Warnings and Precautions

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.

Other warnings and precautions include:

Hypertension

Monitor for high blood pressure and manage as clinically indicated.

Pancreatitis

Monitor serum lipase monthly; interrupt or discontinue ICLUSIG.

Neuropathy

Monitor for symptoms of peripheral and cranial neuropathy.

Ocular Toxicity

Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage

Interrupt ICLUSIG for serious or severe hemorrhage.

Fluid Retention

Monitor patients for fluid retention; interrupt, reduce, or discontinue ICLUSIG.

Cardiac Arrhythmias

Monitor for symptoms of arrhythmias.

Myelosuppression

Thrombocytopenia, neutropenia, and anemia may require dose interruption or reduction. Monitor complete blood counts every 2 weeks for 3 months and then monthly and as clinically indicated. Interrupt ICLUSIG for ANC < 1000/mm³ or thrombocytopenia < 50,000/ mm³.

Tumor Lysis Syndrome

Ensure adequate hydration and correct elevated uric acid levels prior to initiating therapy with ICLUSIG.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Interrupt ICLUSIG 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

Temporarily interrupt therapy in patients undergoing major surgical procedures.

Embryo-Fetal Toxicity

Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

Know Heart Failure

Heart failure occurred in 8% of patients (35/449) treated with ICLUSIG^® (ponatinib) in the PACE trial, with fatal and serious heart failure or left ventricular dysfunction occurring in 5% of ICLUSIG-treated patients (22/449).

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Monitor Heart Failure

Defining heart failure.
In the PACE trial, cardiac events included cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, and right ventricular failure.

Heart failure CTCAE grades¹
Grade 1	Asymptomatic with laboratory or cardiac imaging abnormalities
Grade 2	Symptoms with mild to moderate activity or exertion
Grade 3	Severe with symptoms at rest or with minimal activity or exertions; intervention indicated
Grade 4	Life-threatening consequences; urgent intervention indicated
Grade 5	Death

Helping your patients identify signs of heart failure.
Advise your patients to immediately report symptoms such as:

Shortness of breath
Chest pain
Palpitations
Dizziness
Fainting

REFERENCE
1. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Available at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf.

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Manage Heart Failure

Recommendations for managing ICLUSIG^® (ponatinib) patients with heart failure.
When discussing ICLUSIG treatment with your patients, inform them of the possibility of heart failure. 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.

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Know Hepatotoxicity

ICLUSIG^® (ponatinib) can cause hepatotoxicity, including liver failure and death. The incidence of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation in the PACE trial was:

56% for all grades
8% for grade 3 or 4

ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients. 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 hepatotoxicity occurs in all disease cohorts.

Of note, in patients with hepatic impairment (Child-Pugh A, B, or C) the recommended starting dose is 30 mg once daily.

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Monitor Hepatotoxicity

Defining hepatotoxicity.
Hepatotoxicity is drug induced liver damage as defined by an increase in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST).¹

ALT/AST elevation²
Grade 1	< 3.0 x ULN
Grade 2	> 3.0 – 5.0 x ULN
Grade 3	> 5.0 – 20.0 x ULN
Grade 4	> 20.0 x ULN

ULN = Upper Limit of Normal for the lab

Identifying hepatotoxicity.
Injury to the liver can be identified by testing liver function at regular intervals in patients taking tyrosine kinase inhibitors (TKI). The following are liver and biochemical function tests.³

Liver and biochemical function tests examples	Reference range
Bilirubin	0.3 to 1.0 mg/dL (total) 0 to 0.2 mg/dL (direct)
Alanine aminotransferase (ALT)	Men: 10 to 40 U/L Women: 7 to 35 U/L
Aspartate aminotransferase (AST)	Men: 14 to 20 U/L Women: 10 to 36 U/L
Alkaline phosphatase (ALP)	Adults: 25 to 100 U/L

Helping your patients recognize hepatotoxicity.
Advise patients to immediately report signs and symptoms of potential liver failure, including:

Jaundice
Anorexia
Bleeding or bruising

REFERENCES
1. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-739.
2. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Available at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf.
3. Fischbach FT, Dunning MB III, eds. (2009). Manual of Laboratory and Diagnostic Tests, 8th ed. Philadelphia: Lippincott Williams and Wilkins.

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Manage Hepatotoxicity

Recommendations for managing ICLUSIG^® (ponatinib) patients with hepatotoxicity.
When discussing ICLUSIG treatment with your patients, inform them of the possibility of developing liver function abnormalities and serious hepatic toxicity.

Monitor liver function at baseline, then test at least monthly or as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.

