Gilteritinib instructions

1. Generic name:Giritinib fumarate tablets

Product name:Xikatan(XOSPATA)

All names:Giritinib,Giritinib,Giritinib,Giritinib,XOSPATA,GITELI

2. Indications: Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutations detected by an FDA-approved test.

3. Usage and dosage:

The recommended starting dose is 120 mg once daily with or without food, and in the absence of disease progression or unacceptable toxicity, treatment is recommended for at least 6 months to achieve clinical response.

4. Dosage Form and Strength

Tablet: 40mg.

Five. Contraindications

Allergic to GIRItinib or any excipients. Anaphylaxis has been observed in clinical trials.

6. Warnings and Precautions

1.Posterior reversible encephalopathy syndrome

Among the 319patients who receivedgiritinibin clinical trials,1%Posterior reversible encephalopathy syndrome(PRES) has developed,symptoms include seizures and mental status changes. GiritinibThe symptoms were relieved after stopping the drug. The diagnosis of PRES needs to be confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Geritinib should be discontinued in patients who develop PRES.

2.Interval prolongation

Giritinib is associated with prolonged ventricular repolarization (QT interval). In clinical trials, 317patients receiving giritinib had QTcmeasurements after baseline and found that 1%of patientsQTcInterval greater than 500ms, 7% of patientsQTc increased by more than 60ms from baseline. Electrocardiograms(ECG) were performed before initiating giltinib treatment on days 8 and 15 of cycle 1 and at the beginning of the next two cycles. For patients with QTcF >500ms, interrupt and reduce XOSPATAdose. Hypokalemia or hypomagnesemia may increase the risk of QT interval prolongation. XOSPATACorrect hypokalemia or hypomagnesemia before and during administration.

3.Pancreatitis

Of 319 patients who received geritinib in clinical trials, 4% developed pancreatitis. Evaluate patients who develop symptoms and signs of pancreatitis and interrupt and reduce the dose of geritinib in patients with pancreatitis.

4.Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, geritinib can cause embryo-fetal damage when given to pregnant women. In animal reproduction studies, administration of geritinib to pregnant rats during organogenesis resulted in embryogenesis-Fetal death, fetal growth inhibition, and maternal exposure teratogenicity(AUC24)approximately 0.4 times the AUC in patients receiving recommended doses. Advise women of childbearing potential to use effective contraception during treatment with geritinib and for 6 months after the last dose of geritinib. Advise men who are partners of a female of reproductive potential to use effective contraception during treatment with giritinib and for 4 months after the last dose of XOSPATA. Pregnant women, patients who become pregnant while receivinggiritinibtreatment, or male patients who have a pregnant female partner should be informed of the potential risk to the fetus.

7. Adverse reactions

The most common adverse reactions (≥20%)are elevated transaminases, myalgia, arthralgia, fatigue and discomfort, fever, mucositis, edema, rash, non-infectious diarrhea, dyspnea, nausea, cough, constipation, eye disease, headache, dizziness, hypotension, vomiting and renal damage.

8. drug interactions

1.CombinedP-gpand strongCYP3A inducer

Use of gilitinib with combinations of P-gpand strong CYP3A inducers may reduce gilitinib exposure which may reduce XOSPATA efficacy. Avoid the concomitant use of XOSPATAwith combinedP-gpand strongCYP3A inducers.

2.StrongCYP3Ainhibitor

Concomitant use of gilitinibwithstrong CYP3Ainhibitors may increase gilitinib exposure. Consider alternative therapies that are not strongCYP3Ainhibitors. If concomitant use of these inhibitors is deemed critical to the patient's care, patients should be monitored more frequently for XOSPATA adverse reactions. Interrupt and reduce the dose of XOSPATA in patients with severe or life-threatening toxicity.

3.Drugs targeting5HT2B receptors or Sigma non-specific receptors

Concomitant use of Gritinib may reduce the effect of drugs that target5HT2B receptors or< span>σNon-specific receptors(such as escitalopram, fluoxetine, sertraline). Avoid using these drugs withXOSPATA concurrently.

4.P-gp, BCRP and OCT1substrate

Based on in vitro data, giritinib is an inhibitor of P-gp, breast cancer resistance protein (BCRP) and organic cation transporter 1 (OCT1). Coadministration with giritinib may increase exposure to P-gp, BCRP, and OCT1 substrates, which may increase the incidence and severity of adverse reactions with these substrates. For P-gp, BCRP or OCT1 substrates, if small concentration changes may lead to serious adverse reactions, the dose of such substrates should be reduced or the frequency of dosing should be modified as recommended in the corresponding prescribing information, and adverse reactions should be monitored.

clinical pharmacology

1.Mechanism of action

Gi Ruitinib is a small molecule that inhibits multiple receptor tyrosine kinases, includingFMSlike tyrosine kinase3 (FLT3). Giritinibdemonstrated exogenous expressionFLT3 (includingFLT3-ITD, tyrosine kinase domain mutation(TKD) The ability of FLT3-D835Y and FLT3-ITD-D835Y) inhibits FLT3 receptor signaling and proliferation, and it induces apoptosis in leukemia cells expressing FLT3-ITD.

2.Pharmacodynamics

While receiving120 mg吉RuiIn patients with relapsed or refractory AML treated with AML, FLT3phosphorylation was significantly (> 90%)The inhibitory effect is rapid(within 24 hours) after the first dose and is characterized by the in vitro plasma inhibitory activity(PIA)measurement.

3.Pharmacokinetics

Unless otherwise stated, the following pharmacokinetic parameters were observed following dosing of 120 mg of Gilatinib once daily. In patients with relapsed or refractory AML, the once-daily dose ranges from 20 mg to 450 mg (0.17 to 3.75 times), G Rutinib exposure (Cmax and AUC24) increased proportionally. The mean (SD)steady-state Cmax of giltinib was 374 ng/mL ( 190), and the AUC24 was 6943 ng HR/mL(3221). Steady-state plasma levels are reached within 15 days after administration, and the accumulation is approximately 10 times.

Absorption:

In the fasted state, the observed time to reach maximum geritinib concentrations(tmax) was approximately 4 to 6 hours after dosing.

Metabolism:

Gi Ruitinib is mainly metabolized in the test tube throughCYP3A4. Under steady state, the main metabolites in the human body include M17 ( formed through N-dealkylation and oxidation< span>), M16 and M10( all passedN-Dealkylation forms ). None of these 3 metabolites exceeded 10% of the total maternal exposure.

10. Used by specific groups of people

Lactation period:It is recommended that women not breastfeed.

Pediatrics;Safety and effectiveness in pediatric patients have not been established.

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