Fabhalta (iptacopan HCl)
Complement Inhibitors Oral Capsule
Last reviewed · Source: First Databank (FDB) drug data
Overview
Iptacopan hydrochloride is a complement factor B inhibitor.
Iptacopan 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. In paroxysmal nocturnal hemoglobinuria (PNH), intravascular hemolysis is mediated by the downstream membrane attack complex, while extravascular hemolysis is facilitated by C3 opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis.
In patients with immunoglobulin A nephropathy (IgAN), the deposition of galactose deficient IgA1 containing immune complexes in the kidney locally activates the alternative complement pathway; the binding of iptacopan to Factor B inhibits the effect of the alternative pathway. In patients with complement 3 glomerulopathy (C3G), overactivation of the alternative complement pathway leads to C3 cleavage within the glomeruli resulting in C3 deposition and inflammation. Iptacopan binds to Factor B thus inhibiting the alternative pathway in this condition.
Inhibition of the alternative complement pathway biomarkers, in vitro alternative pathway assay and plasma Bb (fragment Bb of Factor B), starts approximately 2 hours after a single iptacopan dose. Following oral administration, iptacopan reaches peak plasma concentrations approximately 2 hours post dose. At the recommended dosage of 200 mg twice daily, steady state is achieved in approximately 5 days with minor accumulation (1.4-fold).
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. Iptacopan shows concentration-dependent plasma protein binding due to binding to target Factor B in systemic circulation. Iptacopan was 75% to 93% protein bound in vitro at the relevant clinical plasma concentrations.
The half-life of iptacopan at steady state is approximately 25 hours 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, mostly driven by cytochrome P-450 (CYP) 2C8 (99%) with a small contribution from CYP2D6 (1%).
Iptacopan undergoes Phase 2 metabolism through glucuronidation by uridine diphosphate-glucuronosyl transferase (UGT) 1A1, UGT1A3, and UGT1A8. Two acyl glucuronides are the only metabolites detected in the plasma and are minor, accounting for 8% and 5% of the drug related species; iptacopan metabolites are not pharmacologically active. Iptacopan and its metabolites are excreted in the feces (71.5%, 16.8% as parent drug) and urine (24.8%, 17.9% as parent drug), for a total mean excretion >96% of the dose.
Age, body weight, race, and gender did not have a clinically significant effect on iptacopan pharmacokinetics.
USES: Iptacopan is used to treat a certain blood disorder (paroxysmal nocturnal hemoglobinuria - PNH). This disorder causes your body's immune system to break down red blood cells, which results in anemia. Iptacopan works by helping to block the body's breakdown of red blood cells.
This effect helps lessen symptoms of anemia (such as tiredness, shortness of breath) and may reduce the need for blood transfusions. This medication is also used to treat certain kidney problems (such as primary immunoglobulin A nephropathy - IgAN, complement 3 glomerulopathy - C3G). Iptacopan helps lower levels of protein in the urine.
In people with IgAN, it may also help slow the worsening of kidney disease.
Generic name: iptacopan HCl
Pronunciation: (IP-ta-KOE-pan)
Drug class: Complement Inhibitors
Therapeutic class: Hematological Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Fabhalta
Indications
The following indications are listed for Fabhalta:
- Complement Component 3 Glomerulopathy
- Immunoglobulin A Nephropathy
- Paroxysmal Nocturnal Hemoglobinuria
Also known as: Berger's Disease, Iga Nephropathy.
Dosing
Available as iptacopan hydrochloride monohydrate; dosage expressed in terms of iptacopan.
Iptacopan is administered orally twice daily as capsules.
Swallow iptacopan capsules whole without regard to food. Do not open, break, or chew the capsules.
If a dose of iptacopan is missed, advise the patient to take the dose as soon as possible (even if it is soon before the next scheduled dose) and then resume the regular dosing schedule.
Store iptacopan capsules at 20-25degreesC with excursions permitted between 15--30oC.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Fabhalta 200 Mg Capsule | Maintenance | Take 1 capsule (200 mg) by oral route 2 times per day. |
No dosing information is available for this tab.
Drug interactions
Iptacopan is a substrate and inhibitor of cytochrome P-450 (CYP) 2C8. Iptacopan is not a substrate or inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP3A4/5.
