GILTERITINIB Drug Interactions: What You Need to Know

INTERACTIONS

• Combined P-gp and Strong CYP3A Inducers: Avoid concomitant use. ( 7.1 )
• Strong CYP3A Inhibitors: Consider alternative therapies. If the concomitant use of strong CYP3A inhibitors cannot be avoided, monitor patients more frequently for XOSPATA adverse reactions. ( 2.3 , 7.1 )
• P-gp, BCRP, OCT1 Substrates: Decrease the dose of the substrates when coadministered with gilteritinib and as clinically indicated. ( 7.2 )

7.1 Effect of Other Drugs on XOSPATA Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases gilteritinib exposure which may decrease XOSPATA efficacy <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers. Strong CYP3A Inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases gilteritinib exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

7.2 Effect of XOSPATA on Other Drugs Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor Concomitant use of gilteritinib may reduce the effects of drugs that target the 5HT 2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . P-gp, BCRP, and OCT1 Substrates Based on in vitro data, gilteritinib is a P-gp, breast cancer resistant protein (BCRP), and organic cation transporter 1 (OCT1) inhibitor. Coadministration of gilteritinib may increase the exposure of P-gp, BCRP, and OCT1 substrates, which may increase the incidence and severity of adverse reactions of these substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. For P-gp, BCRP, or OCT1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such substrate and monitor for adverse reactions as recommended in the respective prescribing information.

XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials [see Adverse Reactions ( 6 ) and Description ( 11 )] . Hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials. ( 4 , 6.1 )

AND PRECAUTIONS

• Posterior reversible encephalopathy syndrome (PRES): Discontinue XOSPATA in patients who develop PRES. ( 2.3 , 5.2 , 6.1 )
• Prolonged QT Interval: Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration. ( 2.3 , 5.3 , 12.2 , 6.1 )
• Pancreatitis: Interrupt and reduce the dose in patients who develop pancreatitis. ( 2.3 , 5.4 )
• Embryo-Fetal Toxicity: XOSPATA can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )

5.1 Differentiation Syndrome Of 319 patients treated with XOSPATA in the clinical trials, 3% experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and other clinical findings of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 1 day and up to 82 days after XOSPATA initiation and has been observed with or without concomitant leukocytosis. Of the 11 patients who experienced differentiation syndrome, 9 (82%) recovered after treatment or after dose interruption of XOSPATA. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

5.2 Posterior Reversible Encephalopathy Syndrome Of 319 patients treated with XOSPATA in the clinical trials, 1% experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XOSPATA in patients who develop PRES <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ) and Adverse Reactions ( 6.1 )]</span> .

5.3 Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). Of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial, 1% were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF &gt;500 msec <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ) and Clinical Pharmacology ( 12.2 )]</span> . Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

5.4 Pancreatitis Of 319 patients treated with XOSPATA in the clinical trials, 4% experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

5.5 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of gilteritinib to pregnant rats during organogenesis caused embryo-fetal lethality, suppressed fetal growth and teratogenicity at maternal exposures (AUC 24 ) approximately 0.4 times the AUC 24 in patients receiving the recommended dose. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )]</span> .