Iclusig

Last updated on RxList: 2/8/2021
Iclusig Side Effects Center

What Is Iclusig?

Iclusig (ponatinib) is a kinase inhibitor used to treat chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who do not benefit from or who do not tolerate other treatment.

What Are Side Effects of Iclusig?

Common side effects of Iclusig include:

  • skin rash,
  • abdominal or stomach pain,
  • tiredness,
  • headache,
  • dry skin,
  • constipation,
  • fever,
  • joint pain, or
  • nausea.

Tell your doctor if you have serious side effects of Iclusig including:

  • chest pain or heavy feeling,
  • pain spreading to the arm or shoulder;
  • sudden numbness or weakness (especially on one side of the body),
  • problems with vision, speech, or balance;
  • sudden cough, rapid breathing, coughing up blood;
  • easy bruising, unusual bleeding;
  • confusion, severe drowsiness, feeling like you might pass out;
  • fever, chills, flu symptoms, sores in your mouth and throat;
  • irregular heart rate;
  • shortness of breath (even with mild exertion);
  • yellowing skin or eyes;
  • severe pain in your upper stomach spreading to your back;
  • little or no urinating,
  • numbness or tingly feeling around your mouth,
  • overactive reflexes,
  • weak pulse,
  • fainting; or
  • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, seizure).

Dosage for Iclusig

The recommended dose for Iclusig is 45 mg administered orally once daily.

What Drugs, Substances, or Supplements Interact with Iclusig?

Iclusig may interact with conivaptan, imatinib, isoniazid, nefazodone, heart or blood pressure medicines, antibiotics, antifungals, hepatitis C medications, or HIV or AIDS medications. Tell your doctor all medications and supplements you use.

Iclusig During Pregnancy and Breastfeeding

Do not take Iclusig if you are pregnant or plan to become pregnant during treatment. It can harm a fetus. It is unknown if Iclusig passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Iclusig (ponatinib) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

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.

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Iclusig Consumer 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:

  • dizziness, confusion, headache, change in mental status;
  • a seizure;
  • swelling, rapid weight gain, feeling short of breath;
  • a wound that will not heal;
  • eye problems--vision problems, eye pain or swelling, bleeding in the eye, increased sensitivity to light, flashes of light or "floaters" in your vision;
  • heart problems--chest pain, shortness of breath, fast or pounding heartbeats, feeling like you might pass out;
  • a hole or tear in your stomach or intestine--severe pain or swelling in your stomach with a high fever;
  • low blood cell counts--fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet;
  • nerve problems--muscle weakness, trouble moving your eyes or other parts of your face, tingling, burning pain, numbness in your hands and feet;
  • severe bleeding--nosebleeds, bloody or tarry stools, pink or brown urine, heavy menstrual periods, coughing up blood or vomit that is bloody or looks like coffee grounds; or
  • signs of liver or pancreas problems--loss of appetite, upper stomach pain (that may spread to your back), nausea or vomiting, fast heart rate, dark urine, jaundice (yellowing of the skin or eyes).

Common side effects may include:

  • dry 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.

Read the entire detailed patient monograph for Iclusig (Ponatinib Tablets)

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Iclusig Professional Information

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Arterial Occlusive Events [see WARNINGS AND PRECAUTIONS]
  • Venous Thromboembolic Events [see WARNINGS AND PRECAUTIONS]
  • Heart Failure [see WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Hypertension [see WARNINGS AND PRECAUTIONS]
  • Pancreatitis [see WARNINGS AND PRECAUTIONS]
  • Neuropathy [see WARNINGS AND PRECAUTIONS]
  • Ocular Toxicity [see WARNINGS AND PRECAUTIONS]
  • Hemorrhage [see WARNINGS AND PRECAUTIONS]
  • Fluid Retention [see WARNINGS AND PRECAUTIONS]
  • Cardiac Arrhythmias [see WARNINGS AND PRECAUTIONS]
  • Myelosuppression [see WARNINGS AND PRECAUTIONS]
  • Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
  • Reversible Posterior Leukoencephalopathy Syndrome [see WARNINGS AND PRECAUTIONS]
  • Impaired Wound Healing and Gastrointestinal Perforation [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions identified in the Highlights of the Prescribing Information are from a pooled safety population of 543 patients with CML or Ph+ ALL who received Iclusig at a starting dose of 45 mg orally once daily. In this pooled safety population, the most common (>20%) adverse reactions were rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction, and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) were platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.

