DRUG INTERACTIONS 

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 

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. 

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 

2 Effect of XOSPATA on Other Drugs Drugs that Target 5HT2B Receptor or non Sigma specific Receptor                                                                                       Concomitant use of gilteritinib may reduce the effects of drugs that target the 5HT2B 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 

BRIEF SUMMARY

GILTERINIB- (Nov 2018)

Indn-          To treat patients who have relapsed or refractory acute   myeloid leukemia (AML)

Comp-      Tablet: 40 mg.    120 mg orally once-daily. 

ADR-         The most common adverse reactions (=20%) were myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness and vomiting. 

CI-    ­ Hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials. (

 WARNINGS-

­ • Posterior reversible encephalopathy syndrome (PRES):                             Discontinue XOSPATA in patients who develop PRES. 

Pat Infm-                                                                                                                     Posterior Reversible Encephalopathy Syndrome -    Advise patients of the risk of developing posterior reversible encephalopathy syndrome (PRES).

Ask patients to immediately report any symptoms suggestive of PRES, such as seizure and altered mental status, to their healthcare provider for further evaluation

===============================================================

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  55

ADVERSE REACTIONS

The most common adverse reactions (=20%) were myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness and vomiting. 

 CONTRAINDICATIONS

­ Hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials. (4, 6.1) 

 WARNINGS AND PRECAUTIONS

­ • Posterior reversible encephalopathy syndrome (PRES):                             Discontinue XOSPATA in patients who develop PRES. 

• 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. 

• Pancreatitis:                                                                                                          Interrupt and reduce the dose in patients who develop pancreatitis. 

• 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. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Posterior Reversible Encephalopathy Syndrome      

Advise patients of the risk of developing posterior reversible encephalopathy syndrome (PRES).

Ask patients to immediately report any symptoms suggestive of PRES, such as seizure and altered mental status, to their healthcare provider for further evaluation

Prolonged QT Interval                                                                                                 Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. 

Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes 

Pancreatitis                                                                                                                Advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis, which include severe and persistent stomach pain, with or without nausea and vomiting 

Use of Contraceptives                                                                                                         • Advise female patients with reproductive potential to use effective contraceptive methods while receiving XOSPATA and to avoid pregnancy while on treatment and for 6 months after completion of treatment.

• Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during XOSPATA treatment.

• Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA 

Lactation                                                                                                                        Advise women not to breastfeed during treatment with XOSPATA for at least 2 months after the final dose 

Dosing Instructions                                                                                                            • Advise patients not to break, crush or chew the tablets but to swallow them whole with a cup of water.

• Instruct patients that, if they miss a dose of XOSPATA, to take it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose, and return to the normal schedule the following day. Instruct patients to not take 2 doses within 12 hours 

Distributed by:

Astellas Pharma US, Inc. Northbrook, Illinois 60062 XOSPATA® is a registered trademark of Astellas Pharma Inc. ©2018 Astellas Pharma US, Inc. 17G072-GL

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                         Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3).

Gilteritinib demonstrated the ability to inhibit FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3-ITD, tyrosine kinase domain mutations (TKD) FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells expressing FLT3-ITD. 

2 .Pharmacodynamics                                                                                                      In patients with relapsed or refractory AML administered gilteritinib 120 mg, substantial (>90%) inhibition of FLT3 phosphorylation was rapid (within 24 hours after first dose) and sustained, as characterized by an ex vivo plasma inhibitory activity (PIA) assay.

Cardiac Electrophysiology                                                                                           The effect of XOSPATA 120 mg once a day on the QTc interval has been evaluated in patients, which showed an absence of large mean increases (i.e., 20 msec) in the QTc interval.

Of 292 patients treated with gilteritinib at 120 mg tested in clinical trials, 4 patients (1.4%) experienced a QTcF >500 msec. Additionally, across all doses, 2.4% of relapse/refractory subjects had a maximum post baseline QTcF interval >500 msec 

3. Pharmacokinetics                                                                                                      The following pharmacokinetic parameters were observed following administration of gilteritinib 120 mg once daily, unless otherwise specified.

Gilteritinib exposure (Cmax and AUC24) increases proportionally with once daily doses ranging from 20 mg to 450 mg (0.17 to 3.75 times the recommended dosage) in patients with relapsed or refractory AML.

Gilteritinib mean (±SD) steady-state Cmax is 374 ng/mL (±190) and AUC24 is 6943 ng•hr/mL (±3221).

