Iptacopan is an oral complement factor B inhibitor indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). The efficacy and safety of iptacopan in PNH was evaluated in 2 clinical trials. The Adult PNH Patients with Residual Anemia Despite Anti-C5 Antibody Treatment (APPLY-PNH) clinical trial was a multi-center, open-label, 24-week, active comparator-controlled trial. This trial enrolled adults with PNH and residual anemia (hemoglobin less than 10 g/dL) despite previous treatment with a stable regimen of anti-complement 5 (anti-C5) treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization. Efficacy was established based on demonstration of superiority of switching to iptacopan compared to continuing on anti-C5 therapy in achieving hematological response without a need for transfusion after 24 weeks of treatment. A sustained increase of hemoglobin concentrations of 2 g/dL or more from baseline in the absence of transfusions occurred in 82.3% (95% CI 70.5% to 90.8%) of iptacopan-treated subjects (n = 62) compared with 0% (95% CI 0% to 10%) of anti-C5-treated subjects (n = 35) for a between group adjusted difference in proportion of 81.5% (95% CI 71.6% to 91.4%; p less than 0.0001). Additionally, sustained hemoglobin concentrations of 12 g/dL or more in the absence of transfusions occurred in 67.7% (95% CI 54.7% to 79.1%) of iptacopan-treated subjects compared to 0% (95% CI 0% to 10%) of anti-C5-treated subjects for a between group adjusted difference in proportion of 66.6% (95% CI 54.6% to 78.6%; p less than 0.0001). The Adult PNH Patients who are Naive to Complement Inhibitor Therapy (APPOINT-PNH) clinical trial was a single arm clinical trial in adults with PNH who were not previously treated with a complement inhibitor. All subjects (n = 40) received treatment with iptacopan during the 24-week open label core treatment period. A sustained increase in hemoglobin concentrations of 2 g/dL or more from baseline in the absence of red blood cell transfusions occurred in 77.5% (95% CI 61.5% to 89.2%) of iptacopan-treated subjects between days 126 and 168. The use of iptacopan for PNH may predispose persons to serious, life-threatening, or fatal infections caused by encapsulated bacteria; vaccinate for these bacteria at least 2 weeks prior to treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Swallow capsules whole. Do not open, break, or chew capsules.
-Administer without regard to food.
-Missed dose: If a dose or doses are missed, administer 1 dose of iptacopan as soon as possible (even if it is soon before the next scheduled dose), and then resume the regular dosing schedule.
Iptacopan may predispose persons to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including S. pneumoniae, N. meningitidis (caused by any serogroup, including non-groupable strains), and H. influenzae type B. Serious infections may become rapidly life-threatening or fatal if not recognized and treated early. Closely monitor for early signs and symptoms of serious infection, and evaluate immediately if infection is suspected. Promptly treat known infections. Consider interruption of iptacopan in persons who are being treated for serious infections. Serious infections, including bacterial pneumonia, COVID-19, pyelonephritis, and urinary tract infection, were reported in 3% to 5% of iptacopan-treated subjects in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials. Bacterial infections (e.g., pyelonephritis, urinary tract infection, bacterial bronchitis, cholecystitis, folliculitis, cellulitis, bacterial arthritis, sepsis, Klebsiella, Pseudomonas, or staphylococcal infection, hordeolum, or bacterial pneumonia) were reported in 5% to 11% of iptacopan-treated subjects compared to 11% of eculizumab or ravulizumab-treated subjects in PNH clinical trials. Viral infection (e.g., COVID-19, herpes zoster, oral herpes, nasal herpes, or influenza) was reported in 10% to 18% of iptacopan-treated subjects compared to 31% of eculizumab or ravulizumab-treated subjects in PNH clinical trials. Naso-pharyngitis (e.g., allergic rhinitis, pharyngitis, rhinitis, or upper respiratory tract infection) was also reported in 15% to 16% of iptacopan-treated subjects compared to 17% of eculizumab or ravulizumab-treated subjects in PNH clinical trials.