Previously Treated CP-CML

The safety of Iclusig was evaluated in OPTIC [see Clinical Studies]. Patients received one of three starting doses of Iclusig: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94) or 15 mg orally once daily (n=94). Patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. Only the safety information for the recommended starting dosage (45 mg) is described below. Patients who received a starting dose of Iclusig 45 mg orally once daily had a mandatory dose reduction to 15 mg once daily upon achievement of ≤1% BCR-ABL1IS. Of these patients, 70% were exposed for 1 year or longer and 37% were exposed for greater than two years. The median time to the response-based dose reduction to 15 mg was 6.4 months (range 3.1 months to 1.8 years).

Serious adverse reactions occurred in 32% of patients who received Iclusig at a starting dose of 45 mg. Serious adverse reactions in >2% of patients included AOEs (7%; of which 2.1% were sudden death), cardiac arrhythmias (6%), thrombocytopenia (5%), pyrexia (4.3%), anemia (3.2%), abdominal pain (3.2%), pancreatitis/lipase elevation (2.1%), neutropenia (2.1%), and hypertension (2.1%). Fatal adverse reactions occurred in 2 patients (2.1%), both of which were sudden death.

Permanent discontinuation of Iclusig due to an adverse reaction occurred in 18% of patients who received Iclusig at a starting dose of 45 mg. Adverse reactions which resulted in permanent discontinuation in >2% of patients included AOEs, thrombocytopenia, hypertension, and sudden death.

Dose modifications (dose interruption or reductions) of Iclusig due to an adverse reaction occurred in 69% of patients who received Iclusig at a starting dose of 45 mg. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia, pancreatitis/lipase elevation, neutropenia, hepatic dysfunction, rash and related conditions, and anemia.

The most common (>20%) adverse reactions were rash and related conditions, hypertension, arthralgia, hyperlipidemia, hepatic dysfunction, pancreatitis, and abdominal pain. The most common (>20%) Grade 3 or 4 laboratory abnormalities were platelet count decreased and neutrophil cell count decreased.

Table 4 summarizes the adverse reactions in OPTIC for patients who received Iclusig at a starting dose of 45 mg.

Table 4: Adverse Reactions (≥10%) in Patients with CP-CML Who Received Iclusig at Starting Dose of 45 mg Followed by Reduction to 15 mg After Achievement of ≤1% BCR-ABL1IS in OPTIC

Adverse ReactionIclusig 45 mg →15 mg
(N =94)
All Grades (%)Grade 3 or 4 (%)
Skin and Subcutaneous Tissue Disorders
Rash and related conditions513.2
Dry Skin120
Vascular Disorders
Hypertension3210
Arterial occlusive events135
Hemorrhage122.1
Musculoskeletal and Connective Tissue Disorders
Arthralgia(a)280
Metabolism and Nutrition Disorders
Hyperlipidemia(b)282.1
Gastrointestinal Disorders
Abdominal Pain(c)253.2
Pancreatitis/lipase elevation2315
Constipation110
Hepatobiliary Disorders
Hepatotoxicity256
Nervous System Disorders
Headache170
General Disorders and Administration Site Conditions
Pyrexia161.1
Fatigue or asthenia101.1
Cardiac Disorders
Cardiac arrhythmias154.3
Cardiac Failure121.1
Graded using CTCAE v5.0
(a) Arthralgia includes arthralgia, arthritis, back pain, intervertebral disc degeneration, osteoarthritis, pain, neck pain, pain in extremity, pain of skin, sciatica, spinal pain, tendonitis, tenosynovitis
(b) Hyperlipidemia includes blood cholesterol increased, blood triglycerides increased, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low density lipoprotein increased
(c) Abdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, chronic gastritis, colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal pain, gastroesophageal reflux disease, Helicobacter gastritis

Clinically relevant adverse reactions in ≤10% of patients who received Iclusig at a starting dose of 45 mg: neuropathy (7%), fluid retention and edema (5%), and hypothyroidism (3.2%)

Table 5 summarizes the laboratory abnormalities in OPTIC for patients who received Iclusig at a starting dose of 45 mg.

Table 5: Select Laboratory Abnormalities (>20%) that Worsened from Baseline in Patients with CPCML Who Received Iclusig at Starting Dose of 45 mg in OPTIC

Laboratory AbnormalityIclusig 45 mg → 15 mg
(N =94)
All Grades (%)Grade 3 or 4 (%)
Hematologic Laboratory Tests
Platelet count decreased6531
White blood cell decreased5613
Neutrophil cell count decreased5322
Lymphocyte decreased427
Hemoglobin decreased3514
Liver Function Tests
ALT increased491.1
AST increased400
Alkaline phosphatase increased231.1
Chemistry
Glucose increased461.1
Triglycerides increased423.2
Phosphate decreased273.2
Bicarbonate decreased270
Pancreatic Enzymes
Lipase increased3412
ALT = alanine aminotransferase, AST = aspartate aminotransferase
Graded using CTCAE v5.0 (except glucose increased which is graded using CTCAE v4.03)