Recommended dose modifications for hepatic toxicity
Elevation of liver transaminase > 3 x ULN (Grade 2 or higher)	Occurrence at 45 mg: Interrupt ICLUSIG and monitor hepatic function Resume ICLUSIG at 30 mg after recovery to ≤ Grade 1 (< 3 x ULN) Occurrence at 30 mg: Interrupt ICLUSIG and resume at 15 mg after recovery to ≤ Grade 1 Occurrence at 15 mg: Discontinue ICLUSIG
Elevation of AST or ALT ≥ 3 x ULN concurrent with an elevation of bilirubin > 2 x ULN and alkaline phosphatase < 2 x ULN	Discontinue ICLUSIG

Recommended dose modifications for hepatic toxicity

Elevation of liver transaminase > 3 x ULN (Grade 2 or higher)

Occurrence at 45 mg:

Interrupt ICLUSIG and monitor hepatic function
Resume ICLUSIG at 30 mg after recovery to ≤ Grade 1 (< 3 x ULN)

Occurrence at 30 mg:

Interrupt ICLUSIG and resume at 15 mg after recovery to ≤ Grade 1

Occurrence at 15 mg:

Discontinue ICLUSIG

Elevation of AST or ALT ≥ 3 x ULN concurrent with an elevation of bilirubin > 2 x ULN and alkaline phosphatase < 2 x ULN

Discontinue ICLUSIG

ULN = Upper Limit of Normal for the lab

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Know Hypertension

Treatment-emergent hypertension occurred in 67% (300/449) of patients treated with ICLUSIG^® (ponatinib) in the PACE trial.

8 patients experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis.

In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension.

Stage 1 hypertension (defined as systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg)
Stage 2 hypertension (defined as systolic BP ≥ 160 mm Hg or diastolic BP ≥ 100 mm Hg)

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Monitor Hypertension

Defining hypertension.
Hypertension as an adverse reaction in clinical trials is a disorder characterized by a pathological increase in blood pressure; a repeated elevation in the blood pressure exceeding 140 over 90 mm Hg.¹

Hypertension CTCAE grades¹
Grade 1	Prehypertension (systolic BP 120-139 mm Hg or diastolic 80-89 mm Hg)
Grade 2	Stage 1 hypertension (systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg); medical intervention indicated; recurrent or persistent (≥ 24 hrs); symptomatic increase by > 20 mm Hg (diastolic) or to > 140/90 mm Hg if previously within normal limits; monotherapy indicated
Grade 3	Stage 2 hypertension (systolic BP ≥ 160 mm Hg or diastolic BP ≥ 100 mm Hg); medical intervention indicated; more than one drug or more intensive therapy than previously used indicated
Grade 4	Life-threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated
Grade 5	Death

Helping your patients recognize hypertension.
In rare cases, hypertensive emergencies can occur and are characterized by:²

Dizziness
Chest pain
Shortness of breath

REFERENCES
1. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Available at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf.
2. Lepe M, Varon J. Chapter 252. Hypertensive Urgencies. In: Matloff J, Dressler DD, Brotman DJ, Ginsberg JS, eds. Principles and Practice of Hospital Medicine. New York, NY: McGraw-Hill; 2012.
http://www.accessmedicine.com/content.aspx?aID=56215880. Accessed December 26, 2013.

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Manage Hypertension

Recommendations for managing ICLUSIG^® (ponatinib) patients with hypertension.
When discussing ICLUSIG treatment with your patients, inform them of the possibility of new or worsening of existing hypertension, and instruct them to report hypertensive symptoms.

Patients such as these may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.
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.

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Know Pancreatitis

Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with ICLUSIG^® (ponatinib) in the PACE trial. Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%.

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Monitor Pancreatitis

Defining pancreatitis.
Pancreatitis is a disorder characterized by inflammation of the pancreas.¹

Pancreatitis CTCAE grades¹
Grade 1	NA
Grade 2	Enzyme elevation or radiologic findings only
Grade 3*	Severe pain; vomiting; medical intervention indicated (e.g., analgesia, nutritional support)
Grade 4*	Life-threatening consequences; urgent intervention indicated
Grade 5*	Death

*Symptomatic

Identifying pancreatitis.

Elevated levels of these enzymes may indicate pancreatitis²
Enzyme	Function	Normal Test Results
Lipase	Glycoprotein, in the presence of bile salts and colipase, changes fats to fatty acids and glycerol	Adults ≤ 60: 10-140 U/L Adults > 60: 18-180 U/L
Amylase	Converts starch to sugar; is produced in the salivary (parotid) glands and pancreas	Adults ≤ 60: 25-125 U/L Adults > 60: 24-151 U/L

Helping your patients recognize pancreatitis.
The most common symptom of acute pancreatitis is abdominal pain. Typically it is generalized to the upper abdomen, but it may be more localized to the right upper quadrant, epigastric area, or occasionally, left upper quadrant.³

Patients may also present with nausea and vomiting. Blood tests for pancreatitis should be performed during treatment with ICLUSIG.

REFERENCES
1. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Available at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf.
2. Fischbach FT, Dunning MB III, eds. (2009). Manual of Laboratory and Diagnostic Tests, 8th ed. Philadelphia: Lippincott Williams and Wilkins.
3. Capell MS. Acute pancreatitis: etiology, clinical presentation, diagnosis, and therapy. Med Clin N Am. 2008;92(4):889-923

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Manage Pancreatitis

Recommendations for managing ICLUSIG^® (ponatinib) patients with pancreatitis.
When discussing ICLUSIG treatment with your patients, inform them of the possibility of developing pancreatitis and to report nausea, vomiting, abdominal pain, and abdominal discomfort.