Iptacopan increases total cholesterol, low-density lipoprotein (LDL) cholesterol, and serum triglycerides. Monitor serum lipid parameters periodically during treatment with iptacopan and initiate cholesterol-lowering medication, if indicated. Lipid disorder (e.g., dyslipidemia, hypercholesterolemia, hyperlipidemia, increased blood cholesterol, increased LDL cholesterol, or increased blood triglycerides) was reported in 6% to 8% of iptacopan-treated subjects compared to 0% of eculizumab or ravulizumab-treated subjects in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials. Of the 54 iptacopan-treated subjects who had a normal total cholesterol at baseline, 43% developed grade 1 hyperlipidemia during the randomized treatment period in a clinical trial. Hyperlipidemia that worsened to grade 2 from grade 1 at baseline occurred in a single patient. Of the 60 iptacopan-treated subjects who had an LDL cholesterol concentration of 130 mg/dL or less at baseline, 17% developed LDL cholesterol more than 130 to 160 mg/dL, 8% developed LDL cholesterol more than 160 to 190 mg/dL, and 7% developed LDL cholesterol more than 190 mg/dL. Grade 1 hypertriglyceridemia was reported in 23% of iptacopan-treated subjects who had a normal triglyceride concentration at baseline; an increase in triglycerides from grade 1 to grade 2 was reported in 3 iptacopan-treated subjects in this clinical trial. In another clinical trial, of the 34 iptacopan-treated subjects who had a normal total cholesterol concentration at baseline, 24% developed grade 1 hyperlipidemia during the core treatment period. Of the 36 iptacopan-treated subjects who had an LDL-cholesterol concentration of 130 mg/dL or less at baseline, 11% developed LDL cholesterol more than 130 to 160 mg/dL and 3% developed LDL cholesterol 160 to 190 mg/dL. Grade 1 hypertriglyceridemia was reported in 27% of iptacopan-treated subjects who had a normal triglyceride concentration at baseline in this clinical trial. Some persons required cholesterol-lowering medications.
Headache was reported in 19% to 28% of iptacopan-treated subjects in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials compared to 3% of eculizumab or ravulizumab-treated subjects. Dizziness was reported in 3% to 6% of iptacopan-treated subjects compared to 0% of eculizumab or ravulizumab-treated subjects.
Hypertension was reported in up to 6% of iptacopan-treated subjects compared to 0% of eculizumab or ravulizumab-treated subjects in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials.
Abdominal pain (8% to 15%), diarrhea (8% to 15%), and nausea (5% to 10%) were reported in iptacopan-treated subjects more frequently compared to eculizumab or ravulizumab-treated subjects (3%, 6%, and 3%, respectively) in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials.
Arthralgia was reported in up to 8% of iptacopan-treated subjects compared to 3% of eculizumab and ravulizumab-treated subjects in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials.
Rash (e.g., acneiform rash, allergic dermatitis, erythema multiforme, erythematous rash, or maculopapular rash) was reported in 3% to 10% of iptacopan-treated subjects compared to 0% of eculizumab or ravulizumab-treated subjects in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials. Urticaria was reported in 3% of iptacopan-treated subjects.
Thrombocytopenia was reported in up to 6% of iptacopan-treated subjects compared to 0% of eculizumab or ravulizumab-treated subjects in paroxysmal nocturnal hemoglobinuria (PNH) clinical trials. Of 37 iptacopan-treated subjects with normal platelet counts at baseline, 43% experienced any grade thrombocytopenia during the randomized treatment period; 3 iptacopan-treated subjects developed thrombocytopenia that worsened to grade or 3 or more from baseline (1 patient with normal platelet count at baseline worsened to grade 4; 1 patient with baseline grade 1 worsened to grade 4; and 1 patient with baseline grade 3 worsened to Grade 4).
Iptacopan is contraindicated in persons with serious hypersensitivity to iptacopan or any of the excipients.
Iptacopan is contraindicated in persons with unresolved encapsulated bacteria infection, including infections caused by S. pneumoniae, N. meningitidis (caused by any serogroup, including non-groupable strains), and H. influenzae type B. The use of iptacopan may predispose persons to serious, life-threatening, or fatal infections caused by encapsulated bacteria. Vaccinate for encapsulated bacteria according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for persons receiving a complement inhibitor. Note that ACIP recommends an administration schedule in persons receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of iptacopan. Revaccinate persons in accordance with ACIP recommendations considering the duration of iptacopan therapy. If urgent iptacopan therapy is indicated in persons who are not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide antibacterial medication prophylaxis and administer vaccines as soon as possible. Various durations and regimens of antibacterial medication prophylaxis have been considered; however, the optimal durations and medication regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated persons receiving complement inhibitors, including iptacopan. The benefits and risks of treatment with iptacopan in addition to the benefits and risk of antibacterial medication prophylaxis in vaccinated or unvaccinated persons must be considered against the known risk for serious infections caused by encapsulated bacteria. Vaccination reduces, but does not eliminate, the risk of serious encapsulated bacterial infections. Closely monitor for early signs and symptoms of serious infection, and evaluate immediately if infection is suspected. Promptly treat known infections. Consider interruption of iptacopan in persons who are being treated for serious infections. Serious infections may become rapidly life-threatening or fatal if not recognized and treated early.
