Ponatinib

Do not eat large amounts of grapefruit or drink grapefruit juice while taking this medication.

Ponatinib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• rash
• dry skin
• diarrhea
• constipation
• hair loss
• white patches or sores on the lips or in the mouth and throat
• loss of appetite
• weight loss
• cough
• difficulty falling asleep or staying asleep
• night sweats
• muscle cramps
• back, bone, joint, limb, or muscle pain

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, stop taking ponatinib and call your doctor immediately or get emergency medical treatment:

• unusual bruising or bleeding
• bloody or black, tarry stools
• blood in the urine
• bloody vomit
• unusual vaginal bleeding or heavier than usual menstrual bleeding
• vomit that looks like coffee grounds
• frequent nose bleeds
• coughing up blood
• dry, red, painful, or irritated eyes
• sensitivity to light
• blurred vision, floaters, double vision, or other vision changes
• wounds that do not heal
• fever, sore throat, chills, or other signs of infection
• changes in taste; muscle weakness; drooping eyelids or part of face; tingling, burning, pain, or loss of feeling in hands or feet
• headache, seizures, confusion, problems thinking, or changes or loss of vision
• decreased urination
• extreme tiredness or weakness
• weight gain
• swelling of your face, hands, feet, ankles, or lower legs
• pain, swelling, or tenderness in the abdomen (stomach area)
• nausea
• vomiting
• ongoing pain that begins in the stomach area but may spread to the back

Ponatinib may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Ponatinib is a prescription medication used to treat a certain type of chronic myeloid leukemia (CML). Ponatinib is also used to treat a certain type of acute lymphoblastic leukemia (ALL). Ponatinib belongs to a group of drugs called kinase inhibitors. These work by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells.

Ponatinib comes as a tablet to take by mouth. It is usually taken once a day with or without food. Take ponatinib at around the same time every day.

Common side effects include high blood pressure, rash, stomach pain, and fatigue. Do not drive or operate heavy machinery until you know how this medication affects you.

Ponatinib is a cancer medicine that interferes with the growth of some cancer cells.

Ponatinib is used to treat a type of blood cancer called chronic myeloid leukemia (CML), or Philadelphia chromosome positive acute lymphoblastic leukemia (ALL).

Ponatinib is usually given after other similar medications have been tried without success.

Ponatinib may also be used for purposes not listed in this medication guide.

Ponatinib is usually taken once daily. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Do not crush, break, or dissolve a ponatinib tablet. Swallow it whole.

You may take ponatinib with or without food.

You may need frequent medical tests to be sure this medication is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.

If you need surgery, tell the surgeon ahead of time that you are using ponatinib. You may need to stop using the medicine at least 1 week before a surgery.

Do not stop taking ponatinib or change your medication dose without your doctor's advice.

Store at room temperature away from moisture and heat.

• Tell all of your health care providers that you take ponatinib. 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 ponatinib. 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 ponatinib 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 ponatinib 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 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.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Blue or very pale skin in the arms or legs.
• Change in eyesight, eye pain, or very bad eye irritation.
• Loss of eyesight.
• Eye is bothered by bright light.
• Seeing floaters.
• Dry eyes.
• Drooping of part of the face.
• Chest pain or pressure.
• A heartbeat that does not feel normal.
• Fast or slow heartbeat.
• Dizziness or passing out.
• Swelling of belly.
• Very bad belly pain.
• Mouth irritation or mouth sores.
• Feeling very tired or weak.
• Change in taste.
• Call your doctor right away if you have signs of nerve problems. These may include not being able to handle heat or cold; change in sense of touch; or burning, numbness, tingling, pain, or weakness in the arms, hands, legs, or feet.

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); although renal excretion is not a major excretion route for ponatinib.

Concerns related to adverse effects:

• Arrhythmias: Cardiac arrhythmias (bradyarrhythmias and tachyarrhythmias) have been reported. The most commonly reported arrhythmia was atrial fibrillation; ~50% of events were grade 3 or 4. Other grade 3 or 4 rhythm disorders have occurred (case reports). Some events required hospitalization; symptomatic bradyarrhythmia which required pacemaker implantation occurred in a few cases. Monitor for sign/symptoms of bradycardia (fainting, dizziness, chest pain) and tachycardia (palpitations, dizziness). May require therapy interruption and further evaluation.

