Iptacopan Hydrochloride (Monograph)

Brand name: Fabhalta
Drug class: Complement Inhibitor Agents

Medically reviewed by Drugs.com on Jan 10, 2025. Written by ASHP.

[Web]

Introduction

Complement factor B inhibitor.

Uses for Iptacopan Hydrochloride

Paroxysmal Nocturnal Hemoglobinuria

Treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH); designated an orphan drug by FDA for this use.

Treatment options for PNH include supportive care, complement blockade (including anti-C5 monoclonal antibodies and complement inhibitors), and allogeneic hematopoietic stem cell transplant. Only curative treatment to date is stem cell transplantation.

Immunoglobulin A Nephropathy

Used to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio ≥1.5 g/g.

Granted accelerated approval for this indication based on proteinuria reduction; not established whether iptacopan 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.

Treatment of IgAN includes supportive care, lifestyle modifications (exercise, weight control, smoking cessation, restriction of alcohol intake, dietary sodium restriction) for BP control, and interventions to reduce cardiovascular risk; pharmacotherapy may include an ACE inhibitor or angiotensin receptor blocker (ARB), and/or immunosuppressive therapy. Specific place in therapy for iptacopan not yet established.

Iptacopan Hydrochloride Dosage and Administration

General

Pretreatment Screening

• Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y, and B), according to the current ACIP recommendations, at least 2 weeks prior to initiation.

• If urgent therapy is indicated in a patient not up to date with these vaccines, provide antibacterial drug prophylaxis and administer vaccines as soon as possible.

Patient Monitoring

• Comply with the most current ACIP recommendations for vaccinations against encapsulated bacteria.

• Consider interruption in patients undergoing treatment for serious infections.

• Closely monitor for early signs and symptoms of serious infection and evaluate immediately if an infection suspected.

• Monitor serum lipid parameters periodically and initiate cholesterol-lowering medication, if needed.

REMS

• Because of the risk of serious infections caused by encapsulated bacteria, iptacopan is only available through a restricted distribution program (Fabhalta REMS).

• Healthcare providers and pharmacies must be certified with the Fabhalta REMS program before they can prescribe or dispense iptacopan.

• Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria and provide patients with 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 at least 2 weeks prior to the first dose of iptacopan.

• 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.

• Information about the Fabhalta REMS program is available at 833-993-2242 or at [Web].

Administration

Administer orally twice daily as capsules.

Swallow capsules whole without regard to food. Do not open, break, or chew capsules.

If a dose is missed, take the dose as soon as possible (even if soon before next scheduled dose) and then resume regular dosing schedule.

Dosage

Available as iptacopan hydrochloride monohydrate; dosage expressed in terms of iptacopan.

Adults

Paroxysmal Nocturnal Hemoglobinuria

Oral

200 mg twice daily.

Transitioning from Anti-C5 Therapies to Iptacopan

To reduce potential risk of hemolysis with abrupt discontinuation of other PNH therapies, the following is recommended.

When switching from eculizumab to iptacopan, initiate iptacopan no later than 1 week after last dose of eculizumab.

When switching from ravulizumab to iptacopan, initiate iptacopan no later than 6 weeks after last dose of ravulizumab.

No available information regarding timeframe for initiation of iptacopan after other PNH therapies.

Immunoglobulin A Nephropathy

Oral

200 mg twice daily.

Special Populations

Hepatic Impairment

No dosage adjustment required in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Not recommended in severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Iptacopan Hydrochloride

Contraindications

• Serious hypersensitivity to iptacopan or any of the excipients.

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

Warnings/Precautions

Warnings

Serious Infection Caused by Encapsulated Bacteria

Iptacopan increases susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, includingStreptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type B. Life-threatening and fatal infections have occurred in both vaccinated and unvaccinated patients (see Boxed Warning).

Initiation of treatment 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 first dose according to the current ACIP recommendations. Recommended ACIP vaccine administration schedule in patients receiving complement inhibitors differs from vaccine prescribing information.

If urgent therapy is indicated in patients not up-to-date with vaccines, provide antibacterial drug prophylaxis and administer vaccines as soon as possible. Optimal durations and regimens for antibacterial drug prophylaxis in unvaccinated or vaccinated patients receiving complement inhibitors not known. Consider benefits and risks of treatment, as well as benefits and risks of antibacterial drug prophylaxis against known risks for serious infections caused by encapsulated bacteria.

Vaccination does not eliminate risk of serious infections. Closely monitor for early signs and symptoms of serious infection and evaluate immediately if infection is suspected.

Inform patients of signs and symptoms of infection and to seek immediate medical care if these 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 undergoing treatment for serious infections.

Other Warnings and Precautions

Monitoring of PNH Manifestations After Iptacopan Discontinuation

After discontinuing treatment in patients with PNH, closely monitor patients for at least 2 weeks after last dose for signs and symptoms of hemolysis. This includes elevated LDH levels along with 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 is necessary, consider alternative therapy.

If hemolysis occurs after discontinuation, consider restarting treatment, if appropriate, or initiating another treatment for PNH.

Hyperlipidemia

Increased total cholesterol, LDL-cholesterol, and serum triglycerides reported.

Some patients required cholesterol-lowering medications.

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

Specific Populations

Pregnancy

Insufficient evidence in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to mother and fetus associated with untreated PNH and IgAN in pregnancy. Risks include adverse maternal outcomes of worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes including death and premature delivery.

