Imkeldi Dosage

Important Administration Instructions

All doses of Imkeldi should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, and a dose of 800 mg should be administered as 400 mg twice a day. If a dose is missed, the patient should wait until the next scheduled dose and not take two doses at the same time.

Imkeldi is intended for oral use only. It is important that Imkeldi be measured with an accurate measuring device. A household teaspoon is not an accurate measuring device. A pharmacist can provide a press-in bottle adapter and oral dispensing syringe and can provide instructions for measuring the correct dose.

Recommendations for Dose Rounding

Round each dose to the nearest measurable graduation mark on the oral syringe, if necessary.

Continue treatment until disease progression or unacceptable toxicity.

Imkeldi is a hazardous drug. Follow applicable special handling and disposal procedures1.

Adult Patients With Ph+ CML CP, AP, or BC

The recommended dosage of Imkeldi is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

Pediatric Patients With Ph+ CML CP

The recommended dosage of Imkeldi for pediatric patients with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg). Imkeldi treatment can be given as a once daily dose or the daily dose may be split into two–one portion doses in the morning and one portion in the evening. There is no experience with Imkeldi treatment in children under 1 year of age.

Follow recommendations for dose rounding.

Adult Patients With Ph+ ALL

The recommended dosage of Imkeldi is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.

Pediatric Patients With Ph+ ALL

The recommended dosage of Imkeldi to be given in combination with chemotherapy to pediatric patients with newly diagnosed Ph+ ALL is 340 mg/m2/day (not to exceed 600 mg). Imkeldi treatment can be given as a once daily dose.

Follow recommendations for dose rounding.

Adult Patients With MDS/MPD

Determine PDGFRb gene rearrangements status prior to initiating treatment.

The recommended dosage of Imkeldi is 400 mg/day for adult patients with MDS/MPD.

Adult Patients With ASM

Determine D816V c-Kit mutation status prior to initiating treatment.

The recommended dosage of Imkeldi is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c- Kit mutational status is not known or unavailable, treatment with Imkeldi 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

Adult Patients With HES/CEL

The recommended dosage of Imkeldi is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

Adult Patients With DFSP

The recommended dosage of Imkeldi is 800 mg/day for adult patients with DFSP.

Adult Patients With Metastatic and/or Unresectable GIST

The recommended dosage of Imkeldi is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

Adult Patients With Adjuvant GIST

The recommended dosage of Imkeldi is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of imatinib and three years of imatinib were studied. In the patient population defined in Study 2, three years of Imkeldi is recommended. The optimal treatment duration with Imkeldi is not known.

Dosage Modifications for Drug Interactions, Hepatic Impairment, and Renal Impairment

Drug Interactions

Concomitant Strong CYP3A4 inducers

Avoid concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital) with Imkeldi. If concomitant use with a strong CYP3A4 inducer cannot be avoided the Imkeldi dosage should be increased by at least 50%, and clinical response should be carefully monitored.

Hepatic Impairment

A 25% decrease in the approved recommended Imkeldi dosage should be used for patients with severe hepatic impairment (total bilirubin ˃3 to 10 times upper limit of normal [ULN] and any value for AST).

Patients with mild hepatic impairment (total bilirubin ≤ ULN and aspartate aminotransferase [AST] > ULN, or total bilirubin ˃1 to 1.5 times ULN and any value for AST) and moderate hepatic impairment (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) do not require a dose adjustment and should be treated per the approved recommended dosage.

Renal Impairment

Imkeldi should be used with caution in patients with severe renal impairment.

Patients with moderate renal impairment (creatinine clearance [CLcr] = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CLcr = 40-59 mL/min). Doses greater than 400 mg are not recommended for patients with moderate renal impairment.

2.13 Dosage Modifications for Hepatotoxicity and Non-Hematologic Adverse Reactions

If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, Imkeldi should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN. In adults, treatment with Imkeldi may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day.

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Imkeldi should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the reaction.

Dosage Modifications for Hematologic Adverse Reactions

Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.

Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD, myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia.