What are the precautions for giritinib?

In the clinical research of Gilteritinib, warnings and precautions such as differentiation syndrome, posterior reversible encephalopathy syndrome,QT interval prolongation, pancreatitis, embryo-fetal toxicity have emerged. Discontinue and resume at reduced dose upon recovery, or permanently discontinue based on severity.

1. Differentiation syndrome: It is related to the rapid proliferation and differentiation of bone marrow cells. If not treated, it may be life-threatening or fatal. Symptoms and other clinical manifestations of differentiation syndrome in patients treated with geritinib include fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases have been associated with acute febrile neutrophilic dermatosis, occurring as early as 1 to 82 days after initiation of drug therapy, and have been observed with or without leukocytosis.

If differentiation syndrome is suspected, administer dexamethasone 10 mg intravenously every every 12 hours (or an equivalent dose of an alternative oral or intravenous corticosteroid) and monitor hemodynamics until improvement. Taper corticosteroids after symptoms resolve and administer corticosteroids for at least 3 days. Symptoms of differentiation syndrome may return with premature discontinuation of corticosteroid therapy. If severe signs and/or symptoms persist for more than 48 hours after starting corticosteroids, interrupt giritinib until signs and symptoms are no longer severe.

2. Posterior reversible encephalopathy syndrome (PRES): Symptoms include seizures and mental status changes. Symptoms disappeared after discontinuation of geritinib. The diagnosis of PRES needs to be confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue geritinib in patients who develop PRES.

3. QT interval prolongation: Hypokalemia or hypomagnesemia can increase the risk of QT prolongation. Correct hypokalemia or hypomagnesemia before and during administration of giritinib. Patients had electrocardiograms performed before starting treatment with giritinib on days 8 and 15 of cycle 1 and before the start of the next two cycles. Interrupt and reduce geritinib dose in patients with QTcF >500 msec. Resume the 80 mg dose of gilitinib when the QTc interval returns to within 30 milliseconds of baseline or ≤480 milliseconds.

4. Pancreatitis: Among patients treated with giritinib in clinical trials, 4% experienced pancreatitis. Evaluate patients presenting with signs and symptoms of pancreatitis. Interrupt and reduce the dose of progeritinib in patients with pancreatitis, consider a dose reduction to80 mg.

5. Embryo-Fetotoxicity: Based on the results of animal studies and its mechanism of action, geritinib can cause harm to embryos when administered to pregnant women. In animal reproduction studies, administration of gilitinib to pregnant rats during organogenesis resulted in embryonic-fetal lethality, inhibition of fetal growth, and teratogenicity upon maternal exposure (AUC24) that was approximately 0.4 times the AUC24 in patients receiving the recommended dose.

Pregnant women, patients who become pregnant while receiving giritinib, or male patients with a pregnant female partner should be informed of the potential risk to the fetus. Therefore, it is recommended that females of childbearing potential use effective contraception during treatment with giritinib and for 6 months after the last dose of the drug; male and female partners of childbearing potential are advised to use effective contraception during treatment with giritinib and for 4 months after the last dose of the drug.