iptacopan (Fabhalta)

Indications

• treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).

Contraindications

• not recommended with severe renal impairment or severe hepatic impairment

Dosage

• 200 mg PO BID with or without food.

Capsules: 200 mg (3)

Pharmacokinetics

• peak plasma concentrations in ~2 hours
• 1/2life of 25 hours
• steady state level reached in 5 days
• clearance is 8 liters/hour at steady state concentration
• absorption not affected by high fat meals
• protein binding 75-93%
• volume of distribution 288 liters
• metabolism by CYP2C8 via N-dealkylation, O-deethylation, oxidation, & dehydrogenation with phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, & UGT1A8
• iptacopan is major component in plasma (83%)
• no active metabolites

Monitor

• monitor for hemolysis after discontinuation

Adverse effects

• > 10%
  • headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection*, viral infection, nausea and rash
• no effect on QTc interval

* serious & life-threatening infections caused by encapsulated bacteria, including

• Streptococcus pneumoniae, Neisseria meningitidis, & Haemophilus influenzae type B

Drug interactions

• CYP2C8 inducers (rifampin) reduces plasma levels of iptacopan

Mechanism of action

• complement factor B inhibitor
  • regulates cleavage of complement C3, generation of downstream effectors, & amplification of the terminal pathway.

Notes

• available only through a restricted program under a Risk Evaluation & Mitigation Strategy (REMS) called FABHALTA REMS.

More general terms

• hematologic agent

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=90467622
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=117823351
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=156613702