• Arterial occlusion: [US Boxed Warning]: Arterial occlusions have occurred in at least 35% of ponatinib-treated patients. Some patients experienced more than 1 type of event. Events included fatal myocardial infarction (MI), stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures; incidents were observed in patients with and without cardiovascular risk factors (including patients ≤50 years of age). Monitor closely for arterial occlusion; interrupt or discontinue therapy immediately for arterial occlusion. Consider risk:benefit ratio when deciding to restart therapy. Fatal and life-threatening arterial occlusion may occur within 2 weeks of therapy initiation and is not dose dependent (events have occurred at doses as low as 15 mg daily), and may cause recurrent or multisite occlusion. The most common risk factors for developing arterial occlusive events were hypertension, hyperlipidemia, and history of cardiac disease. Increasing age and a prior history of ischemia, hypertension, diabetes, or hyperlipidemia are also risk factors for development of ponatinib-associated vascular occlusion. Patients have required a revascularization procedure (cerebrovascular, coronary, and peripheral arterial) due to serious arterial thrombosis/occlusion. MI and coronary artery occlusion may result in heart failure due to myocardial ischemia. Cerebrovascular occlusion (including fatal stroke) has occurred; may cause stenosis over multiple segments in major arterial vessels that supply the brain. Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, have occurred. Some patients have required amputation due to digital or distal extremity necrosis. Renal artery stenosis (associated with worsening or refractory hypertension) has been reported.

• Bone marrow suppression: Severe myelosuppression (grade 3 or 4) is commonly observed with ponatinib, and the incidence was greater in patients with accelerated or blast phase CML and Ph+ ALL. The median onset to severe myelosuppression was 1 month (range: up to 40 months). Monitor blood counts closely; may require therapy interruption and/or dosage reduction.

• Fluid retention/edema: Serious fluid retention events, including fatality due to brain edema (case report), were observed in ponatinib-treated patients. Peripheral edema, pleural effusions, pericardial effusions, and peripheral swelling were commonly seen. Monitor patients for fluid retention; may require therapy interruption, dosage reduction, or discontinuation.

• Gastrointestinal perforation: Serious gastrointestinal perforation (fistula) occurred very rarely; monitor for signs/symptoms of perforation and/or fistula.

• Heart failure:[US Boxed Warning]: Serious heart failure (HF) or left ventricular dysfunction, including fatalities, were reported in clinical trials. Monitor for signs/symptoms of HF; interrupt or discontinue ponatinib therapy for new or worsening HF.The most commonly reported heart failure events were congestive heart failure and decreased ejection fraction. Treat as clinically warranted if HF develops. Consider ponatinib discontinuation in the event of serious HF.

• Hemorrhage: Hemorrhagic events occurred in ponatinib-treated patients, including serious events such as cerebral (subdural hematoma) and gastrointestinal hemorrhages; fatalities were reported. Serious bleeding episodes occurred more frequently in patients with accelerated or blast phase CML, and Ph+ ALL; most patients had grade 4 thrombocytopenia. Monitor platelet levels closely and for signs/symptoms of bleeding, and interrupt therapy if necessary.

• Hepatotoxicity: [US Boxed Warning]: Liver failure and death resulting from ponatinib-induced hepatotoxicity were observed; monitor liver function prior to and at least monthly (or as clinically indicated) during treatment. The median time to onset was 3 months (range: less than 1 month to 47 months). Hepatotoxicity may require treatment interruption (followed by dose reduction) or discontinuation. One case of fulminant hepatic failure leading to death occurred within 1 week of therapy initiation; acute liver failure has also occurred. Treatment may commonly result in ALT and/or AST, bilirubin, and alkaline phosphatase elevations. ALT/AST elevations may be irreversible.

• Hypertension: Treatment-emergent blood pressure elevations (systolic or diastolic) developed in over two-thirds of ponatinib-treated patients; symptomatic hypertension or hypertensive crisis were reported in several patients, requiring urgent intervention. Blood pressure may worsen in patients with preexisting hypertension. Monitor blood pressure closely, and manage elevated pressures as clinically indicated. May require therapy interruption, dosage reduction, or discontinuation if hypertension is resistant to medical management. Renal artery stenosis (associated with worsening, labile, or treatment-resistant hypertension) has occurred in some patients receiving ponatinib. Evaluate for renal artery stenosis for hypertension that significantly worsens, is labile, or treatment-resistant.

