Iclusig

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Ponatinib may cause heart or blood vessel problems that could lead to heart attack or stroke. Call your doctor right away or get emergency medical help if you have:

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, feeling short of breath;
• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance; or
• signs of a blood clot--severe stomach pain, pain or swelling in your arms or legs, coughing up blood.

Call your doctor at once if you have:

• numbness, tingling, or burning pain in your hands or feet;
• drooping eyelids, trouble moving your eyes or other parts of your face;
• eye pain or itching, dry eyes, and seeing flashes of light or "floaters" in your vision;
• severe stomach pain or swelling;
• fever, flu symptoms;
• dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, severe chest pain, shortness of breath;
• fluid retention--cough, shortness of breath, swelling, rapid weight gain;
• pancreas problems--severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
• severe bleeding--nosebleeds, bloody or tarry stools, pink or brown urine, heavy menstrual periods, vomit that is bloody or looks like coffee grounds; or
• signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urination; numbness or tingly feeling around your mouth; muscle weakness or tightness; fast or slow heart rate, weak pulse, feeling short of breath; confusion, fainting.

Common side effects may include:

• dry skin, mild skin rash;
• stomach pain, nausea, constipation;
• fever;
• tired feeling; or
• headache, joint pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Mechanism of Action

Kinase inhibitor; inhibits activity of ABL and T315I mutant ABL; inhibits additional kinases including BEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3

Absorption

Bioavailability: Unknown

Peak Plasma Time: 6 hr Peak

Plasma Concentration: 73 ng/mL(45 mg/day)

AUC: 1253 mcg•h/mL (45 mg/day)

Aqueous solubility is pH dependent, with higher pH resulting in lower solubility

Distribution

Protein Bound: >99%

Vd: 1223 L (steady-state at day 28)

Metabolism

Metabolized predominantly by CYP3A4, and to a lesser extent CYP2C8, CYP2D6, and CYP3A5

Also metabolized by esterases and/or amidases P-gp substrate (weak)

Elimination

Half-life: 24 hr (range: 12-66 hr)

Excretion: 87% feces, 5% urine

Pharmacogenomics

Inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I

Instructions

May take with or without food

Swallow tablets whole; do not chew, crush, or split

Included as part of the PRECAUTIONS section.

Common side effects include the following:

• elevated blood pressure
• rash
• stomach pain
• fatigue
• headache
• dry skin
• constipation
• joint pain
• nausea
• fever
• low blood counts

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if this medication crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using this medication.

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• Store Iclusig at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep this and all other medications out of the reach of children.

• Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig 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. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion.
• Heart Failure, including fatalities, occurred in 8% 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.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Ponatinib may cause heart or blood vessel problems that could lead to heart attack or stroke. Call your doctor right away or get emergency medical help if you have:

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, feeling short of breath;

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance; or

• signs of a blood clot--severe stomach pain, pain or swelling in your arms or legs, coughing up blood.

Call your doctor at once if you have:

• headache, confusion, change in mental status, vision loss, seizure (convulsions);

• severe stomach pain or swelling;

• fever, flu symptoms;

• effects on your eyes--eye pain or itching, swollen eyes, dry eyes, bleeding in the eye, increased sensitivity to light, seeing flashes of light or "floaters" in your vision;

• nerve problems--muscle weakness, trouble moving your eyes or other parts of your face, double vision, altered sense of taste, numbness, tingling, or burning pain in your hands or feet;

• dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, severe chest pain, shortness of breath;

• fluid retention--cough, shortness of breath, swelling, rapid weight gain;

• pancreas problems--severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;

• severe bleeding--nosebleeds, bloody or tarry stools, pink or brown urine, heavy menstrual periods, vomit that is bloody or looks like coffee grounds; or

• signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urination; numbness or tingly feeling around your mouth; muscle weakness or tightness; fast or slow heart rate, weak pulse, feeling short of breath; confusion, fainting.

