Included as part of the "PRECAUTIONS" Section
Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease have occurred in at least 35% of Iclusig-treated patients from the Phase 1 and Phase 2 trials. With a minimum of 48 months follow-up for ongoing patients (N=133) in the Phase 2 trial, 33% (150/449) of Iclusig-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event; some patients experienced more than 1 type of arterial occlusive event.
Iclusig can cause fatal and life-threatening arterial occlusion within 2 weeks of starting treatment, and at dose levels as low as 15 mg per day. Iclusig can also cause recurrent or multisite vascular occlusion. Patients have required revascularization procedures (coronary, cerebrovascular, and peripheral arterial).
In the Phase 2 trial, the median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193 (range: 1 to 1355), 526 (range: 5 to 1339), and 478 (range: 3 to 1344) days, respectively.
Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed in patients with arterial occlusive events were hypertension (62%; 93/150), hyperlipidemia (61%; 91/150), and history of cardiac disease (48%; 72/150). Arterial occlusion adverse events were more frequent with increasing age and in patients with history of ischemia, hypertension, diabetes, or hyperlipidemia (see Table 4).
Table 4: Arterial Occlusion Incidence in Iclusig-Treated Patients in Phase 2 Trial According to Risk Categories: 4 year follow-up
(At time of study entry)
|History of ischemia, hypertension, diabetes, or hyperlipidemia|
|No history of ischemia, hypertension, diabetes, or hyperlipidemia|
|49 or younger||31% (11/36)||19% (21/108)|
|50 to 74 years||40% (64/158)||30% (32/109)|
|75 and older||58% (14/24)||57% (8/14)|
|All age groups||41% (89/218)||26% (61/231)|
Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 21% (94/449) of Iclusig-treated patients. Patients have developed heart failure concurrent or subsequent to the myocardial ischemic event [see Heart Failure].
Cerebrovascular occlusion, including fatal stroke, has occurred in 9% (40/449) of Iclusig-treated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery).
Peripheral arterial occlusion, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, have occurred in 12% (52/449) of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations. Renal artery stenosis, associated with worsening, labile or treatment-resistant hypertension, has occurred in some Iclusigtreated patients [see Hypertension].
Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial occlusive events, interrupt or stop Iclusig. A benefit-risk consideration should guide a decision to restart Iclusig therapy [see DOSAGE AND ADMINISTRATION].
Venous thromboembolic events occurred in 6% (25/449) of Iclusig-treated patients, including deep venous thrombosis (10 patients), pulmonary embolism (7 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients) with vision loss.
In the Phase 2 trial, the incidence of venous thromboembolism was 9% (3/32) in patients with Ph+ ALL, 10% (6/62) in patients with blast phase (BP) CML, 4% (3/85) in patients with AP-CML, and 5% (13/270) in patients with CP-CML. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see DOSAGE AND ADMINISTRATION].
Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of Iclusig-treated patients (N=29/449) in the Phase 2 trial (48 months follow-up). Nine percent of patients (N=39) experienced any grade of heart failure or left ventricular dysfunction. The most frequently reported heart failure events were congestive cardiac failure and decreased ejection fraction (in 14 patients each; 3%).
Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure [see DOSAGE AND ADMINISTRATION].
Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within 1 week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase (BP) CML or Ph+ ALL. Severe (Grade 3 or 4) hepatotoxicity occurred in all disease cohorts.
With 48 months follow-up, 11% (50/449) of Iclusig-treated patients experienced Grade 3 or 4 hepatotoxicity in the Phase 2 trial. The most common forms of hepatotoxicity were elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase. The incidence of AST or ALT elevation was 54% (all Grades) and 8% (Grade 3 or 4). ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.
Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months, with a range of <1 month to 47 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see DOSAGE AND ADMINISTRATION].
Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% (306/449) of patients in the Phase 2 clinical trial (48 months of follow-up). Fifty-three patients (12%) treated with Iclusig in this clinical trial experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath [see ADVERSE REACTIONS].
In patients with baseline systolic BP <140 mm Hg and baseline diastolic BP <90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension (defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) while 37% developed Stage 2 hypertension (defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg). In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension.
Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.
Pancreatitis occurred in 7% (31/449, 6% serious or Grade 3/4) of Iclusig-treated patients with 48 months of follow-up in the Phase 2 trial. The incidence of treatment-emergent lipase elevation was 42% (16% Grade 3 or greater).
Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (26/449). The median time to onset of pancreatitis was 14 days (range: 3 to 1452). Twenty-three of the 31 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction.
Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see DOSAGE AND ADMINISTRATION]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5x ULN.
Increased Toxicity In Newly Diagnosed Chronic Phase CML
In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent Iclusig 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013.
Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the Iclusig arm compared to the imatinib arm. Compared to imatinib-treated patients, Iclusig-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.
Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 20% (90/449) of Iclusig-treated patients in the pivotal Phase 2 trial experienced a peripheral neuropathy event of any grade (2%, Grade 3/4) (48 months follow-up). The most common peripheral neuropathies reported were paresthesia (5%, 23/449), neuropathy peripheral (4%, 19/449), hypoesthesia (3%, 15/449), dysgeusia (2%, 10/449), muscular weakness (2%, 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 2% (10/449) of Iclusig-treated patients (<1%, 3/449 -Grade 3/4).
Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.
Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients in the Phase 2 trial (48 months follow-up). Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2% of Iclusig-treated patients. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14% of patients. Visual blurring occurred in 6% of patients. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment [see ADVERSE REACTIONS].
Serious hemorrhage events including fatalities, occurred in 6% (28/449) of patients treated with Iclusig in the Phase 2 trial, with 48 months follow-up. Hemorrhage occurred in 28% (124/449) of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% (4/449 and 4/449, respectively). Most hemorrhagic events, but not all, occurred in patients with Grade 4 thrombocytopenia [see Myelosuppression]. Interrupt Iclusig for serious or severe hemorrhage and evaluate [see DOSAGE AND ADMINISTRATION].
Fluid retention events judged as serious occurred in 4% (18/449) of patients treated with Iclusig in the Phase 2 trial (48 months follow-up). One instance of brain edema was fatal. For fluid retention events occurring in more than 2% of the patients (treatment-emergent), serious cases included: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema peripheral (2/449, <1%).
In total, fluid retention occurred in 31% of the patients. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%).
Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see DOSAGE AND ADMINISTRATION].
Arrhythmias occurred in 19% (86/449) of Iclusig-treated patients, of which 7% (33/449) were Grade 3 or greater. Arrhythmia of ventricular origin was reported in 3% (3/86) of all arrhythmias, with one case being Grade 3 or greater.
Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% (3/449) of Iclusigtreated patients.
Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/449) of patients, approximately half of which were Grade 3 or 4. Other Grade 3 or 4 arrhythmia events included syncope (9 patients; 2.0%), tachycardia and bradycardia (2 patients each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (1 patient each 0.2%). For 27 patients, the event led to hospitalization.
In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt Iclusig and evaluate.
Myelosuppression was reported as an adverse reaction in 59% (266/449) of patients, and severe (Grade 3 or 4) myelosuppression occurred in 50% (226/449) of patients treated with Iclusig. With 48 months of follow-up, the incidence of these events was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML.
Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range <1 to 40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see DOSAGE AND ADMINISTRATION].
Tumor Lysis Syndrome
Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. One case occurred in a patient with advanced AP-CML and one case occurred in a patient with BP-CML. Hyperuricemia occurred in 7% (31/449) of patients. Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
Postmarketing cases of reversible posterior leukoencephalopathy syndrome (RPLS – also known as Posterior Reversible Encephalopathy Syndrome – PRES) have been reported in Iclusig-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present and diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. If RPLS is diagnosed, interrupt Iclusig treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.
Impaired Wound Healing And Gastrointestinal Perforation
Impaired wound healing occurred in patients receiving Iclusig [see ADVERSE REACTIONS]. Withhold Iclusig for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Iclusig after resolution of wound healing complications has not been established.
Gastrointestinal perforation or fistula occurred in patients receiving Iclusig [see ADVERSE REACTIONS]. Permanently discontinue in patients with gastrointestinal perforation.
Based on its mechanism of action and findings from animal studies, Iclusig can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose [see Use In Specific Populations and CLINICAL PHARMACOLOGY].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Arterial Occlusions And Venous Thromboembolism
Inform patients that serious arterial thromboses (including arterial stenosis sometimes requiring revascularization) and venous thromboembolism events have occurred. Advise patients to immediately contact their healthcare provider with any symptoms suggestive of a blood clot such as chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, or leg swelling [see WARNINGS AND PRECAUTIONS].
Heart Failure And Cardiac Arrhythmias
Inform patients of the possibility of heart failure, and abnormally slow or fast heart rates. Advise patients to contact their healthcare provider if they experience symptoms such as shortness of breath, chest pain, palpitations, dizziness, or fainting [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of new or worsening of existing hypertension. Advise patients to contact their healthcare provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache, dizziness, chest pain, or shortness of breath [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, abdominal pain, or abdominal discomfort, and to promptly report these symptoms [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of developing peripheral or cranial neuropathy while being treated with Iclusig. Advise patients to report symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of ocular toxicity while being treated with Iclusig. Advise patients to report symptoms of ocular toxicity, such as blurred vision, dry eye, or eye pain [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of serious bleeding and to immediately contact their healthcare provider with any signs or symptoms suggestive of hemorrhage such as unusual bleeding or easy bruising [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of developing fluid retention and to contact their healthcare provider for symptoms such as leg swelling, abdominal swelling, weight gain, or shortness of breath [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of developing low blood cell counts; inform patients to report immediately should fever develop, particularly in association with any suggestion of infection [see WARNINGS AND PRECAUTIONS].