Previously Treated CML Or Ph+ALL

The safety of Iclusig was evaluated in PACE [see Clinical Studies]. Eligible patients had CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior kinase inhibitor, including those with the BCR-ABL T315I mutation. Patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the 3 months prior to the first dose of Iclusig, were excluded. Patients received a starting dose of Iclusig 45 mg orally once daily (N=449). Dose reductions to 30 mg orally once daily or 15 mg orally once daily were allowed for the management of adverse reactions. After approximately 2 years of follow-up, patients who were still taking a 45 mg orally once daily dose were recommended to undergo a dose reduction in response to the continued occurrence of AOEs and VTEs in the clinical trial [see WARNINGS AND PRECAUTIONS]. At study completion (60 months of follow-up), the median duration of treatment with Iclusig was 32 months in patients with CP-CML, 19 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL.

Serious adverse reactions occurred in 69% of patients who received Iclusig. Serious adverse reactions in >2% of patients included AOEs (20%), pneumonia (10%), cardiac arrhythmias (8%), pancreatitis/lipase elevation (7%), abdominal pain (6%), cardiac failure (6%), hemorrhage (6%), sepsis (5%), VTEs (5%), fluid retention and edema (4.5%), pyrexia (4.5%), secondary malignancies (5%), anemia (3.3%), hypertension (3.1%), thrombocytopenia (3.1%), febrile neutropenia (2.9%), cellulitis (2.7%), and arthralgia (2.2%). Fatal adverse reactions occurred in 9% of patients who received Iclusig; the most frequent fatal adverse reactions were AOEs (2%), sepsis (1.6%), and hemorrhage (1.3%).

Permanent discontinuation of Iclusig due to an adverse reaction occurred in 21% of CP-CML, 12% of AP-CML, 15% of BP-CML, and 9% of Ph+ ALL patients. The most frequent adverse reactions that led to treatment discontinuation were thrombocytopenia (4.5%) and AOEs (4%).

Dose interruption of Iclusig for more than 3 days due to an adverse reaction occurred in 71% of patients and dose reduction of Iclusig due to an adverse reaction occurred in 68% of patients. Adverse reactions which required a dosage interruption or dose reduction in >5% of patients included thrombocytopenia (31%), pancreatitis/lipase elevation (17%), abdominal pain (14%), rash and related conditions (14%), neutropenia (14%), hepatic dysfunction (12%), AOEs (10%), arthralgia (8%), anemia (7%), ALT increased (6%), and AST increased (5%).

The most common (>20%) non-hematologic adverse reactions were rash and related conditions, arthralgia, abdominal pain, fatigue, constipation, headache, dry skin, fluid retention and edema, hepatic dysfunction, hypertension, pyrexia, nausea, hemorrhage, pancreatitis/lipase elevation, AOEs, diarrhea, vomiting, and myalgia.

Table 6 summarizes the adverse reactions in PACE.

Table 6: Adverse Reactions (>10%) in Patients with CML or Ph+ ALL Who Received Iclusig in PACE

Adverse ReactionCP-CML
(N = 270)
AP-CML
(N = 85)
BP-CML
(N = 62)
Ph+ ALL
(N = 32)
All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)
Skin and Subcutaneous Tissue Disorders
Rash and related conditions7596812557503.1
Dry skin423.3321.2261.6250
Alopecia801108060
Musculoskeletal and Connective Tissue Disorders
Arthralgia619586524.8410
Myalgia241.121018060
Muscle spasms140704.80130
Bone pain140.4131.211393
Musculoskeletal pain111.5708.1063
Gastrointestinal Disorders
Abdominal pain54114994513346
Constipation422.6292.4270533.1
Pancreatitis/lipase elevation32192115191696
Nausea290.7320341.6220
Diarrhea200.7292.4243.2133.1
Vomiting191.5270271.6250
Oral mucositis(a)161.1201.224093.1
General Disorders
Fatigue or asthenia443.7478364.8343.1
Fluid retention and edema313.7373.5324.8416
Pyrexia261.1407373.2250
Chills80120131.690
Nervous System Disorders
Headache433.3311.2313.2250
Neuropathy263.3182.4130130
Dizziness170.41104.803.10
Vascular Disorders
Hypertension(b)423053284863125
Arterial occlusive events311722121310136
Hemorrhage23338123783113
Hepatobiliary Disorders
Hepatotoxicity3210391434191613
Cardiac Disorders
Cardiac arrhythmias197174.7248256
Cardiac failure9584.7161063.1
Respiratory, Thoracic, and Mediastinal Disorders
Cough(c)19024021060
Dyspnea(d)193203.5236160
Infections
Upper respiratory tract infection(e)141.1130131.63.10
Urinary tract infection(f)122.2143.51.61.690
Nasopharyngitis1201803.203.10
Pneumonia84.8181118132216
Cellulitis4.41.983.5134.800
Sepsis(g)2.61.91161862825
Metabolism and Nutrition Disorders
Decreased appetite130.4141.280310
Hyperlipidemia130.7703.203.10
Investigations
Weight decreased100.4904.80130
Psychiatric Disorders
Insomnia110130110130
Anxiety4.801808060
Blood and Lymphatic System Disorders
Febrile neutropenia1.11.14.74.713132525
Graded using CTCAE v4.03.
(a) Oral mucositis includes aphthous ulcer, gingival pain, lip blister, lip pain, lip swelling, mouth ulceration, oropharyngeal pain, oral mucosal blistering, oral mucosal eruption, oral pain, pharyngeal ulceration, stomatitis, and tongue ulceration
(b) Derived from blood pressure (BP) measurement
(c) Cough includes cough, productive cough, and upper airway cough syndrome
(d) Dyspnea includes dyspnea and dyspnea exertional
(e) Upper respiratory tract infection includes upper respiratory tract infection and viral upper respiratory tract infection
(f) Urinary tract infection includes escherichia urinary tract infection, urinary tract infection, and urinary tract infection bacterial
(g) Sepsis includes abdominal sepsis, bacteremia, device-related sepsis, escherichia bacteremia, fungemia, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis, streptococcal bacteremia, and urosepsis