Iptacopan is not recommended for use in persons with severe hepatic disease (Child-Pugh class C).
Iptacopan is not recommended for use in persons with severe renal impairment (eGFR less than 30 mL/minute/1.73m2) with or without dialysis.
The use of iptacopan in pregnancy or those planning to become pregnant may be considered after an assessment of the risks and benefits. Available data from clinical trials with iptacopan use in pregnancy 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 paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy. 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. In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures of 4 to 6 times the human exposure at the maximum recommended human dose (MRHD) did not induce embryo or fetal toxicity.
Discontinue breast-feeding during iptacopan treatment and for 5 days after the final dose since many medications are secreted in human milk and due to the potential for serious adverse reactions in a breast-fed child. There are no data on the presence of iptacopan or its metabolite in either human or animal milk, the effects on the breast-fed child, or on milk production.
General Dosing Information
-Vaccinate against encapsulated bacteria, including S. pneumoniae and N. meningitidis, at least 2 weeks prior to initiation of iptacopan therapy.
-Provide antibacterial medication prophylaxis if iptacopan must be initiated immediately and vaccines are administered less than 2 weeks before iptacopan initiation.
-Conversion from eculizumab: Start iptacopan no later than 1 week after the last dose of eculizumab.
-Conversion from ravulizumab: Start iptacopan no later than 6 weeks after the last dose of ravulizumab.
For the treatment of paroxysmal nocturnal hemoglobinuria (PNH):
NOTE: Iptacopan is designated as an orphan drug by the FDA for this indication.
Oral dosage:
Adults: 200 mg PO twice daily.
Therapeutic Drug Monitoring:
-After discontinuing treatment with iptacopan, closely monitor for signs and symptoms of hemolysis for at least 2 weeks after the last dose. If hemolysis occurs after discontinuation of iptacopan, consider restarting treatment with iptacopan or initiating another treatment for paroxysmal nocturnal hemoglobinuria (PNH). Consider alternative therapy if iptacopan discontinuation is necessary.
-Signs of hemolysis include elevated lactate dehydrogenase (LDH) concentrations and a sudden decrease in hemoglobin or PNH clone size, fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (e.g., thrombosis, stroke, and myocardial infarction), dysphagia, or erectile dysfunction.
Maximum Dosage Limits:
-Adults
400 mg/day PO.
-Geriatric
400 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Iptacopan is not recommended for use in persons with severe hepatic impairment (Child-Pugh class C). No dosage adjustment is necessary for persons with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.
Patients with Renal Impairment Dosing
Iptacopan is not recommended for use in persons with severe renal impairment (eGFR less than 30 mL/minute/1.73m2) with or without hemodialysis. No dosage adjustment is necessary in persons with mild (eGFR 60 to less than 90 mL/minute/1.73m2) or moderate (eGFR 30 to less than 60 mL/minute/1.73m2) renal impairment.
*non-FDA-approved indication
Carbamazepine: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and carbamazepine; discontinue use of carbamazepine if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and carbamazepine is a CYP2C8 inducer.
Gemfibrozil: (Major) Avoid concomitant use of iptacopan and gemfibrozil due to the risk for increased iptacopan exposure which may increase the risk for adverse effects. Iptacopan is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and rifampin; discontinue use of rifampin if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and rifampin is a CYP2C8 inducer.
Isoniazid, INH; Rifampin: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and rifampin; discontinue use of rifampin if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and rifampin is a CYP2C8 inducer.
Meropenem: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and meropenem; discontinue use of meropenem if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and meropenem is a CYP2C8 inducer.
Meropenem; Vaborbactam: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and meropenem; discontinue use of meropenem if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and meropenem is a CYP2C8 inducer.
Omaveloxolone: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and omaveloxolone; discontinue use of omaveloxolone if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and omaveloxolone is a CYP2C8 inducer.