Reversible Posterior Leukoencephalopathy Syndrome (RPLS – Also known As Posterior Reversible Encephalopathy Syndrome – PRES)
Inform patients of the possibility of developing Reversible Posterior Leukoencephalopathy Syndrome while being treated with Iclusig. Advise patients to report symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances [see WARNINGS AND PRECAUTIONS].
Impaired Wound Healing And Gastrointestinal Perforation
Inform patients that impaired wound healing and gastrointestinal fistula or perforation have been reported. Advise patients to inform their healthcare provider of any planned surgical procedure [see WARNINGS AND PRECAUTIONS].
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Advise women not to breastfeed during treatment with Iclusig and for 6 days after the last dose [see Use In Specific Populations].
Advise females of reproductive potential of the potential for reduced fertility from Iclusig [see Use In Specific Populations and Nonclinical Toxicology].
Instructions For Taking Iclusig
Advise patients to take Iclusig exactly as prescribed and not to change their dose or to stop taking Iclusig unless they are told to do so by their healthcare provider. Iclusig may be taken with or without food. Iclusig tablets should be swallowed whole. Patients should not crush or dissolve the tablets.
Patients should not take two doses at the same time to make up for a missed dose.
Inform patients that Iclusig contains 121 mg of lactose monohydrate in a 45 mg daily dose.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 2-year carcinogenicity study, male and female rats were administered daily oral doses of ponatinib of 0.05 mg/kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day and 0.2 mg/kg/day, 0.4 mg/kg/day, and 0.8 mg/kg/day, respectively. Exposures in animals at the highest dose tested were 0.3-to 0.8-fold the human exposure (based on AUC) at doses of 15 mg and 45 mg daily. Ponatinib induced a statistically significant increase in malignant squamous neoplasms of the clitoral gland in females at 0.8 mg/kg/day.
Ponatinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, nor was it clastogenic in an in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg.
Ponatinib may impair female fertility. In a fertility study in male and female rats, female fertility parameters were reduced at 1.5 mg/kg/day with exposure equivalent to 0.43 times and 1.23 times, of human daily steady state AUC at the recommended dose of 45 mg/day (AUC = 1296 h•ng/mL) and 15 mg/day (451.8 h•ng/mL), respectively. Evidence of pre-and postimplantation loss of embryos was observed in female rats. Although there were no effects on male fertility parameters in the rat fertility study, repeat dose toxicology studies in monkeys showed degeneration of epithelium of the testes in monkeys at exposures approximately 3.3 times the plasma drug exposure (AUC) in patients receiving the recommended dose of 45 mg/day.
Use In Specific Populations
Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman [see Data]. 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 recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
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 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 recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.
There is no data on the presence of ponatinib in human milk, the effects on the breastfed infant or on milk production.
Because of the potential for serious adverse reactions in breastfed infants from ponatinib including arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity, advise women not to breastfeed during treatment with Iclusig and for 6 days following the last dose.
Females And Males Of Reproductive Potential
Iclusig can cause fetal harm when administered to pregnant women [see Pregnancy and CLINICAL PHARMACOLOGY].
Verify the pregnancy status of females of reproductive potential prior to initiating Iclusig treatment.
Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose.
Based on animal data, ponatinib may impair fertility in females of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology].
Safety and effectiveness 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 clinical dose on a mg/m2 basis for a child.
One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥65 years had a lower major cytogenetic response rate (40%) as compared with patients <65 years of age (65%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥65 years had a similar hematologic response rate (45%) as compared with patients <65 years of age (44%). Forty percent of patients ≥65 years had arterial occlusion events. Patients of age ≥65 years 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.
Administer Iclusig at a dose of 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B, or C) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
In a single-dose (30 mg) pharmacokinetic (PK) study; compared to subjects with normal liver function, no major differences in ponatinib PK were observed in subjects with hepatic impairment (Child-Pugh A, B, or C). However, there was an increased overall incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in the subjects with hepatic impairment following the single 30 mg dose compared to subjects with normal liver function. The safety of multiple ponatinib doses, or doses higher than 30 mg have not been studied in patients with hepatic impairment.