Steady-state plasma levels are reached within 15 days of dosing with an approximate 10-fold accumulation.

Absorption                                                                                                                     The time to maximum gilteritinib concentration (tmax) observed is approximately between 4 and 6 hours post dose in the fasted state.

Effect of Food                                                                                                                   In healthy adults administered a single gilteritinib 40 mg dose (0.3 times the recommended dosage), gilteritinib Cmax decreased by 26% and AUC decreased by less than 10% when co-administered with a high-fat meal (approximately 800 to 1,000 total calories with 500 to 600 fat calories, 250 carbohydrate calories, 150 protein calories) compared to a fasted state.

Median tmax was delayed 2 hours when gilteritinib was administered with a high-fat meal.

Distribution                                                                                                                      The population mean (%CV) estimates of apparent central and peripheral volume of distribution were 1092 L (9.22%) and 1100 L (4.99%), respectively, which may indicate extensive tissue distribution.

In vivo, gilteritinib is approximately 94% bound to human plasma proteins. In vitro, gilteritinib is primarily bound to human serum albumin.

Elimination                                                                                                                     The estimated half-life of gilteritinib is 113 hours, and the estimated apparent clearance is 14.85 L/h.

Metabolism                                                                                                           Gilteritinib is primarily metabolized via CYP3A4 in vitro. At steady state, the primary metabolites in humans include M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via N-dealkylation).

None of these 3 metabolites exceeded 10% of overall parent exposure. 

Excretion                                                                                                                        After a single radiolabeled dose, gilteritinib is excreted in feces with 64.5% of the total administered dose recovered in feces. Of the total radiolabeled dose of gilteritinib, 16.4% was recovered in urine as unchanged drug and metabolites.

Specific Populations                                                                                                        Age (20-87 years), sex, race, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment and mild (creatinine clearance (CLCr) 50-80 mL/min) or moderate (CLCr 30-50 mL/min) renal impairment do not have clinically meaningful effects on the pharmacokinetics of gilteritinib.

The effect of severe hepatic (Child-Pugh Class C) or severe renal impairment (CLCr = 29 mL/min) on gilteritinib pharmacokinetics is unknown.

Drug Interaction Studies                                                                                          Clinical Studies Combined P-gp and Strong CYP3A Inducers:                          Gilteritinib Cmax decreased approximately 30% and AUC decreased approximately 70% when co-administered with rifampin (a combined P-gp and strong CYP3A inducer).

Strong CYP3A Inhibitors:                                                                                    Gilteritinib Cmax increased approximately 20% and AUC increased approximately 120% when co-administered with itraconazole (a strong CYP3A inhibitor).

Moderate CYP3A Inhibitors: Gilteritinib Cmax increased approximately 16% and AUC increased approximately 40% when co-administered with fluconazole (a moderate CYP3A inhibitor).

CYP3A Substrates: Midazolam (a CYP3A substrate) Cmax and AUC increased approximately 10% when co-administered with gilteritinib.

MATE1 Substrates: Cephalexin (a MATE1 substrate) Cmax and AUC decreased by less than 10% when co-administered with gilteritinib.

In Vitro Studies Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs that target these receptors such as escitalopram, fluoxetine, sertraline.

Gilteritinib is a substrate of P-gp transporter and has the potential to inhibit breast cancer resistance protein (BCRP) and organic cation transporter 1 (OCT1) transporters.

  USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                    Based on findings from animal studies (see Data) and its mechanism of action, XOSPATA can cause fetal harm when administered to a pregnant woman 

There are no available data on XOSPATA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

Advise pregnant women of the potential risk to a fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%­ 20%, respectively.

2 Lactation Risk Summary                                                                                        There are no data on the presence of gilteritinib and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with XOSPATA and for 2 months after the last dose.

3.Females and Males of Reproductive Potential Pregnancy testing               Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating XOSPATA treatment [see 

Contraception Females                                                                                            Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose of XOSPATA. 

Males                                                                                                                          Advise males of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose of XOSPATA.

4. Pediatric Use                                                                                                          Safety and effectiveness in pediatric patients have not been established.

5. Geriatric Use                                                                                                                Of the 292 patients in clinical studies of XOSPATA, 41% were age 65 years or older, and 13% were 75 years or older.

No overall differences in effectiveness or safety were observed between patients age 65 years or older and younger patients.