Dosage of Ponatinib

The active ingredient of this product is Ponatinib Hydrochloride, with the dosage calculated based on ponatinib.

Dosage for Adults

Chronic Myeloid Leukemia (CML) in Chronic Phase

Administer orally at an initial dose of 45 mg once daily. When the patient achieves a BCR-ABL1 International Standard (IS) ≤ 1%, the dose may be reduced to 15 mg once daily.

If the patient loses efficacy at a dose of 15 mg once daily, the dose may be escalated back to the previously tolerated level (30 mg or 45 mg once daily).

Continue treatment until the patient loses efficacy again after dose escalation or experiences intolerable toxic reactions.

Discontinuation should be considered if no hematologic response is achieved after 3 months of treatment.

Chronic Myeloid Leukemia (CML) in Accelerated or Blast Phase

Administer orally at an initial dose of 45 mg once daily; the optimal dose has not been established.

For patients with accelerated-phase CML who achieve a major cytogenetic response, dose reduction may be considered.

Continue treatment until the patient loses efficacy or experiences intolerable toxic reactions.

Discontinuation should be considered if no hematologic response is achieved after 3 months of treatment.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL)

Newly Diagnosed Ph+ALL

Administer orally at an initial dose of 30 mg once daily in combination with chemotherapy. At the end of induction therapy, if the patient achieves a complete remission status with minimal residual disease (MRD) negativity (BCR::ABL1/ABL1 ≤ 0.01%), the dose may be reduced to 15 mg once daily. Continue combined chemotherapy for up to 20 cycles until the patient loses efficacy or experiences intolerable toxic reactions.

Ph+ALL with No Other Tyrosine Kinase Inhibitors Available or T315I Mutation-Positive Ph+ALL

Administer orally at an initial dose of 45 mg once daily as monotherapy; the optimal dose has not been established. Continue treatment until the patient loses efficacy or experiences intolerable toxic reactions. Discontinuation should be considered if no response is achieved after 3 months of treatment.

Dose Adjustments for Toxicity

In case of adverse reactions, treatment interruption, dose reduction, or permanent discontinuation should be implemented based on the specific situation. If dose adjustment is necessary, refer to the following stepwise regimen:

For Patients with Chronic-Phase CML

First dose adjustment: 30 mg once daily;

Second dose adjustment: 15 mg once daily;

Third dose adjustment: 10 mg once daily;

Permanent discontinuation is required if the patient remains unable to tolerate a dose of 10 mg once daily thereafter.

For Patients with Accelerated/Blast-Phase CML or Ph+ALL Treated with Monotherapy

First dose adjustment: 30 mg once daily

Second dose adjustment: 15 mg once daily

Permanent discontinuation is required if the patient is unable to tolerate a dose of 15 mg once daily thereafter.

For Patients with Newly Diagnosed Ph+ALL (Combined with Chemotherapy)

First dose adjustment: 15 mg once daily

Second dose adjustment: 10 mg once daily

Permanent discontinuation is required if the patient remains unable to tolerate a dose of 10 mg once daily thereafter.

Permanent discontinuation is mandatory for patients who cannot tolerate the above minimum recommended doses.

Dose Adjustments for Specific Adverse Reactions

The following dose adjustment measures are recommended based on the type and severity of specific adverse reactions:

Cardio- and Cerebrovascular Arterial Occlusive Events

Grade 1 event: Interrupt treatment until symptoms resolve, then resume the original dose.

Grade 2 event: Interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose; discontinue treatment if the event recurs.

Grade 3–4 events: Discontinue treatment permanently.

Peripheral Vascular or Other Arterial Occlusive Events

Grade 1 event: Interrupt treatment until symptoms resolve, then resume the original dose.

Grade 2 event: Interrupt treatment until symptoms improve to Grade 0–1, then resume the original dose; if the event recurs, interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose.

Grade 3 event: Interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose; discontinue treatment if the event recurs.

Grade 4 event: Discontinue treatment permanently.

Venous Thromboembolism

Grade 1 event: Interrupt treatment until symptoms resolve, then resume the original dose.

Grade 2 event: Interrupt treatment until symptoms improve to Grade 0–1, then resume the original dose; if the event recurs, interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose.

Grade 3 event: Interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose; discontinue treatment if the event recurs.

Grade 4 event: Discontinue treatment permanently.

Heart Failure

Grade 2–3 events: Interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose; discontinue treatment if the event recurs.

Grade 4 event: Discontinue treatment permanently.

Hepatotoxicity

If aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceed 3 times the upper limit of normal (ULN), interrupt treatment until levels return to Grade 0–1, then resume at the next lower dose. Permanent discontinuation is required if AST or ALT ≥ 3×ULN is accompanied by bilirubin > 2×ULN and alkaline phosphatase < 2×ULN.

Pancreatitis or Elevated Serum Lipase

Serum lipase > 1–1.5×ULN: Consider interrupting treatment until symptoms resolve, then resume the original dose.

Serum lipase > 1.5–2×ULN; or serum lipase 2–5×ULN without symptoms; or asymptomatic pancreatitis confirmed by imaging: Interrupt treatment until symptoms improve to Grade 0–1 (lipase < 1.5×ULN), then resume at the next lower dose.

Serum lipase 2–5×ULN with symptoms; or Grade 3 symptomatic pancreatitis; or serum lipase > 5×ULN without symptoms: Interrupt treatment until symptoms resolve completely and lipase levels return to Grade 0–1, then resume at the next lower dose.

Symptomatic pancreatitis with serum lipase > 5×ULN: Discontinue treatment permanently.

Myelosuppression

If the absolute neutrophil count (ANC) < 1,000/mm³ or platelet count < 50,000/mm³, interrupt treatment until ANC ≥ 1,500/mm³ and platelet count ≥ 75,000/mm³, then resume the original dose. If myelosuppression recurs, interrupt treatment until parameters recover, then resume at the next lower dose.

Other Non-hematologic Adverse Reactions

Grade 1 event: Interrupt treatment until symptoms resolve, then resume the original dose.

Grade 2 event: Interrupt treatment until symptoms improve to Grade 0–1, then resume the original dose; if the adverse reaction recurs, interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose.

Grade 3–4 events: Interrupt treatment until symptoms improve to Grade 0–1, then resume at the next lower dose; discontinue treatment permanently if the adverse reaction recurs.

Dose Adjustments When Coadministered with Potent CYP3A Inhibitors

Coadministration of ponatinib with potent CYP3A inhibitors should be avoided whenever possible. If coadministration is unavoidable, reduce the dose of ponatinib according to the current dosage:

Current dose: 45 mg once daily → Recommended dose during coadministration: 30 mg once daily

Current dose: 30 mg once daily → Recommended dose during coadministration: 15 mg once daily

Current dose: 15 mg once daily → Recommended dose during coadministration: 10 mg once daily

Current dose: 10 mg once daily → Coadministration with potent CYP3A inhibitors should be avoided

Resume the patient’s tolerated pre-coadministration dose of ponatinib 3–5 elimination half-lives after discontinuation of the potent CYP3A inhibitor.

FDA,2022.02