Drug Detail:Iclusig (Ponatinib [ poe-na-ti-nib ])
Generic Name: ponatinib hydrochloride 15mg
Dosage Form: tablet, film coated
Drug Class: BCR-ABL tyrosine kinase inhibitors Multikinase inhibitors VEGF/VEGFR inhibitors
Recommended Dosage
CP-CML
The recommended starting dosage is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR-ABL1IS. Patients with loss of response can re-escalate the dose of Iclusig to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue Iclusig until loss of response at the re-escalated dose or unacceptable toxicity.
Consider discontinuing Iclusig if hematologic response has not occurred by 3 months.
AP-CML, BP-CML, and Ph+ ALL
The optimal dose of Iclusig has not been identified.
The recommended starting dosage of Iclusig is 45 mg orally once daily. Consider reducing the dose of Iclusig for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Continue Iclusig until loss of response or unacceptable toxicity.
Consider discontinuing Iclusig if response has not occurred by 3 months.
Dosage Modifications for Adverse Reactions
Recommended dosage modifications of Iclusig for adverse reactions are provided in Table 1 and recommended dose reductions of Iclusig for adverse reactions are presented in Table 2.
| Adverse Reaction | Severity | Iclusig Dosage Modifications |
|---|---|---|
| Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count |
||
| AOE: cardiovascular or cerebrovascular [see Warnings and Precautions (5.1)] |
Grade 1 | Interrupt Iclusig until resolved, then resume at same dose. |
| Grade 2 | Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. Discontinue Iclusig if recurrence. |
|
| Grade 3 or 4 | Discontinue Iclusig. | |
| AOE: peripheral vascular and other or VTE [see Warnings and Precautions (5.1, 5.2)] |
Grade 1 | Interrupt Iclusig until resolved, then resume at same dose. |
| Grade 2 | Interrupt Iclusig until Grade 0 or 1, then resume at same dose. If recurrence, interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. |
|
| Grade 3 | Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. Discontinue Iclusig if recurrence. |
|
| Grade 4 | Discontinue Iclusig. | |
| Heart Failure [see Warnings and Precautions (5.3)] |
Grade 2 or 3 | Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. Discontinue Iclusig if recurrence. |
| Grade 4 | Discontinue Iclusig. | |
| Hepatotoxicity [see Warnings and Precautions (5.4)] |
AST or ALT greater than 3 times ULN | Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. |
| AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN | Discontinue Iclusig. | |
| Pancreatitis and Elevated Lipase [see Warnings and Precautions (5.6)] |
Serum lipase greater than 1 to 1.5 times ULN | Consider interrupting Iclusig until resolution, then resume at same dose. |
| Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis | Interrupt Iclusig until Grade 0 or 1 (less than 1.5 times ULN), then resume at next lower dose. | |
| Serum lipase greater than 2 to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomatic | Interrupt Iclusig until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose. | |
| Symptomatic pancreatitis and serum lipase greater than 5 times ULN | Discontinue Iclusig. | |
| Myelosuppression [see Warnings and Precautions (5.13)] |
ANC less than 1 × 109/L or Platelets less than 50 × 109/L |
Interrupt Iclusig until ANC at least 1.5 × 109/L and platelet at least 75 × 109/L, then resume at same dose. If recurrence, interrupt Iclusig until resolution, then resume at next lower dose. |
| Other Non-hematologic Adverse Reactions [see Warnings and Precautions (5.5, 5.8, 5.10, 5.11, 5.12)] |
Grade 1 | Interrupt Iclusig until resolved, then resume at same dose. |
| Grade 2 | Interrupt Iclusig until Grade 0 or 1, then resume at same dose. If recurrence, interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. |
|
| Grade 3 or 4 | Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. Discontinue Iclusig if recurrence. |
|
| Dose Reduction | Dosage for Patients with CP-CML | Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL |
|---|---|---|
| First | 30 mg orally once daily | 30 mg orally once daily |
| Second | 15 mg orally once daily | 15 mg orally once daily |
| Third | 10 mg orally once daily | Permanently discontinue Iclusig in patients unable to tolerate 15 mg orally once daily. |
| Subsequent Reduction | Permanently discontinue Iclusig in patients unable to tolerate 10 mg orally once daily. |
Dosage Modification for Coadministration of Strong CYP3A Inhibitors
Avoid coadministration of Iclusig with strong CYP3A inhibitors. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the dosage of Iclusig as recommended in Table 3.
After the strong CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Iclusig dosage that was tolerated prior to initiating the strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
| Current Iclusig Dosage | Recommended Iclusig Dosage with a Strong CYP3A Inhibitor |
|---|---|
| 45 mg orally once daily | 30 mg orally once daily |
| 30 mg orally once daily | 15 mg orally once daily |
| 15 mg orally once daily | 10 mg orally once daily |
| 10 mg orally once daily | Avoid coadministration of Iclusig with a strong CYP3A inhibitor |
