Dosage & Administration
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Iclusig Prescribing Information
Arterial Occlusive Events:
- Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].
Venous Thromboembolic Events:
- Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
Heart Failure:
- Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
Hepatotoxicity:
- Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].
ICLUSIG is indicated for the treatment of adult patients with:
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
- Newly diagnosed Ph+ ALL in combination with chemotherapy.
This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). - As monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL.
Chronic Myeloid Leukemia (CML)
- Chronic phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors.
- Accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated.
- T315I-positive CML (chronic phase, accelerated phase, or blast phase).
Limitations of Use: ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML [see Warnings and Precautions (5.7)].
Recommended Dosage
Newly Diagnosed Ph+ ALL
The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Continue ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity [see Clinical Studies (14)].
For a description of dosing of agents administered in combination with ICLUSIG, [see Clinical Studies (14)].
Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL
The optimal dose of ICLUSIG has not been identified.
The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Continue ICLUSIG until loss of response or unacceptable toxicity.
Consider discontinuing ICLUSIG if response has not occurred by 3 months.
CP-CML
The recommended starting dosage of ICLUSIG 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 and BP-CML
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.
Administration
Advise patients of the following:
- ICLUSIG may be taken with or without food.
- Swallow tablets whole. Do not crush, break, cut or chew tablets.
- If a dose is missed, take the next dose at the regularly scheduled time the next day.
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 Monotherapy | Dosage for Patients with Newly Diagnosed Ph+ ALL |
|---|---|---|---|
| First | 30 mg orally once daily | 30 mg orally once daily | 15 mg orally once daily |
| Second | 15 mg orally once daily | 15 mg orally once daily | 10 mg orally once daily |
| Third | 10 mg orally once daily | Permanently discontinue ICLUSIG in patients unable to tolerate 15 mg orally once daily. | Permanently discontinue ICLUSIG in patients unable to tolerate 10 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 |
Dosage for Patients with Hepatic Impairment
For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG from 45 mg orally once daily to 30 mg orally once daily in patients with pre-existing hepatic impairment (Child-Pugh A, B, or C).
For patients with newly diagnosed Ph+ ALL, no dosage adjustment is recommended when administering ICLUSIG to patients with mild hepatic impairment (Child-Pugh A). Closely monitor patients with moderate or severe hepatic impairment (Child-Pugh B or C) and modify the ICLUSIG dosage in the event of adverse reactions [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].
Tablets, film-coated:
- 10 mg of ponatinib: Oval, white to off-white, biconvex, debossed "NZ" on one side and plain on the other side
- 15 mg of ponatinib: Round, white, biconvex, debossed "A5" on one side and plain on the other side
- 30 mg of ponatinib: Round, white, biconvex, debossed "C7" on one side and plain on the other side
- 45 mg of ponatinib: Round, white, biconvex, debossed "AP4" on one side and plain on the other side
Pregnancy
Risk Summary
Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], ICLUSIG can cause fetal harm when administered to a pregnant woman. There are no available data on ICLUSIG use in pregnant women. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the maximum recommended human dose of 45 mg/day (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day during organogenesis (25 rats per group). At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the maximum recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the maximum recommended dose of 45 mg/day) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.
Lactation
Risk Summary
There are no data on the presence of ponatinib in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ICLUSIG and for 1 week after the last dose.
Females and Males of Reproductive Potential
ICLUSIG can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating ICLUSIG.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.
Infertility
Females
Based on animal data, ponatinib may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)]. It is not known whether these effects on fertility are reversible.
Pediatric Use
Safety and effectiveness of ICLUSIG have not been established in pediatric patients.
Juvenile Animal Toxicity Data
A juvenile toxicity study in 15 day old rats was conducted with daily oral gavage administration of ponatinib at 0.75 mg/kg/day, 1.5 mg/kg/day, or 3 mg/kg/day for 21 days. There were no adverse effects of ponatinib on juvenile rat developmental parameters (vaginal opening, preputial separation or bone measurements) observed in this study. Once daily oral administration of 3 mg/kg/day ponatinib to juvenile rats beginning on Day 15 postpartum (pp) resulted in mortality related to inflammatory effects after 6 to 7 days following initiation of treatment. The dose of 3 mg/kg/day is approximately 0.32 times the maximum recommended human dose of 45 mg/day on a mg/m2 basis for a child.
Geriatric Use
Of the 163 patients with Ph+ALL who received ICLUSIG in PhALLCON, 21% were 65 years and older and 7% were 75 years and older. Overall, no differences in efficacy of ICLUSIG were observed between patients 65 years of age or older compared to younger patients. AOEs occurred in 21% (7/34) of patients 65 years and older and 2.3% (3/129) of patients less than 65 years of age.
Of the 94 patients with CP-CML who received ICLUSIG at a starting dose of 45 mg in OPTIC, 17% were 65 years and older and 2.1% were 75 years and older. Patients aged 65 years and older had a lower ≤1% BCR::ABL1IS rate at 12 months (27%) as compared with patients less than 65 years of age (47%). AOEs occurred in 38% (6/16) of patients 65 years and older and 9% (7/78) of patients less than 65 years of age [see Warnings and Precautions (5.1)].
Of the 449 patients who received ICLUSIG in PACE, 35% were 65 years and older and 8% were 75 years and older. In patients with CP-CML, patients aged 65 years and older had a lower major cytogenetic response rate (40%) as compared with patients less than 65 years of age (65%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients aged 65 years and older had a similar hematologic response rate (45%) as compared with patients less than 65 years of age (44%). AOEs occurred in 35% (54/155) of patients 65 years and older and in 21% (61/294) of patients less than 65 years of age [see Warnings and Precautions (5.1)].
Patients aged 65 years or older are more likely to experience adverse reactions including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Hepatic Impairment
Patients with hepatic impairment are more likely to experience adverse reactions compared to patients with normal hepatic function. For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG for patients with pre-existing hepatic impairment (Child-Pugh A, B, or C). For patients with newly diagnosed Ph+ ALL, dosage adjustment is not recommended when administering ICLUSIG to patients with mild hepatic impairment (Child-Pugh A). Clinical data in patients with newly diagnosed Ph+ ALL with pre-existing moderate or severe hepatic impairment (Child-Pugh B or C) is not available and patients should be closely monitored for potential increased incidence of adverse reactions. Modify the ICLUSIG dosage in the event of adverse reactions [see Dosage and Administration (2.2, 2.4), Clinical Pharmacology (12.3)]. The safety of multiple doses, or doses higher than 30 mg, has not been studied in patients with hepatic impairment.
None.