IMPORTANT SAFETY INFORMATION
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE,
See full prescribing information for complete boxed warning.
Arterial occlusion has occurred in at least 35% of ICLUSIG®
(ponatinib)-treated patients including 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 less than 50 years
old, experienced these events. Interrupt or stop ICLUSIG
immediately for arterial occlusion. A benefit-risk consideration
should guide a decision to restart ICLUSIG.
Venous Thromboembolism has occurred in 6% of ICLUSIG-treated
patients. Monitor for evidence of thromboembolism. Consider dose
modification or discontinuation of ICLUSIG in patients who develop
serious venous thromboembolism.
Heart Failure, including fatalities occurred in 9% of
ICLUSIG-treated patients. Monitor cardiac function. Interrupt or
stop ICLUSIG for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in
ICLUSIG-treated patients. Monitor hepatic function. Interrupt
ICLUSIG if hepatotoxicity is suspected.
ICLUSIG® (ponatinib) is a kinase inhibitor indicated for the:
Treatment of adult patients with chronic phase, accelerated phase, or
blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome
positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other
tyrosine kinase inhibitor (TKI) therapy is indicated.
Treatment of adult patients with T315I-positive chronic myeloid
leukemia (chronic phase, accelerated phase, or blast phase) or
T315I-positive Ph+ ALL.
Limitations of use:
ICLUSIG is not indicated and is not recommended for the treatment of
patients with newly diagnosed chronic phase CML.
WARNINGS AND PRECAUTIONS
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. 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 event. Fatal and life-threatening events have occurred
within 2 weeks of starting treatment, with doses as low as 15 mg per day.
ICLUSIG can also cause recurrent or multi-site vascular occlusion. Patients
have required revascularization procedures. The median time to onset of the
first cardiac vascular, cerebrovascular, and peripheral vascular arterial
occlusive events was 193, 526, and 478 days, respectively. Patients with and
without cardiovascular risk factors, some age 50 years or younger,
experienced these events. The most common risk factors observed with these
events were hypertension, hyperlipidemia, and history of cardiac disease.
Arterial occlusive events were more frequent with increasing age and in
patients with a history of ischemia, hypertension, diabetes, or
hyperlipidemia. In patients suspected of developing arterial occlusive
events, interrupt or stop ICLUSIG.
Venous thromboembolic events occurred in 6% (25/449) of ICLUSIG-treated
patients with an incidence rate of 5% (13/270 CP-CML), 4% (3/85 AP-CML), 10%
(6/62 BP-CML) and 9% (3/32 Ph+ ALL). Events included: deep venous
thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal
vein thrombosis with vision loss. Consider dose modification or
discontinuation of ICLUSIG in patients who develop serious venous
Fatal or serious heart failure or left ventricular dysfunction occurred in
6% of ICLUSIG-treated patients (29/449). Nine percent of patients (39/449)
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 (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 if serious heart failure develops.
ICLUSIG can cause hepatotoxicity, including liver failure and death.
Fulminant hepatic failure leading to death occurred in a patient within one
week of starting ICLUSIG. Two additional fatal cases of acute liver failure
also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL.
Severe hepatotoxicity occurred in all disease cohorts, with 11% (50/449)
experiencing grade 3 or 4 hepatotoxicity. The most common forms of
hepatotoxicity were elevations of AST or ALT (54% all grades, 8% grade 3 or
4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase.
Hepatotoxic events were observed in 29% of patients. The median time to
onset of hepatotoxicity event was 3 months. Monitor liver function tests at
baseline, then at least monthly or as clinically indicated. Interrupt,
reduce or discontinue ICLUSIG as clinically indicated.
Treatment-emergent elevation of systolic or diastolic blood pressure (BP)
occurred in 68% (306/449) of ICLUSIG-treated patients. Fifty-three patients
(12%) 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. 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, 37% developed Stage 2 hypertension. 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. 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. 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. Do not consider restarting
ICLUSIG until patients have complete resolution of symptoms and lipase
levels are less than 1.5 x 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 experienced a peripheral
neuropathy event of any grade (2%, grade 3/4). 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. 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.
Serious hemorrhage events including fatalities, occurred in 6% (28/449) of
patients treated with ICLUSIG. 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) each. Most hemorrhagic events, but not all, occurred in
patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or
severe hemorrhage and evaluate.
Fluid retention events judged as serious occurred in 4% (18/449) of patients
treated with ICLUSIG. One instance of brain edema was fatal. For fluid
retention events occurring in >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
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 ICLUSIG-treated 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
ICLUSIG-treated patients and grade 3/4 myelosuppression occurred in 50%
(226/449) of patients. 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 <1-40 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.
Tumor Lysis Syndrome:
Two patients (<1%, one with AP-CML and one with BP-CML) treated with ICLUSIG
developed serious tumor lysis syndrome. Hyperuricemia occurred in 7%
(31/449) of patients. Due to the potential for tumor lysis syndrome in
patients with advanced disease, 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.
Compromised Wound Healing and Gastrointestinal Perforation:
Since ICLUSIG may compromise wound healing, interrupt ICLUSIG for at least 1
week prior to major surgery. Serious gastrointestinal perforation (fistula)
occurred in one patient 38 days post-cholecystectomy.
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.
Most Common Adverse Reactions:
Overall, the most common non-hematologic adverse reactions (≥20%) were
abdominal pain, rash, constipation, headache, dry skin, arterial occlusion,
fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase
increased, vomiting, myalgia and pain in extremity. Hematologic adverse
reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and
To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-844-T-1POINT
(1-844-817-6468) or FDA at 1-800-FDA-1088 or
Strong CYP3A Inhibitors:
Avoid concurrent use or reduce ICLUSIG dose if co-administration cannot be
Strong CYP3A Inducers:
Avoid concurrent use.
Use in Specific Populations
Females and Males of Reproductive Potential:
ICLUSIG can cause fetal harm when administered to pregnant women. Advise
females to use effective contraception during treatment with ICLUSIG and for
3 weeks after the last dose. Ponatinib may impair fertility in females and
it is not known if these effects are reversible. Verify pregnancy status of
females of reproductive potential prior to initiating ICLUSIG.
Advise women not to breastfeed during treatment with ICLUSIG and for six
days after last dose.
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