevymis MSD K.K. 2024 Intravenous Infusion 240 mg Talazoparib tosilate  April 23, Pfizer Japan Inc. Talzenna capsules 0.1 mg, 0.25 mg, 1 mg 2024 Evinacumab (genetical recombination)  April 17, Ultragenyx Japan K.K. Evkeeza for Intravenous Infusion 345 mg 2024 Danicopan  Alexion Pharma Godo April 17, Voydeya tablets 50 mg Kaisha 2024 Aflibercept (genetical recombination)  April 17, Bayer Yakuhin, Ltd. Eylea 8 mg solution for IVT inj. 114.3 mg/mL 2024 Efgartigimod alfa (genetical recombination)/ vorhyaluronidase alfa (genetical  recombination) April 17, argenx Japan K.K. 2024 Vyvdura Combination Subcutaneous Injection Perampanel hydrate  April 17, Eisai Co., Ltd. Fycompa for intravenous infusion 2 mg 2024 *1 Prevention of disease caused by SARS-CoV-2 infection (COVID-19) *2 Excessive motor activity or physically/verbally aggressive behavior due to rapid changes in mood, irritability, and/or outbursts associated with dementia due to Alzheimer's disease *3 Pulmonary hypertension associated with interstitial lung disease *4 Prophylaxis of pneumococcal disease (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V,10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F) in the elderly and individuals who are considered to be at high risk of pneumococcal disease *5 Chronic sinusitis with nasal polyps (for use only in patients who have not sufficiently responded to conventional treatments) *6 Severe fever with thrombocytopenia syndrome virus infection *7 Prevention of bleeding tendency in patients with congenital haemophilia who don’t have inhibitors against blood coagulation factor VIII or IX *8 Addition of a pediatric dosage indicated for the following diseases in patients who have not responded sufficiently to conventional treatments Pruritus associated with atopic dermatitis Prurigo nodularis *9 Prevention of infections caused by RS virus in individuals aged 60 years and older *10 Addition of a pediatric dosage indicated for chronic heart failure *11 Prophylaxis of cytomegalovirus infections in organ transplant recipients This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Pharmaceuticals and Medical Devices Safety Information No. 414 November 2024 - 25 -  Accessed November 2024.
9. Fabhalta^®. NMPA drug insert. Novartis Pharma Schweiz AG; 2024. Available from: https://www.ccfdie.org/en/gzdt/webinfo/2024/05/1716632195327630.html Accessed November 2024.
10. Dighriri IM, Al-Qahtani RM, Almutairi AO, et al. Iptacopan Efficacy and Safety to Treat Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Meta-Analysis. Cureus. 2024;16(8):e67830.
11. Novartis. Press release. Novartis receives FDA accelerated approval for Fabhalta® (iptacopan), the first and only complement inhibitor for the reduction of proteinuria in primary IgA nephropathy (IgAN). Available from: https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-fabhalta-iptacopan-first-and-only-complement-inhibitor-reduction-proteinuria-primary-iga-nephropathy-igan Accessed October, 2024.
12. Risitano AM, Araten DJ, Kuter D, et al. Pb2063: APPULSE-PNH: A phase IIIB trial to evaluate the efficacy and safety of switching to iptacopan in patients with paroxysmal nocturnal hemoglobinuria (PNH) on anti-c5 therapy with hemoglobin >10g/dl. Hemasphere. 2023;7(Suppl):e08587b7.
13. Cançado RD, Araújo ADS, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021;43(3):341-348.
14. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3:17028.
15. Röth A, Maciejewski J, Nishimura JI, Jain D, Weitz JI. Screening and diagnostic clinical algorithm for paroxysmal nocturnal hemoglobinuria: Expert consensus. Eur J Haematol. 2018;101(1):3-11.
16. Risitano AM, Marotta S, Ricci P, et al. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT. Front Immunol. 2019;10:1157.
17. Shammo et al. HemaSphere 2023 Shammo J, Kim J, Georget M, et al. P796: Hospitalization in patients with paroxysmal nocturnal hemoglobinuria: a retrospective analysis of observational study data from the United States. Hemasphere. 2023;7(Suppl):e22585a2.
18. Debureaux PE, Kulasekararaj AG, Cacace F, et al. Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: a multicenter real-life study. Bone Marrow Transplant. 2021;56(10):2600-2602.
19. Schrezenmeier H, Kulasekararaj A, Mitchell L, et al. One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study. Ther Adv Hematol. 2020;11:2040620720966137.
20. Young NS, Meyers G, Schrezenmeier H, Hillmen P, Hill A. The management of paroxysmal nocturnal hemoglobinuria: recent advances in diagnosis and treatment and new hope for patients. Semin Hematol. 2009;46(1 Suppl 1):S1-S16.

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