Use in pregnant women or women planning to become pregnant may be considered following assessment of risks and benefits.

Lactation

No data on the presence of iptacopan or metabolites in human milk, effects on the breast-fed child, or effects on milk production. Since many drugs are distributed into human milk, and because of potential for serious adverse reactions in a breast-fed child, discontinue breastfeeding during treatment and for 5 days after final dose.

Pediatric Use

Safety and effectiveness in pediatric patients not established.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger patients.

Hepatic Impairment

Not recommended in severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No clinically relevant differences in exposure to iptacopan between patients with an eGFR of 25 to <90 mL/minute per 1.73 m² and those with normal eGFR. Pharmacokinetics of iptacopan in patients on hemodialysis not known.

Common Adverse Effects

Most common adverse effects (≥10%) in PNH: headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, rash.

Most common adverse effects (≥5%) in IgAN: upper respiratory tract infection, lipid disorder, abdominal pain.

Drug Interactions

Substrate and inhibitor of CYP2C8. Not a substrate or inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP3A4/5.

Substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, organic anion transporter polypeptide (OATP) 1B1, OATP1B3, and P-glycoprotein (P-gp). Inhibits multidrug and toxin extrusion (MATE) 1, organic anion transporter (OAT) 3, OATP1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, and P-gp.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use of CYP2C8 inducers may decrease iptacopan exposure, which may result in loss of or reduced efficacy of iptacopan. Monitor clinical response and discontinue use of CYP2C8 inducer if loss of efficacy of iptacopan is evident.

Concomitant use of strong CYP2C8 inhibitors may increase iptacopan exposure, which may result in an increased risk of adverse reactions. Coadministration with a strong CYP2C8 inhibitor not recommended.

Specific Drugs

Iptacopan Hydrochloride Pharmacokinetics

Absorption

Onset

Time to peak plasma concentration (T_max): 2 hours.

Effect of Food

High-fat meal does not affect exposure to clinically meaningful degree.

Distribution

Plasma Protein Binding

Concentration-dependent due to binding target Factor B in systemic circulation; 75% to 93%.

Elimination

Metabolism

Approximately 50% metabolized via oxidative pathways; includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (99%) and CYP2D6 (1%).

Undergoes Phase 2 metabolism through glucuronidation by uridine diphosphate-glucuronosyl transferase (UGT) 1A1, UGT1A3, and UGT1A8.

Two acyl glucuronides metabolites detected in plasma (8% and 5% of drug related species); not pharmacologically active.

Elimination Route

Excreted in feces (71.5%, 16.8% as parent drug) and urine (24.8%, 17.9% as parent drug), for total mean excretion >96%.

Half-life

Approximately 25 hours.

Special Populations

No clinically relevant differences in exposure between normal renal function compared to mild (eGFR 60 to <90 mL/minute per 1.73 m²) or moderate (eGFR 30 to <60 mL/minute per 1.72 m²) renal impairment. Pharmacokinetics in severe renal impairment (eGFR <30 mL/minute per 1.73 m²) with or without hemodialysis not known.

Negligible effects of hepatic impairment on total (bound and unbound) exposure between normal hepatic function and mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment.

Age, body weight, race, and gender do not have a clinically significant effect on pharmacokinetics.

Stability

Storage

Oral

Capsules

Store at 20-25°C; excursions permitted between 15-30°C.

Actions

• Complement factor B inhibitor.

• In PNH, intravascular hemolysis mediated by downstream membrane attack complex, while extravascular hemolysis facilitated by C3 opsonization.

• Binds to factor B of the alternative complement pathway and regulates the cleavage of C3, the generation of downstream effectors, and the amplification of the terminal pathway.

• Acts proximally in alternative pathway of complement cascade to control both C3b-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis.

• In IgAN, deposition of galactose deficient IgA1-containing immune complexes in the kidney locally activates the alternative complement pathway; binding of iptacopan to Factor B inhibits alternative pathway effect.

Advice to Patients

• Advise the patient and/or caregiver 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 iptacopan treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current Advisory Committee on Immunization Practices (ACIP) recommendations for encapsulated bacteria while on iptacopan therapy.

• Inform patients that vaccinations may not prevent serious infection and to seek immediate medical attention if the following signs and symptoms of infection occur: fever with or without shaking or chills; fever with rash; fever with chest pain and cough; fever with breathlessness or fast breathing; fever with high heart rate; headache with nausea or vomiting; headache with fever; headache with stiff neck or 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. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation.

• Inform patients that iptacopan is available only through a restricted program called FabhaltaREMS. Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria and must receive written educational materials about this risk.

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

• Inform patients with PNH that they may develop serious hemolysis if iptacopan is discontinued and that they should be monitored by their clinicians for at least 2 weeks following discontinuation of iptacopan. Inform patients who discontinue iptacopan to keep the Patient Safety Card with them for 2 weeks after the last dose. The increased risk of serious infection may continue for a few weeks after the last dose.

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

• Advise patients to inform their clinician if they are or plan to become pregnant or if they plan to breast-feed. Breastfeeding should be discontinued during treatment and for 5 days after the final dose of iptacopan.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Iptacopan is obtained through designated specialty pharmacies and distributors that are certified through the Fabhalta REMS (see REMS Program under Dosage and Administration). Contact manufacturer or consult the iptacopan website ([Web]) for specific availability information.

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