Iclusig Drug Information

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. For a description of dosing of agents administered in combination with ICLUSIG,.

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. 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::ABL1 IS.

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. AP-CML and BP-CML The optimal dose of ICLUSIG has not been identified.

Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. 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. Table 1: Recommended Dosage Modifications for ICLUSIG for AOE: peripheral vascular and other or VTE

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.

Table 3: Recommended ICLUSIG Dosage for Coadministration of Strong CYP3A Inhibitors

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most common adverse reactions identified in the Highlights of the Prescribing Information are based on two safety populations. The first is from a pooled safety population of 543 patients with CML or resistant or intolerant Ph+ ALL (OPTIC and PACE studies) who received ICLUSIG as a single agent at a starting dose of 45 mg orally once daily.

In this pooled safety population, the most common (>20%) adverse reactions were rash and related conditions, arthralgia, abdominal pain, fatigue, headache, constipation, hypertension, dry skin, hepatotoxicity, fluid retention and edema, pyrexia, pancreatitis/lipase elevation, nausea, hemorrhage, anemia, AOEs and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) were platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. The second safety population is from 163 patients with newly diagnosed Ph+ ALL (PhALLCON study) who received ICLUSIG in combination with chemotherapy at a starting dose of 30 mg orally once daily.

The most common adverse reactions (>20%) included hepatotoxicity, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias. Newly Diagnosed Ph+ ALL The safety of ICLUSIG was evaluated in PhALLCON, a randomized, active-controlled, multicenter trial conducted in patients with newly diagnosed Ph+ ALL. Patients received ICLUSIG (n=163) or imatinib 600 mg (n=81) in combination with reduced-intensity chemotherapy followed by continued treatment with ICLUSIG or imatinib as a single agent (imatinib in combination with chemotherapy is not an approved regimen in adult patients).

In the ICLUSIG arm, patients received a starting dosage of ICLUSIG 30 mg orally once daily in combination with chemotherapy, with a reduction to 15 mg orally once daily upon achievement of MRD-negative CR at the end of induction. Patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, history of myocardial infarction, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were excluded. Serious adverse reactions occurred in 63% of patients receiving ICLUSIG in combination with chemotherapy.

Serious adverse reactions in >2% of patients included febrile neutropenia ( %). Fatal adverse reactions occurred in 6% of patients who received ICLUSIG in combination with chemotherapy, including sepsis (3.7%), sudden death, pneumonitis and respiratory failure (0.6%, each). Permanent discontinuation of ICLUSIG due to adverse reactions occurred in 13% of patients.

Adverse reactions resulting in permanent discontinuation of ICLUSIG in >2% of patients included arterial occlusive events and sepsis. Dosage modifications (dose interruption or reduction) of ICLUSIG due to adverse reactions occurred in 71% of patients. Adverse reactions leading to dose interruption or reduction of ICLUSIG in >5% of patients included increased ALT, neutropenia, increased lipase, thrombocytopenia, increased AST, febrile neutropenia, and abdominal pain.

Table 4 summarizes the adverse reactions in patients receiving ICLUSIG or imatinib in combination with chemotherapy in PhALLCON. Table 5 summarizes the laboratory abnormalities in PhALLCON for patients who received ICLUSIG or imatinib in combination with chemotherapy. Table 5: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Newly Diagnosed Ph+ ALL in PhALLCON Previously Treated CP-CML The safety of ICLUSIG was evaluated in OPTIC.

Patients received one of three starting doses of ICLUSIG: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94), or 15 mg orally once daily (n=94). Only the safety information for the recommended starting dosage (45 mg) is described below. Patients who received a starting dose of ICLUSIG 45 mg orally once daily had a mandatory dose reduction to 15 mg once daily upon achievement of ≤1% BCR::ABL1 IS.

Serious adverse reactions occurred in 40% of patients who received ICLUSIG at a starting dose of 45 mg. Permanent discontinuation of ICLUSIG due to an adverse reaction occurred in 24% of patients who received ICLUSIG at a starting dose of 45 mg. Adverse reactions which resulted in permanent discontinuation in >2% of patients included AOEs, thrombocytopenia, hypertension, and sudden death.

Dose modifications (dose interruption or reductions) of ICLUSIG due to an adverse reaction occurred in 81% of patients who received ICLUSIG at a starting dose of 45 mg. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia, pancreatitis/lipase elevation, neutropenia, hepatotoxicity, rash and related conditions, anemia, cardiac arrhythmias, AOEs, and cardiac failure. Table 6 summarizes the adverse reactions in OPTIC for patients who received ICLUSIG at a starting dose of 45 mg.

Table 7 summarizes the laboratory abnormalities in OPTIC for patients who received ICLUSIG at a starting dose of 45 mg. Table 7: Select Laboratory Abnormalities (>20%) that Worsened from Baseline in Patients with CP-CML Who Received ICLUSIG at Starting Dose of Previously Treated CML or Ph+ ALL The safety of ICLUSIG was evaluated in PACE. Eligible patients had CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior kinase inhibitor, including those with the BCR::ABL T315I mutation.