• Neuropathy: Peripheral and cranial neuropathy have been reported. Peripheral neuropathy, paresthesia, hypoesthesia, hyperesthesia, dysguesia, and muscular weakness occurred most frequently; cranial neuropathy occurred rarely. In one-quarter of patients who experienced symptoms, neuropathy developed during the first month of therapy. Monitor for signs/symptoms of neuropathy; consider interrupting treatment if neuropathy develops.

• Ocular toxicity: Serious ocular events such as blindness and blurred vision have occurred with ponatinib use. Macular edema, retinal vein occlusion, and retinal hemorrhage have been reported in a small percentage of patients; conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema, or eye pain occurred more frequently. Other toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Perform comprehensive ophthalmic exams prior to therapy initiation and periodically during treatment.

• Pancreatitis: Treatment-related lipase elevations and clinical pancreatitis occurred in clinical studies, including grade 3 and 4 events. The median time to onset was 14 days (range; 3 days to ~48 months); the majority of cases resolved within 2 weeks of therapy interruption or dose reduction. Monitor serum lipase every 2 weeks for the first 2 months and monthly thereafter or as clinically indicated; more frequent monitoring may be considered in patients with a history of pancreatitis or alcohol abuse. Monitor for clinical signs of pancreatitis, such as abdominal symptoms; interrupt therapy if necessary. Do not reinitiate treatment until complete resolution of symptoms and lipase level is <1.5 times ULN.

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in postmarketing surveillance. Signs/symptoms include seizure, headache, decreased awareness, altered mental status, vision loss, and other visual and/or neurological disturbances. Hypertension is common; RPLS is diagnosed through MRI of the brain. Discontinue ponatinib for RPLS diagnosis; resume only if RPLS resolves and the benefit of treatment outweighs the risk.

• Tumor lysis syndrome: Hyperuricemia and serious tumor lysis syndrome (rare) were reported. Patients should receive adequate hydration and be monitored for elevated uric acid levels and/or the development of tumor lysis syndrome. Manage elevated uric acid levels prior to initiating therapy.

• Venous thromboembolism: [US Boxed Warning]: Venous occlusive events have occurred in 6% of ponatinib-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of ponatinib in patients who develop serious venous thromboembolism. Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis have been reported.

• Wound healing impairment: As ponatinib inhibits VEGF activity, therapy may impair wound healing. Hold therapy for at least 1 week prior to major surgery; resume therapy post procedure based on clinical judgment of appropriate wound healing.

Disease-related concerns:

• Cardiovascular disease: Patients with or without cardiovascular risk factors, and those with a prior history of ischemia, hypertension, diabetes, or hyperlipidemia may be at increased risk for vascular occlusion when treated with ponatinib. Monitor for signs/symptoms of occlusion; interrupt therapy and consider discontinuation if thrombosis/occlusion occurs.

• Chronic phase CML (newly diagnosed): In a randomized study of first-line treatment of newly diagnosed chronic phase CML, a 2-fold increased risk of serious adverse reaction was demonstrated for ponatinib as compared to imatinib; the study was stopped due to safety concerns. Arterial and venous thrombosis and occlusion events occurred at least twice as frequently in the ponatinib arm of the study (compared to the imatinib arm); a higher incidence of hematologic toxicity, pancreatitis, hepatotoxicity, heart failure, hypertension, and dermatologic/subcutaneous tissue disorders was also observed in patients receiving ponatinib. Ponatinib is not indicated and not recommended for treatment of newly diagnosed chronic phase CML.