Clinically relevant adverse reactions occurring in ≤10% of patients: impaired glucose tolerance (9%)*, venous thromboembolic events (6%)*, secondary malignancies* (6%), and hypothyroidism (3%).

* Grouped terms: secondary malignancies includes basal cell carcinoma, squamous cell carcinoma of the skin, melanoma, chronic myelomonocytic leukemia, colon cancer, epithelioid mesothelioma, large cell lung cancer recurrent, lung neoplasm, malignant ascites, myelodysplastic syndrome, neuroendocrine carcinoma metastatic, non-Hodgkin lymphoma, pancreatic cancer, thyroid neoplasm, vulval cancer; venous thromboembolic events includes deep vein thrombosis, pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, superficial thrombophlebitis, venous embolism, venoocclusive liver disease, portal vein thrombosis; impaired glucose tolerance includes blood glucose increased, diabetes mellitus, glucose tolerance impaired, glycosylated hemoglobin increased, hyperglycemia, insulin resistance, and type 2 diabetes mellitus

Tables 7 and 8 summarize the Grade 3 or 4 hematologic laboratory abnormalities or all grades non-hematologic abnormalities in PACE.

Table 7: Select Grade 3 or 4* Hematologic Laboratory Abnormalities in Patients Who Received Iclusig in PACE

Laboratory AbnormalityCP-CML
(N = 270) (%)
AP-CML
(N = 85) (%)
BP-CML
(N = 62) (%)
Ph+ ALL
(N = 32) (%)
Hematology
Platelet count decreased35494547
Neutrophil cell count decreased23524859
White blood cell decreased12374863
Lymphocyte decreased10253219
Hemoglobin decreased8315234
*Graded using CTCAE v4.03

Table 8: Select Non-Hematologic Laboratory Abnormalities (≥20%) in Patients Who Received Iclusig in PACE

Laboratory AbnormalityPooled Safety Population
(N = 449)
All Grades* (%)Grade 3 or 4 (%)
Chemistry
Glucose increased547
Phosphate decreased3410
Calcium decreased300.9
Sodium decreased274.9
Creatinine increased210.2
Potassium increased202.2
Bicarbonate decreased200.2
Liver Function Tests
ALT increased416
Alkaline phosphatase increased402
AST increased353.6
Albumin decreased280.2
Bilirubin increased130.9
Pancreatic Enzymes
Lipase increased4014
Amylase increased183.6
ALT = alanine aminotransferase, AST = aspartate aminotransferase
* Graded using CTCAE v4.03

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Iclusig. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Blood and Lymphatic System Disorders: Thrombotic microangiopathy

Endocrine Disorders: Hyperthyroidism

Gastrointestinal Disorders: Gastrointestinal perforation, fistula

Metabolism and Nutrition Disorders: Dehydration

Nervous System Disorders: Reversible posterior leukoencephalopathy syndrome (RPLS)

Skin and Subcutaneous Tissue Disorders: Severe cutaneous reaction (e.g., Erythema multiforme, Stevens-Johnson syndrome), impaired wound healing Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

Read the entire FDA prescribing information for Iclusig (Ponatinib Tablets)

© Iclusig Patient Information is supplied by Cerner Multum, Inc. and Iclusig Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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