"The U.S. Food and Drug Administration today approved Venclexta (venetoclax) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with a least one pr"...
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 observe d in clinical practice.
The following adverse reactions are discussed in greater detail in other sections of the prescribing information:
- Vascular Occlusion [see WARNINGS AND PRECAUTIONS]
- Heart Failure [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Pancreatitis [see DOSAGE AND ADMINISTRATION and 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 DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]
The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CPCML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg or 83% of the expected 45 mg dose. The events of arterial ischemia, cardiac failure, and peripheral neuropathy reported in Tables 5 and 6 below include data from an additional 13 months of follow-up (median duration of treatment CP-CML: 672 days, AP-CML: 590 days, BP-CML: 89 days, Ph+ ALL: 81 days).
Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 5. Overall, the most common non-hematologic adverse reactions ( ≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.
The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).
Dose modifications (dose delays or dose reductions) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions ( ≥ 5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%).
Table 5: Adverse Reactions Occurring in > 10% of
Patients, Any Group
|System Organ Class||CP-CML
|Any Grade (%)||CTCAE Grade 3 / 4 (%)||Any Grade (%)||CTCAE Grade 3 / 4 (%)||Any Grade (%)||CTCAE Grade 3 / 4 (%)||Any Grade (%)||CTCAE Grade 3 / 4 (%)|
|Cardiac or Vascular disorders|
|Arterial ischemia b*||20||11||19||9||10||5||3||0|
|Cardiac Failure c*||7||4||6||4||15||8||6||3|
|Oral mucositis e||10||1||15||1||23||0||9||3|
|GI hemorrhagef||2||< 1||8||1||11||5||9||6|
|Blood and lymphatic system disorders|
|Febrile neutropenia||1||< 1||4||4||11||11||25||25|
|Infections and infestations|
|Urinary tract infection||7||1||12||1||0||0||9||0|
|Upper respiratory tract infection||11||1||8||0||11||2||0||0|
|Nervous system disorders|
|Respiratory, thoracic, and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
|Rash and related conditions||54||5||48||8||39||5||34||6|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||17||2||17||0||13||0||9||0|
|Bone pain||12||< 1||12||1||11||3||9||3|
|General disorders and administration site conditions|
|Fatigue or asthenia||39||3||36||6||35||5||31||3|
|Edema, peripheral||13||< 1||19||0||13||0||22||0|
|Metabolism and nutrition disorders|
|Decreased appetite||8||< 1||12||1||8||0||31||0|
|Weight decreased||6||< 1||7||0||5||0||13||0|
|Adverse drug reactions,
reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology
Criteria for Adverse Events) for assessment of toxicity. Treatment-emergent,
all causality events
a derived from blood pressure (BP) measurement recorded monthly while on trial
b includes cardiovascular, cerebrovascular, and peripheral vascular ischemia
c includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure
d includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort
e includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration
f includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage
g includes burning sensation, skin burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, polyneuropathy
* represents an additional 13 months of follow-up
Table 6: Serious Adverse Reactions (SAR)
|Arterial ischemic event*||53 (11.8%)|
|Peripheral vascular||16 (3.6%)|
|CNS hemorrhage||10 (2.2%)|
|Gastrointestinal hemorrhage||10 (2.2%)|
|Cardiac failure*||22 (4.9%)|
|Atrial fibrillation||11 (2.4%)|
|Venous thromboembolism||10 (2.2%)|
|Abdominal pain||17 (3.8%)|
|Blood and lymphatic system disorders|
|Febrile neutropenia||13 (2.9%)|
|a includes pericardial effusion, pleural effusion, and
* represents an additional 13 months of follow-up
Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 7).
Table 7: Incidence of Clinically Relevant Grade 3/4*
|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|
|ANC=absolute neutrophil count,
Hgb=hemoglobin, WBC=white blood cell count
*Reported using NCI-CTC-AE v 4.0
Table 8: Incidence of
Clinically Relevant Non-Hematologic Laboratory Abnormalities
|Laboratory Test||Safety Population
|Any Grade* (%)||CTCAE Grade 3/4 (%)|
|Liver function tests|
|Alkaline phosphatase increased||37||2|
|Amylase increased||3||< 1|
|Sodium increased||10||< 1|
|Bicarbonate decreased||11||< 1|
|Creatinine increased||7||< 1|
|Triglycerides increased||3||< 1|
*Graded using NCI-CTC-AE v 4.0
Read the Iclusig (ponatinib tablets) Side Effects Center for a complete guide to possible side effects
Based on in vitro studies, ponatinib is a substrate of CYP3A and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see CLINICAL PHARMACOLOGY].
Drugs That Are Strong Inhibitors Of CYP3A Enzymes
In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see CLINICAL PHARMACOLOGY]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced [see DOSAGE AND ADMINISTRATION]. Patients taking concomitant strong CYP3A inhibitors may be at increased risk for adverse reactions [see CLINICAL PHARMACOLOGY].
Drugs That Are Strong Inducers Of CYP3A Enzymes
Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John's Wort) with Iclusig should be avoided unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medication with no or minimal CYP3A induction potential is recommended. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of rifampin resulted in decreased ponatinib AUC0-inf and Cmax values by 62% and 42%, respectively [see CLINICAL PHARMACOLOGY].
Drugs That Elevate Gastric pH
Iclusig may be co-administered with gastric pH-elevating medications. In a drug interaction study in healthy volunteers, coadministration of Iclusig following multiple doses of lansoprazole resulted in a minimal (6%) decrease in ponatinib exposure. [see CLINICAL PHARMACOLOGY].
Drugs That Are Substrates Of The P-gp Or ABCG2 Transporter Systems
In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/6/2016
Additional Iclusig Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.