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.
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.

Recommended dose modifications for pancreatitis and elevation of lipase
Asymptomatic Grade 1 or 2 elevation of serum lipase	Consider interruption or dose reduction of ICLUSIG
Asymptomatic Grade 3 or 4 elevation of lipase (> 2 x ULN) or asymptomatic radiologic pancreatitis (Grade 2 pancreatitis)	Occurrence at 45 mg: Interrupt ICLUSIG and resume at 30 mg after recovery to ≤ Grade 1 (< 1.5 x ULN) Occurrence at 30 mg: Interrupt ICLUSIG and resume at 15 mg after recovery to ≤ Grade 1 Occurrence at 15 mg: Discontinue ICLUSIG
Symptomatic Grade 3 pancreatitis	Occurrence at 45 mg: Interrupt ICLUSIG and resume at 30 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1 Occurrence at 30 mg: Interrupt ICLUSIG and resume at 15 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1 Occurrence at 15 mg: Discontinue ICLUSIG
Grade 4 pancreatitis	Discontinue ICLUSIG

ULN = Upper Limit of Normal for the lab

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Know Myelosuppression

Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with ICLUSIG^® (ponatinib) in the PACE trial. The incidence of these events was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML.

*Incidence of clinically relevant grade 3/4 hematologic abnormalities**
Laboratory Test	CP-CML (N=270) (%)	AP-CML (N=85) (%)	BP-CML (N=62) (%)	Ph+ ALL (N=32) (%)
Hematology
Thrombocytopenia (platelet count decreased)	36	47	57	47
Neutropenia (ANC decreased)	24	51	55	63
Leukopenia (WBC decreased)	14	35	53	63
Anemia (Hgb decreased)	9	26	55	34
Lymphopenia	10	26	37	22

ANC = absolute neutrophil count, Hgb = hemoglobin, WBC = white blood cell count
*Reported using NCI-CTC-AE v 4.0

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Monitor Myelosuppression

Defining myelosuppression.
Relevant myelosuppression is characterized by decreased bone marrow activity, resulting in fewer red blood cells, white blood cells, and platelets.¹

Helping patients recognize myelosuppression.
Patients should look for fever, particularly in association with any sign or suggestion of an infection.

REFERENCE
1. Myelosuppression. NCI Dictionary of Cancer Terms. National Cancer Institute. Available at:
http://www.cancer.gov/dictionary?cdrid=44173. Accessed May 6, 2014.

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Manage Myelosuppression

Recommendations for managing ICLUSIG^® (ponatinib) patients with myelosuppression.
When discussing ICLUSIG treatment with your patients, inform them of the possibility of developing low blood cell counts. Advise patients to report immediately should a fever develop, particularly in association with any suggestion of infection.

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.

Suggested dose modifications for myelosuppression
ANC < 1 x 10⁹/L or platelet < 50 x 10⁹/L	First occurrence: Interrupt ICLUSIG and resume initial 45 mg dose after recovery to ANC ≥ 1.5 x 10⁹/L and platelet ≥ 75 x 10⁹/L
Second occurrence: Interrupt ICLUSIG and resume at 30 mg after recovery to ANC ≥ 1.5 x 10⁹/L and platelet ≥ 75 x 10⁹/L
Third occurrence: Interrupt ICLUSIG and resume at 15 mg after recovery to ANC ≥ 1.5 x 10⁹/L and platelet ≥ 75 x 10⁹/L

Suggested dose modifications for myelosuppression

ANC < 1 x 10⁹/L
or
platelet < 50 x 10⁹/L

First occurrence:

Interrupt ICLUSIG and resume initial 45 mg dose after recovery to ANC ≥ 1.5 x 10⁹/L and platelet ≥ 75 x 10⁹/L

Second occurrence:

Interrupt ICLUSIG and resume at 30 mg after recovery to ANC ≥ 1.5 x 10⁹/L and platelet ≥ 75 x 10⁹/L

Third occurrence:

Interrupt ICLUSIG and resume at 15 mg after recovery to ANC ≥ 1.5 x 10⁹/L and platelet ≥ 75 x 10⁹/L

ANC = absolute neutrophil count

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Other Warnings and Precautions

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^® (ponatinib)-treated patients. Overall, 13% (59/449) of ICLUSIG-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of ICLUSIG-treated patients (<1%, grade 3/4).

Of the patients who developed neuropathy, 31% (20/65) 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 interruping ICLUSIG and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicites 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 3% of ICLUSIG-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with ICLUSIG. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and evaluate.

Fluid retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with ICLUSIG. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of ICLUSIG-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of ICLUSIG-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt ICLUSIG and evaluate.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with ICLUSIG developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 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.

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.

Embryo-Fetal Toxicity: ICLUSIG can cause fetal harm. If ICLUSIG is used during pregnancy, or if the patient becomes pregnant while taking ICLUSIG, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ICLUSIG.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

For a complete list of adverse reactions associated with ICLUSIG^® (ponatinib), and more in-depth learning, please see the full Prescribing Information, including the Boxed Warning.