ICLUSIG SIDE EFFECTS

SIDE EFFECTS

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

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

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. 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-ABL1^IS. 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 1 summarizes the adverse reactions in OPTIC for patients who received Iclusig at a starting dose of 45 mg.

Table 1: 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

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

Table 2: Select Laboratory Abnormalities (>20%) that Worsened from Baseline in Patients with CPCML Who Received Iclusig at Starting Dose of 45 mg in OPTIC

Previously Treated CML Or Ph+ALL

The safety of Iclusig was evaluated in PACE. 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. 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 3 summarizes the adverse reactions in PACE.

Table 3: Adverse Reactions (>10%) in Patients with CML or Ph+ ALL Who Received Iclusig in PACE

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 4 and 5 summarize the Grade 3 or 4 hematologic laboratory abnormalities or all grades non-hematologic abnormalities in PACE.

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

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

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