Common side effects may include:

• dry skin, mild skin rash;

• stomach pain, nausea, vomiting, diarrhea, constipation;

• headache, muscle or joint pain;

• pain in your arms, hands, legs, or feet;

• increased blood pressure; or

• fever, tired feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Principally metabolized by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2D6, and 3A5.1 Ponatinib is a substrate of CYP3A4/5 and, to a lesser extent, CYP2C8 and 2D6.1

Does not inhibit metabolism of substrates for CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A; does not induce metabolism of substrates for CYP1A2, 2B6, or 3A.1

Inhibits P-glycoprotein (P-gp, ABCB1), ABCG2 (breast cancer resistance protein [BCRP]), and BSEP (bile salt export pump); appears to be a weak substrate for P-gp and ABCG2.1

Not a substrate for organic anion transport protein (OATP) 1B1 or OATP1B3; does not inhibit the organic cation transporters (OCT) 1, OCT2, OAT1, or OAT3.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of ponatinib).1 Reduce dosage of ponatinib.1

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased systemic exposure of ponatinib).1 Avoid concomitant use unless potential benefit outweighs possible risk of reduced ponatinib exposure.1 Monitor for signs of reduced ponatinib efficacy if concomitant use cannot be avoided.1

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased oral bioavailability of ponatinib) with drugs that increase gastric pH.1 Avoid concomitant use unless potential benefit outweighs possible risk of reduced ponatinib exposure.1 Monitor for signs of reduced ponatinib efficacy if concomitant use cannot be avoided.1

Substrates of P-glycoprotein or ABCG2 Transport Systems

Substrates of P-gp: Ponatinib inhibits P-gp and ABCG2.1

Specific Drugs and Food

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

• Tell all of your health care providers that you take Iclusig. This includes your doctors, nurses, pharmacists, and dentists.
• If you are allergic to lactose, talk with the doctor.
• If you have just been diagnosed with chronic myeloid leukemia (CML), talk with your doctor. A study showed that patients with newly diagnosed CML had more bad side effects with this medicine than with a certain other drug.
• This medicine may cause eye problems that may lead to loss of eyesight or blindness. Tell your doctor if you have or have ever had eye problems. Call your doctor right away if you have any changes in eyesight.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Very bad and sometimes deadly bleeding problems have happened with Iclusig. Talk with the doctor.
• High blood pressure has happened with this medicine. Have your blood pressure checked as you have been told by your doctor.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely. Tell your doctor if you get signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Holes in the GI (gastrointestinal) tract may rarely happen.
• Patients with cancer who take Iclusig may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
• A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with this medicine. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache.
• If you are 65 or older, use Iclusig with care. You could have more side effects.
• This medicine may cause fertility problems. This may affect being able to have children. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting this medicine. Talk with your doctor.
• Use birth control that you can trust to prevent pregnancy while taking Iclusig (ponatinib) and for at least 3 weeks after your last dose.
• If you get pregnant while taking this medicine or within 3 weeks after your last dose, call your doctor right away.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about Iclusig, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Iclusig. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Iclusig.

Review Date: October 4, 2017

None.

Arterial Occlusion

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 multi-site 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 - 1355), 526 (range: 5 - 1339), and 478 (range: 3 - 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).

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 Warnings and Precautions (5.3)].

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 Iclusig-treated patients [see Warnings and Precautions (5.5)].

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 (2.3)].

Venous Thromboembolism

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 (2.3)].

Heart Failure

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 (2.3)].

Hepatotoxicity

Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one 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 (2.3)].

Hypertension

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 (6)].

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

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 - 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 (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 × 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.

Neuropathy

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.

Ocular Toxicity

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 (6)].

Hemorrhage

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 Warnings and Precautions (5.13)]. Interrupt Iclusig for serious or severe hemorrhage and evaluate [see Dosage and Administration (2.3)].

Fluid Retention

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 (2.3)].

Cardiac Arrhythmias

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

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– 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 (2.2)].

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)

Post marketing 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

No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.

Embryo-Fetal Toxicity

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 (8.1 ,8.3) and Clinical Pharmacology (12.1)].

Iclusig (ponatinib) is a kinase inhibitor. The chemical name for ponatinib hydrochloride is 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride. The molecular formula is C29H28ClF3N6O which corresponds to a formula weight of 569.02 g/mol. Its structure is shown below:

Ponatinib HCl is an off-white to yellow powder with pKa of 2.77 and 7.8. The solubility of ponatinib in pH 1.7, 2.7, and 7.5 buffers is 7790 mcg/ml, 3.44 mcg/ml, and 0.16 mcg/ml, respectively, indicating a decrease in solubility with increasing pH. Iclusig tablets are available as white, round, film-coated tablets for oral administration. Each tablet contains ponatinib hydrochloride equivalent to 15, 30 or 45 mg ponatinib with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type B), colloidal silicon dioxide, magnesium stearate and a tablet coating. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.