IMPORTANT SAFETY INFORMATION
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY
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 thromboembolism.
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 indicated.
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 leukopenia.
To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-844-T-1POINT (1-844-817-6468) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Strong CYP3A Inhibitors:
Avoid concurrent use or reduce ICLUSIG dose if co-administration cannot be avoided.
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.
Please see full Prescribing Information including Boxed Warnings.