Iptacopan (Monograph)

Brand name: Fabhalta
Drug class: Complement Inhibitors

Introduction

Iptacopan hydrochloride is a complement factor B inhibitor.

Uses for Iptacopan

Iptacopan hydrochloride has the following uses:

Iptacopan is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).

Iptacopan Dosage and Administration

General

Iptacopan hydrochloride is available in the following dosage form(s) and strength(s):

Capsules: 200 mg (of iptacopan)

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Recommended dosage is 200 mg orally twice daily with or without food.

See Full Prescribing Information for recommendations on switching from anti-C5 therapy (eculizumab, ravulizumab) to iptacopan.

Cautions for Iptacopan

Contraindications

• Serious hypersensitivity to iptacopan or any of the excipients.

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

Warnings/Precautions

Serious Infections Caused by Encapsulated Bacteria

Iptacopan hydrochloride, 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 iptacopan 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 iptacopan, 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 iptacopan. 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 iptacopan 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 iptacopan. The benefits and risks of treatment with iptacopan, 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 iptacopan in patients who are undergoing treatment for serious infections.

REMS

Iptacopan is available only through a restricted program under a REMS called Fabhalta REMS, because of the risk of serious infections caused by encapsulated bacteria.

Notable requirements of the REMS program 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 2 weeks prior to the first dose of iptacopan.

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 2 weeks prior to the first dose of iptacopan.

Pharmacies that dispense iptacopan must be certified in the REMS program 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 iptacopan.

Further information is available by telephone: 1-833-99FABHA or online at www.FABHALTA-REMS.com.

Monitoring of PNH Manifestations after Iptacopan Discontinuation

After discontinuing treatment with iptacopan, 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 iptacopan is necessary, consider alternative therapy.

If hemolysis occurs after discontinuation of iptacopan, consider restarting treatment with the drug, if appropriate, or initiating another treatment for PNH.

Hyperlipidemia

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

Of the 54 iptacopan-treated patients who had a normal total cholesterol level at baseline in the APPLY-PNH study, 43% developed Grade 1 hypercholesterolemia during the randomized treatment period. One iptacopan-treated patient in APPLY-PNH experienced increased total cholesterol that worsened to Grade 2 from Grade 1 at baseline.

Of the 34 iptacopan-treated patients who had a normal cholesterol level at baseline in the APPOINT-PNH study, 24% developed Grade 1 hypercholesterolemia during the core treatment period.

Of the 60 iptacopan-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 iptacopan-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 iptacopan-treated patients in APPLY-PNH experienced an increase in triglycerides from Grade 1 to Grade 2.

Of the 37 iptacopan-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 iptacopan and initiate cholesterol-lowering medication, if indicated.

Specific Populations

Pregnancy

Available data from clinical trials with iptacopan 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. The use of iptacopan 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.

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.

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.

Lactation

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.

Pediatric Use

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

Geriatric Use

There were 29 PNH patients 65 years of age and older in the APPLY-PNH and APPOINT-PNH studies. Of the total number of iptacopan-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 iptacopan did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently from younger subjects.

Renal Impairment

The use of iptacopan 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.

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.

Common Adverse Effects

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

Related/similar drugs

Tarpeyo, Empaveli, Ultomiris, Soliris, eculizumab, Fabhalta, ravulizumab

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

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

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

Actions

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.

Advice to Patients

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

• 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 iptacopan or receive antibacterial drug prophylaxis if 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 iptacopan therapy.

• Inform patients that vaccination may not prevent serious infection and to seek immediate medical attention if the following signs or symptoms occur: fever with or without shivers or chills; fever and a rash; fever with chest pain and cough; fever with breathlessness/fast breathing; fever with high heart rate; headache with nausea or vomiting; headache and a fever; headache with a stiff neck or stiff back; confusion; body aches with flu-like symptoms; clammy skin; eyes sensitive to light.

• Inform patients that they will be given a Patient Safety Card for iptacopan that they should carry with them at all times during and for 2 weeks following treatment with the drug. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation.

• Iptacopan is available only through a restricted program called Fabhalta REMS. Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria. Patients must receive written educational materials about this risk.

• Inform patients with PNH of the importance of taking iptacopan as prescribed in order to minimize the risk of hemolysis.

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

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

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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