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Iclusig(ponatinib)tablets
Generic Name: ponatinib hydrochloride
Dosage Form: tablet, film coated
WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY
Arterial Thrombosis:
•Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Hepatotoxicity:
•Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].
Indications and Usage for Iclusig
Recommended Dosing
The recommended dose and schedule for Iclusig is 45 mg administered orally once daily. Continue treatment as long as the patient does not show evidence of disease progression or unacceptable toxicity.
Iclusig may be taken with or without food. Tablets should be swallowed whole.
Dose Modifications for Myelosuppression
Suggested dose modifications for neutropenia (ANC* less than 1.0 × 109/L) andthrombocytopenia (platelet less than 50 × 109/L) that are unrelated to leukemia are summarized in Table
1.
Table 1: Suggested Dose Modifications for Myelosuppression *
ANC = absolute neutrophil count
ANC* < 1 × 109/L
or
platelet < 50 × 109/L First occurrence:
•Interrupt Iclusig and resume initial 45 mg dose after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
Second occurrence:
•Interrupt Iclusig and resume at 30 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
Third occurrence:
•Interrupt Iclusig and resume at 15 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
Dose Modifications for Non-Hematologic Adverse Reaction1.
Table 1: Suggested Dose Modifications for Myelosuppression *
ANC = absolute neutrophil count
ANC* < 1 × 109/L
or
platelet < 50 × 109/L First occurrence:
•Interrupt Iclusig and resume initial 45 mg dose after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
Second occurrence:
•Interrupt Iclusig and resume at 30 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
Third occurrence:
•Interrupt Iclusig and resume at 15 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
Dose Modifications for Non-Hematologic Adverse Reactions
If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do not restart Iclusig in patients with serious ischemic reactions unless the potential benefit outweighs the risk of recurrent ischemia and the patient has no other treatment options. For serious reactions other than ischemia, do not restart Iclusig until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk.
Hepatic Toxicity
Recommended modifications for hepatic toxicity are summarized in Table 2.
Table 2: Recommended Dose Modifications for Hepatic Toxicity
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Elevation of liver transaminase > 3 × ULN (Grade 2 or higher) |
Occurrence at 45 mg: |
-
Interrupt Iclusig and monitor hepatic function
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Resume Iclusig at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN)
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Occurrence at 30 mg: |
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-
Interrupt Iclusig and resume at 15 mg after recovery to ≤ Grade 1
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Occurrence at 15 mg: |
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Elevation of AST or ALT ≥ 3 × ULN concurrent with an elevation of bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN |
Discontinue Iclusig |
Pancreatitis and Elevation of Lipase
Recommended modifications for pancreatic adverse reactions are summarized in Table 3.
Table 3: Recommended Dose Modifications for Pancreatitis and Elevation of Lipase
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Asymptomatic Grade 1 or 2 elevation of serum lipase |
Consider interruption or dose reduction of Iclusig |
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Asymptomatic Grade 3 or 4 elevation of lipase (> 2 × 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 × ULN)
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Occurrence at 30 mg: |
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-
Interrupt Iclusig and resume at 15 mg after recovery to ≤ Grade 1
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Occurrence at 15 mg: |
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Symptomatic Grade 3 pancreatitis |
Occurrence at 45 mg: |
-
Interrupt Iclusig and resume at 30 mg complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1
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Occurrence at 30 mg: |
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-
Interrupt Iclusig and resume at 15 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1
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Occurrence at 15 mg: |
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Grade 4 pancreatitis |
Discontinue Iclusig |
Dose Modification for Use With Strong CYP3A Inhibitors
The recommended dose should be reduced to 30 mg once daily when administering Iclusig with strong CYP3A inhibitors [see Drug Interactions (7.1)].
Dosage Forms and Strengths
15 mg and 45 mg round, white, film-coated tablets
Contraindications
None
Warnings and Precautions
Thrombosis and Thromboembolism
Arterial Thrombosis
Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.
Serious arterial thrombosis occurred in 8% (34/449) of Iclusig-treated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.
Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.
Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery).
Serious peripheral arterial events were reported in 2% (7/449) of Iclusig treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations.
Thirty of 34 Iclusig patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].
Venous Thromboembolism
Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].
Hepatotoxicity
Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ALL. Severe hepatotoxicity occurred in all disease cohorts.
The incidence of aspartate aminotransferase (ALT) or alanine aminotransferase (AST) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig-treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.
Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].
Congestive Heart Failure
Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].
Hypertension
Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.
Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.
Pancreatitis
Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%.
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. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and eva luate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 × ULN.
Hemorrhage
Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)]. Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].
Fluid Retention
Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).
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 [see Dosage and Administration (2.3)].
Cardiac Arrhythmias
Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).
Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).
Myelosuppression
Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ALL than in patients with chronic phase CML (CP-CML). 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 [see Dosage and Administration (2.2)].
Tumor Lysis Syndrome
Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.
Compromised Wound Healing and Gastrointestinal Perforation
No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.
Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.
Embryo-Fetal Toxicity
Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].
Adverse Reactions
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 following adverse reactions are discussed in greater detail in other sections of the prescribing information:
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 chronic phase CP-CML, 362 days in patients with accelerated phase 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.
Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, and 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 reduction) 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 4: Adverse Reactions Occurring in >10% of Patients, Any Group
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CP-CML
(N=270) |
AP-CML
(N=85) |
BP-CML
(N=62) |
Ph+ ALL
(N=32) |
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System Organ Class |
Any Grade
(%) |
CTCAE Grade
3 / 4
(%) |
Any Grade
(%) |
CTCAE Grade
3 / 4
(%) |
Any Grade
(%) |
CTCAE Grade
3 / 4
(%) |
Any Grade
(%) |
CTCAE Grade
3 / 4
(%) |
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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. |
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Treatment-emergent, all causality events |
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Cardiac or Vascular disorders |
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Hypertension |
68 |
39 |
71 |
36 |
65 |
26 |
53 |
31 |
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Arterial ischemia |
13 |
7 |
12 |
6 |
8 |
5 |
3 |
0 |
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Cardiac Failure |
6 |
4 |
6 |
2 |
15 |
11 |
6 |
6 |
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Gastrointestinal disorders |
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Abdominal pain |
49 |
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| 以下是“全球医药”详细资料 |
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