• Hepatic impairment: A single-dose (30 mg) pharmacokinetic study found that ponatinib exposure was not increased in patients with hepatic impairment (Child-Pugh class A, B, or C) as compared to patients with normal hepatic function. While generally well tolerated, patients with hepatic impairment did have an increased overall incidence of adverse reactions (eg, gastrointestinal disorders, pancreatitis). Monitor closely when administering to patients with impaired hepatic function. The starting dose should be reduced in patients with hepatic impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Patients ≥65 years of age may be more likely to experience vascular occlusion, weakness, decreased appetite, dyspnea, increased lipase, muscle spasms, peripheral edema, and thrombocytopenia; monitor closely. Cautious dose selection is recommended based on greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Commonly reported side effects of ponatinib include: arterial thrombosis, venous thrombosis, cardiac failure, congestive heart failure, pleural effusion, bone marrow depression, conjunctival irritation, dizziness, dyspnea, eye pain, fluid retention, gastrointestinal hemorrhage, headache, hyperesthesia, hypertension, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, increased serum lipase, paresthesia, peripheral edema, peripheral neuropathy, and xerophthalmia. Other side effects include: myocardial infarction, pancreatitis, severe bone marrow depression, supraventricular tachycardia, blurred vision, coronary artery disease, hemorrhage, hyperuricemia, and tachyarrhythmia. See below for a comprehensive list of adverse effects.

Applies to ponatinib: oral tablet

General

-A safety analysis showed a significant increase in grade 3 or greater adverse reactions (thrombocytopenia, neutropenia, rash, elevated ALT/AST, pancreatitis, elevated lipase) with an increase in dose intensity.[Ref]

Cardiovascular

-Very common (10% or more): Hypertension (74%), elevated blood pressure (68%), arterial ischemia (42%), arterial occlusion (35%), hemorrhage (28%), arrhythmia (19%), heart failure/left ventricular dysfunction (15%)
-Common (1% to 10%): Venous thromboembolism, atrial fibrillation, myocardial infarction, myocardial ischemia, congestive cardiac failure, coronary artery disease, angina pectoris, decreased ejection fraction, acute coronary syndrome, atrial flutter, peripheral arterial occlusive disease, peripheral ischemia, peripheral artery stenosis, intermittent claudication, deep vein thrombosis, hot flush, flushing, palpitations, poor peripheral circulation, splenic infarction
-Uncommon (0.1% to 1%): Hypertensive crisis, renal artery stenosis, cardiac discomfort
Frequency not reported: Ischemic cardiomyopathy, coronary arteriospasm[Ref]

Dermatologic

-Very common (10% or more): Rash and related conditions (63%), dry skin (42%), pruritus (13%), alopecia (11%), cellulitis (11%), erythema (10%)
-Common (1% to 10%): Folliculitis, skin exfoliation, night sweats, hyperhidrosis, petechia, ecchymosis, skin pain, exfoliative dermatitis, hyperkeratosis, skin hyperpigmentation[Ref]

Hematologic

-Very common (10% or more): Leukopenia (63%), myelosuppression (59%), neutropenia (59%), febrile neutropenia (25%), anemia (52%), thrombocytopenia (49%), lymphopenia (32%)
-Common (1% to 10%): Pancytopenia[Ref]

Endocrine

-Very common (10% or more): Increased glucose (54%), decreased glucose (13%)
-Common (1% to 10%): Hypothyroidism[Ref]

Gastrointestinal

-Very common (10% or more): Constipation (53%), abdominal pain (48%), increased lipase (42%), nausea (34%), diarrhea (29%), vomiting (27%), oral mucositis (23%), increased amylase (18%)
-Common (1% to 10%): GI hemorrhage, pancreatitis, gastroesophageal reflux disease, stomatitis, dyspepsia, abdominal distention, abdominal discomfort, dry mouth
-Frequency not reported: GI fistula, GI perforation[Ref]

Other

-Very common (10% or more): Asthenia/fatigue (49%), pyrexia (40%), peripheral edema (25%), pain (60%), chills (13%), sepsis (13%)
-Common (1% to 10%): Effusions (pericardial, pleural, ascites), influenza-like illness, peripheral swelling, non-cardiac chest pain, face edema, malaise[Ref]

Nervous system

-Very common (10% or more): Headache (43%), peripheral neuropathy (24%), dizziness (16%)
-Common (1% to 10%): Cranial neuropathy, cerebrovascular accident, cerebral infarction, lethargy, migraine, hyperesthesia, hypoesthesia, paresthesia, transient ischemic attack
-Uncommon (0.1% to 1%): Cerebral artery stenosis, cerebral hemorrhage, intracranial hemorrhage
-Postmarketing reports: Reversible posterior leukoencephalopathy syndrome/posterior reversible encephalopathy syndrome (RPLS/PRES)[Ref]