Rifampin: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and rifampin; discontinue use of rifampin if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and rifampin is a CYP2C8 inducer.
Rifapentine: (Moderate) Monitor for a decrease in iptacopan efficacy during concomitant use of iptacopan and rifapentine; discontinue use of rifapentine if loss of efficacy of iptacopan is evident. Concomitant use may decrease iptacopan exposure. Iptacopan is a CYP2C8 substrate and rifapentine is a CYP2C8 inducer.
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. Intravascular hemolysis (IVH) in paroxysmal hemoglobinuria (PNH) is mediated by the downstream membrane attack complex 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.
Iptacopan is administered orally. Iptacopan is 75% to 93% protein bound in vitro and displays concentration-dependent plasma protein binding to the target factor B in the systemic circulation. The apparent steady-state Vd is approximately 288 L after administration of iptacopan 200 mg twice daily. Metabolism is the 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. CYP2C8 is the major hepatic isozyme responsible for iptacopan metabolism (98%) with a small contribution from CYP2D6 (2%). Phase 2 metabolism of iptacopan occurs through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan accounts for 83% of the medication-related species and inactive metabolites (2 acyl glucuronides) account for 8% and 5% of the medication-related species. After a single radiolabeled dose of iptacopan 100 mg, mean total excretion of radioactivity was 71.5% in feces and 24.8% in the urine, for a total mean excretion of more than 96% of the dose. Iptacopan clearance at steady-state is 7.96 L/hour and the half-life of iptacopan at steady-state is approximately 25 hours after administration of iptacopan 200 mg twice daily. Iptacopan displays non-linear pharmacokinetics at doses between 25 and 200 mg twice daily and linear pharmacokinetics at doses between 100 and 200 mg.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8, CYP2D6, UGT1A1, UGT1A3, and UGT1A8
Iptacopan is a CYP2C8, CYP2D6, UGT1A1, UGT1A3, and UGT1A8 substrate. Metabolism of iptacopan is mostly driven by CYP2C8 with a minor contribution from CYP2D6.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, iptacopan reaches peak plasma concentrations (Tmax) approximately 2 hours post dose. Steady-state is achieved in approximately 5 days with minor accumulation (1.4-fold) at the recommended dosage of 200 mg twice daily. A high-fat meal does not have a clinically significant effect on the exposure of iptacopan. Inhibition of complement pathway biomarkers [in vitro alternative pathway assay and plasma Bb (fragment Bb of factor B)] started approximately 2 hours after a single iptacopan dose in healthy volunteers. In paroxysmal nocturnal hemoglobinemia (PNH) subjects receiving concomitant anti-complement 5 (anti-C5) treatment and iptacopan 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 day of observation (day 8). 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 disposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment-naive PNH subjects, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with iptacopan 200 mg twice daily. The mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks. Additionally, there were negligible PNH type II + III RBCs with C3 disposition in this population due to the predominance of intravascular hemolysis. In PNH subjects previously treated with eculizumab, all subjects treated with iptacopan 200 mg twice daily achieved a reduction in LDH concentrations to less than 1.5 times the upper limit of normal (ULN) at 13 weeks. In treatment-naive PNH subjects, iptacopan 200 mg twice daily decreased LDH by more than 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years.
-Special Populations
Hepatic Impairment
There was a negligible effect of hepatic impairment on the total (bound and unbound) exposure of iptacopan. However, unbound iptacopan exposure increased by 1.5, 1.6, and 3.7-fold in persons with mild (Child-Pugh class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) hepatic impairment, respectively, compared to persons with normal hepatic function.
Renal Impairment
There were no clinically significant differences in the exposure of iptacopan between persons with normal renal function and persons with mild renal impairment (eGFR 60 to less than 90 mL/minute/1.73m2) or moderate renal impairment (eGFR 30 to less than 60 mL/minute/1.73m2). The population pharmacokinetic analysis did not include a sufficient number of persons with severe renal impairment with or without hemodialysis.
Geriatric
No significant differences in iptacopan pharmacokinetics were observed based on age.
Gender Differences
No significant differences in iptacopan pharmacokinetics were observed based on gender.
Ethnic Differences
No significant differences in iptacopan pharmacokinetics were observed based on race.
Obesity
No significant differences in iptacopan pharmacokinetics were observed based on body weight.