FABHALTA Capsule Ref.[107283] Active ingredients: Iptacopan

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.

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.

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 or online at www.FABHALTA-REMS.com.

5.3 Monitoring of PNH Manifestations After FABHALTA Discontinuation

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 increases total cholesterol, LDL-cholesterol, and serum triglycerides.

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-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.

Some patients required cholesterol-lowering medications.

Monitor serum lipid parameters periodically during treatment with FABHALTA and initiate cholesterol-lowering medication, if indicated.

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)]

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

The data described below reflects the exposure in adults with PNH who received FABHALTA (n=62) or anti-C5 treatment (US-approved and non-US-approved eculizumab product or US-approved and non-US-approved ravulizumab product, n=35) in APPLY-PNH [NCT04558918] and adults who received FABHALTA (n=40) in APPOINT-PNH [NCT04820530] at the recommended dosing regimen for 24 weeks. In APPLY-PNH, serious adverse reactions were reported in 2 (3%) patients with PNH receiving FABHALTA. Serious adverse reactions included pyelonephritis, urinary tract infection and COVID-19. In APPOINT-PNH, serious adverse reactions were reported in 2 (5%) patients with PNH receiving FABHALTA. Serious adverse reactions included COVID-19 and bacterial pneumonia. The most common adverse reactions (≥10%) with FABHALTA were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash.

Table 1 describes the adverse reactions that occurred in >5% of patients treated with FABHALTA in the APPLY-PNH or APPOINT-PNH studies.

Table 1. Adverse Reactions Reported in >5% of Patients Treated with FABHALTA in APPLY-PNH or APPOINT-PNH Studies (24-Week Treatment Period):

^a Includes similar terms.
^b Nasopharyngitis contains: rhinitis allergic, upper respiratory tract infection, pharyngitis, rhinitis.
^c Bacterial infection contains: pyelonephritis, urinary tract infection, bronchitis bacterial, bronchitis haemophilus, cholecystitis, folliculitis, cellulitis, arthritis bacterial, sepsis, klebsiella infection, staphylococcal infection, Pseudomonas infection, hordeolum, pneumonia bacterial.
^d Viral infection contains: COVID-19, herpes zoster, oral herpes, nasal herpes, influenza A virus test positive, influenza.
^e Lipid Disorder contains: dyslipidemia, blood cholesterol increased, low density lipoprotein increased, hypercholesterolemia, blood triglycerides increased, hyperlipidemia.
^f Rash contains: dermatitis allergic, acne, erythema multiforme, rash maculo-papular, rash erythematous.

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).

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.

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 in pregnancy (see Clinical Considerations). The use of FABHALTA in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits.

In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4 to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Consideration

Disease-Associated Maternal and/or Embryo/Fetal Risk

PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.

Data

Animal Data

In an embryo-fetal development study in rats, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC.

In an embryo-fetal development study in rabbits, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 450 mg/kg/day, which corresponds to 6-times the MRHD based on AUC.

In a pre- and postnatal development study in rats, oral administration of iptacopan during gestation, parturition, and lactation did not cause adverse effects in offspring when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC.

Risk Summary

There are no data on the presence of iptacopan or its metabolite in either human or animal milk, the effects on the breastfed child or on milk production. Since many medicinal products are secreted into human milk, and because of the potential for serious adverse reactions in a breastfed child, breastfeeding should be discontinued during treatment and for 5 days after the final dose.

Safety and effectiveness in pediatric patients with PNH have not been established.

There were 29 PNH patients 65 years of age and older in APPLY-PNH and APPOINT-PNH [see Clinical Studies (14)]. Of the total number of FABHALTA-treated patients during the 24-week treatment period in these studies, 21 (20.6%) were 65 years of age and older, while 7 (6.9%) were 75 years of age and older. Clinical studies of FABHALTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

The use of FABHALTA is not recommended in patients with severe renal impairment (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²) with or without hemodialysis. No dose adjustment is required in patients with mild (eGFR 60 to <90 mL/min/1.73 m²) or moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment [see Clinical Pharmacology (12.3)].

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)].