Hepatic

-Very common (10% or more): Increased ALT (41%), increased alkaline phosphatase (40%), increased AST (35%), hepatotoxicity (29%), decreased albumin (27%), increased bilirubin (13%)
-Common (1% to 10%): Increased gamma-glutamyltransferase
-Uncommon (0.1% to 1%): Hepatic failure, jaundice
-Frequency not reported: Acute liver failure[Ref]

Metabolic

-Very common (10% or more): Decreased phosphorus (33%), decreased calcium (30%), decreased appetite (31%), fluid retention (31%), decreased sodium (27%), increased creatinine (21%), decreased bicarbonate (19%), increased potassium (19%), decreased potassium (18%), decreased weight (13%), increased calcium (12%), increased sodium (10%)
-Common (1% to 10%): Hypertriglyceridemia, dehydration, increased blood cholesterol
-Uncommon (0.1% to 1%): Tumor lysis syndrome[Ref]

Musculoskeletal

-Very common (10% or more): Arthralgia (33%), myalgia (24%), pain in extremity (23%), back pain (21%), bone pain (14%), muscle spasms (14%), musculoskeletal pain (11%)
-Common (1% to 10%): Neck pain, musculoskeletal chest pain[Ref]

Respiratory

-Very common (10% or more): Cough (22%), dyspnea (20%), pleural effusion (19%), nasopharyngitis (18%), pneumonia (16%), upper respiratory tract infection (14%)
-Common (1% to 10%): Epistaxis, dysphonia, pulmonary hypertension, pulmonary embolism[Ref]

Genitourinary

-Very common (10% or more): Urinary tract infection (14%)
-Common (1% to 10%): Hyperuricemia[Ref]

Psychiatric

-Very common (10% or more): Insomnia (13%)
-Common (1% to 10%): Confusional state, erectile dysfunction[Ref]

Ocular

-Very common (10% or more): Ocular toxicities (14%; conjunctival irritation, corneal erosion/abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperemia, eye pain)
-Common (1% to 10%): Blurred vision, periorbital edema, eyelid edema, visual impairment, retinal toxicities (macular edema, retinal vein occlusion/thrombosis, retinal artery occlusion, retinal hemorrhage)
-Uncommon (0.1% to 1%): Vision loss[Ref]

Some side effects of ponatinib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

ANY LEVEL OF HEPATIC IMPAIRMENT (CHILD-PUGH A, B, OR C): Reduce the initial dose to 30 mg once a day; monitor for adverse reactions.

IF HEPATOTOXICITY DEVELOPS DURING TREATMENT:
Elevation of Liver Transaminase Greater Than 3 x ULN (Grade 2 or Higher):
-Occurrence at 45 mg: Interrupt dosing and monitor hepatic function; resume treatment at 30 mg after recovery to Grade 1 or less (less than 3 x ULN).
-Occurrence at 30 mg: Interrupt dosing and resume treatment at 15 mg after recovery to Grade 1 or less.
-Occurrence at 15 mg: Discontinue treatment.

Elevation of AST or ALT 3 x ULN or Greater WITH an Elevation of Bilirubin Greater Than 2 x ULN AND Alkaline Phosphatase Less Than 2 x ULN: Discontinue treatment.

US REMS: The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for ponatinib. It includes a communication plan. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNING:
-Arterial occlusions, venous thromboembolism, heart failure, and hepatotoxicity/liver failure have occurred.
-There were fatalities among the reported arterial occlusion, heart failure, and hepatotoxic cases.
-Monitor cardiac function, hepatic function, and for evidence of arterial occlusion and venous thromboembolism.
-Consider dose modification or discontinuation in patients who develop serious venous thromboembolism; interrupt treatment if hepatotoxicity is suspected; interrupt or stop treatment immediately for arterial occlusion and for new or worsening heart failure.
-A benefit-risk consideration should guide a decision to restart therapy.
-ARTERIAL OCCLUSION: Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Some patients experienced more than 1 type of event, including myocardial infarction, stroke, stenosis of large arterial brain vessels, severe peripheral vascular disease, and the needs for urgent revascularization procedures.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.