In PACE, dose modification was commonly used to manage adverse reactions.

68% of patients in the PACE trial experienced dose reductions during therapy.

Consider the dose intensity-safety relationship when assessing the benefit-risk profile of ICLUSIG patients.

Dose Modifications for Myelosuppression

Suggested dose modifications for neutropenia (ANC less than 1.0 x 109/L) and thrombocytopenia (platelet less than 50 x 109/L) that are unrelated to leukemia appear below.


Suggested dose modifications for myelosuppression
ANC < 1 x 109/L
or
platelet < 50 x 109/L

First occurrence:

  • Interrupt ICLUSIG and resume initial 45 mg dose after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

Second occurrence:

  • Interrupt ICLUSIG and resume at 30 mg dose after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

Third occurrence:

  • Interrupt ICLUSIG and resume at 15 mg dose after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

ANC = absolute neutrophil count

Dose Modifications for Non-Hematologic Adverse Reactions

If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do not restart ICLUSIG® (ponatinib) in patients with arterial or venous occlusive reactions unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions and the patient has no other treatment options. For serious reactions other than arterial or venous occlusion, do not restart ICLUSIG until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk.


Recommended dose modifications for hepatotoxicity
Elevation of liver transaminase > 3 x ULN* (Grade 2 or higher)

Occurrence at 45 mg:

  • Interrupt ICLUSIG and monitor hepatic function
  • Resume ICLUSIG at 30 mg after recovery to ≤ Grade 1 (< 3 x ULN)

Occurrence at 30 mg:

  • Interrupt ICLUSIG and resume at 15 mg after
    recovery to ≤ Grade 1

Occurrence at 15 mg:

  • Discontinue ICLUSIG
Elevation of AST or ALT ≥ 3 x ULN concurrent with an elevation of bilirubin > 2 x ULN and alkaline phosphatase < 2 x ULN Discontinue ICLUSIG

Recommended dose modifications for pancreatitis and elevation of lipase
Asymptomatic Grade 1 or 2 elevation of serum lipase Consider interruption or dose reduction of ICLUSIG
Asymptomatic Grade 3 or 4 elevation of lipase (> 2 x ULN ) or asymptomatic radiologic pancreatitis (Grade 2 pancreatitis)

Occurrence at 45 mg:

  • Interrupt ICLUSIG and resume at 30 mg after recovery to ≤ Grade 1 (< 1.5 x ULN)

Occurrence at 30 mg:

  • Interrupt ICLUSIG and resume at 15 mg after recovery to ≤ Grade 1

Occurrence at 15 mg:

  • Discontinue ICLUSIG
Symptomatic Grade 3 pancreatitis

Occurrence at 45 mg:

  • Interrupt ICLUSIG and resume at 30 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1

Occurrence at 30 mg:

  • Interrupt ICLUSIG and resume at 15 mg after recovery of lipase elevation to ≤ Grade 1

Occurrence at 15 mg:

  • Discontinue ICLUSIG
Grade 4 pancreatitis Discontinue ICLUSIG

*ULN = Upper Limit of Normal for the lab