Patients received a starting dose of ICLUSIG 45 mg orally once daily (N=449). Dose reductions to 30 mg orally once daily or 15 mg orally once daily were allowed for the management of adverse reactions. After approximately 2 years of follow-up, patients who were still taking a 45 mg orally once daily dose were recommended to undergo a dose reduction in response to the continued occurrence of AOEs and VTEs in the clinical trial.

The most frequent adverse reactions that led to treatment discontinuation were thrombocytopenia (4.5%) and AOEs (4%). Dose interruption of ICLUSIG for more than 3 days due to an adverse reaction occurred in 71% of patients and dose reduction of ICLUSIG due to an adverse reaction occurred in 68% of patients. Adverse reactions which required a dosage interruption or dose reduction in >5% of patients included thrombocytopenia ( %) non-hematologic adverse reactions were rash and related conditions, arthralgia, abdominal pain, fatigue, constipation, headache, dry skin, fluid retention and edema, hepatotoxicity, hypertension, pyrexia, nausea, hemorrhage, pancreatitis/lipase elevation, AOEs, diarrhea, vomiting, and myalgia.

Table 8 summarizes the adverse reactions in PACE. Table 8: Adverse Reactions (>10%) in Patients with CML or Ph+ ALL Who Received ICLUSIG in PACE Clinically relevant adverse reactions occurring in ≤10% of patients: impaired glucose tolerance (9%) Grouped terms: secondary malignancies includes basal cell carcinoma, squamous cell carcinoma of the skin, melanoma, chronic myelomonocytic leukemia, colon cancer, epithelioid mesothelioma, large cell lung cancer recurrent, lung neoplasm, malignant ascites, myelodysplastic syndrome, neuroendocrine carcinoma metastatic, non-Hodgkin lymphoma, pancreatic cancer, thyroid neoplasm, vulval cancer; venous thromboembolic events includes deep vein thrombosis, pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, superficial thrombophlebitis, venous embolism, veno-occlusive liver disease, portal vein thrombosis; impaired glucose tolerance includes blood glucose increased, diabetes mellitus, glucose tolerance impaired, glycosylated hemoglobin increased, hyperglycemia, insulin resistance, and type 2 diabetes mellitus, venous thromboembolic events (6%), secondary malignancies (6%), and hypothyroidism (3%). Table 9: Select Grade 3 or 4 Graded using CTCAE v4.03 Hematologic Laboratory Abnormalities in Patients Who Received ICLUSIG in PACE: Select Non-Hematologic Laboratory Abnormalities (≥20%) in Patients Who Received ICLUSIG in PACE

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ICLUSIG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and Lymphatic System Disorders: Thrombotic microangiopathy Endocrine Disorders: Hyperthyroidism Gastrointestinal Disorders: Gastrointestinal perforation, fistula Metabolism and Nutrition Disorders: Dehydration Nervous System Disorders: Reversible posterior leukoencephalopathy syndrome (RPLS) Skin and Subcutaneous Tissue Disorders: Severe cutaneous reaction (e.g., Erythema multiforme, Stevens-Johnson syndrome), impaired wound healing, panniculitis (including erythema nodosum) Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

Effects of Other Drugs on ICLUSIG Strong CYP3A Inhibitors Coadministration of ICLUSIG with a strong CYP3A inhibitor increases ponatinib plasma concentrations, which may increase the risk of ICLUSIG adverse reactions. Avoid coadministration of ICLUSIG with strong CYP3A inhibitors. If coadministration of ICLUSIG with strong CYP3A inhibitors cannot be avoided, reduce the ICLUSIG dosage.

Strong CYP3A Inducers Coadministration of ICLUSIG with a strong CYP3A inducer decreases ponatinib plasma concentrations. Avoid coadministration of ICLUSIG with strong CYP3A inducers unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy.

Selection of concomitant medication with no or minimal CYP3A induction potential is recommended.

Pregnancy Risk Summary Based on findings in animals and its mechanism of action, 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 respectively. 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.

Pediatric Use Safety and effectiveness of ICLUSIG have not been established in pediatric patients. There were no adverse effects of ponatinib on juvenile rat developmental parameters (vaginal opening, preputial separation or bone measurements) observed in this study.

Overdoses with ICLUSIG were reported in clinical trials. One patient was estimated to have been administered 540 mg via nasogastric tube. Two hours after the overdosage, the patient had an uncorrected QT interval of 520 ms.

Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 ms and 400 ms. The patient died 9 days after the overdosage from pneumonia and sepsis. Another patient self-administered 165 mg on Cycle 1 Day 2.

The patient experienced fatigue and non-cardiac chest pain on Day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdosage, stop ICLUSIG, observe the patient and provide supportive treatment as appropriate.