Iptacopan is a substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, organic anion transporter polypeptide (OATP) 1B1, OATP1B3, and P-glycoprotein (P-gp). Iptacopan inhibits multidrug and toxin extrusion (MATE) 1, organic anion transporter (OAT) 3, OATP1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, and P-gp.
There are no contraindication interactions for this drug.
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Iptacopan/Strong Cyp2c8 Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of iptacopan.(1)
CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP2C8 may result in elevated levels of and clinical effects of iptacopan, including the risk of serious infections caused by encapsulated bacteria and hyperlipidemia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of iptacopan states that concomitant administration of strong CYP2C8 inhibitors is not recommended.(1)
DISCUSSION: No studies have been done evaluating the effects of strong CYP2C8 inhibitors on iptacopan. A Phase 1 drug-drug interaction study with clopidogrel 300 mg x 1 then 75 mg daily (moderate CYP2C8 inhibitor) in healthy volunteers demonstrated no clinically relevant effects on the plasma pharmacokinetics of iptacopan 100 mg daily. In the presence of clopidogrel, the geometric mean maximum concentration (Cmax) of iptacopan increased by 5% and the area-under-curve (AUC) increased by 36%.(2) Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)
There are no moderate interactions for this drug.
Contraindications
*Serious hypersensitivity to iptacopan or any of the excipients.
*Initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type B.
- Lactation
- Meningococcal meningitis
- Meningococcemia
- Infection
- Hyperlipidemia
Adverse reactions
The most common adverse effects of iptacopan (>=10% of patients) reported in clinical studies in adults with PNH include headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash.
The most common adverse effects of iptacopan (>=5% of patients) reported in clinical studies in adults with IgAN include upper respiratory tract infection, lipid disorder, and abdominal pain.
The most common adverse effects of iptacopan (>=10% of patients) reported in clinical studies in adults with C3G include nasopharyngitis and viral infections.
More Frequent
- Bacterial infection
- Viral infection
Less Frequent
- COVId-19
- Pyelonephritis
- Urinary tract infection
Rare or Very Rare
- Bacteremia
- Pneumonia
More Frequent
- Acute abdominal pain
- Allergic rhinitis
- Diarrhea
- Headache disorder
- Nausea
- Pharyngitis
- Rhinitis
- Skin rash
- Upper respiratory infection
Less Frequent
- Arthralgia
- Dizziness
- Hypertension
- Thrombocytopenic disorder
- Urticaria
Precautions
No enhanced messaging available.
Safety and effectiveness of iptacopan in pediatric patients have not been established.
There is insufficient evidence with iptacopan in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH, IgAN, and complement 3 glomerulopathy (C3G) in pregnancy. These risks include adverse maternal outcomes of worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes including death and premature delivery. The use of iptacopan in pregnant women or women planning to become pregnant may be considered following an assessment of 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. In a pre- and postnatal development study in rats, oral administration of iptacopan during gestation, parturition, and lactation did not cause adverse effects in the offspring when given up to the highest dosage of 1,000 mg/kg per day, which corresponds to 4-times the MRHD based on AUC.
There are no data on the presence of iptacopan or its metabolite in human milk, the effects on the breast-fed child, or the effects on milk production. Since many drugs are distributed into human milk, and because of the potential for serious adverse reactions in the breast-fed child, breastfeeding should be discontinued during treatment and for 5 days after the final dose.
The manufacturer makes no specific dosage recommendations for geriatric patients.
Clinical studies with iptacopan did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger patients. There were 29 PNH patients >=65 years of age in the APPLY-PNH and APPOINT-PNH trials. 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. In the APPLAUSE-IgAN trial, there were 8 patients with IgAN who were >=65 years of age. Of the total number of iptacopan-treated patients during the trial, 3 (2.4%) were 65 years of age and older.
ICD codes
| Code | Type | Description |
|---|---|---|
| Complement component 3 glomerulopathy | ||
| N04.6 | ICD10CM | Nephrotic syndrome with dense deposit disease |
| N04.A | ICD10CM | Nephrotic syndrome with c3 glomerulonephritis |
| Immunoglobulin A nephropathy | ||
| N02.B9 | ICD10CM | Other recurrent and persistent immunoglobulin A nephropathy |
| Paroxysmal nocturnal hemoglobinuria | ||
| D59.5 | ICD10CM | Paroxysmal nocturnal hemoglobinuria [marchiafava-micheli] |
ICD code information from First Databank (FDB).
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Last reviewed · Source: First Databank (FDB) drug data
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