Precautions of Ponatinib

Before using this product, the relevant risks should be fully understood. During the treatment period, the patient's condition shall be closely monitored and appropriate measures shall be taken.

Arterial Occlusive Events

Arterial occlusive events (including fatal cases) have been reported in patients receiving ponatinib treatment. These events include cardiovascular, cerebrovascular and peripheral vascular events, which can occur in patients with or without cardiovascular risk factors. Signs of arterial occlusive events need to be monitored. Depending on the recurrence or severity of the event, treatment may be resumed at the same dose or a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued. The benefits and risks should be evaluated before restarting treatment.

Venous Thromboembolic Events

Severe venous thromboembolic events have been reported in patients receiving ponatinib treatment, including deep vein thrombosis, embolism, pulmonary embolism, superficial vein thrombosis, thrombosis, jugular vein thrombosis, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. Signs of venous thromboembolic events need to be monitored. Depending on the recurrence or severity of the event, treatment may be resumed at the same dose or a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued.

Heart Failure

Fatal, severe or life - threatening heart failure events have been reported, including elevated brain natriuretic peptide, left ventricular hypertrophy, left ventricular dysfunction, congestive heart failure, heart failure, left atrial dilatation and decreased ejection fraction. Signs or symptoms of heart failure should be monitored and managed according to clinical indications. For new - onset or worsening heart failure, treatment should be resumed at a reduced dose after temporary discontinuation, or ponatinib should be permanently discontinued.

Hepatotoxicity

Ponatinib can cause hepatotoxicity (including liver failure and death). Fatal cases due to fulminant liver failure have been reported. The most common hepatotoxicity events are elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma - glutamyl transferase (GGT), bilirubin and alkaline phosphatase, as well as decreased albumin and fibrinogen. Liver function should be monitored at baseline and then at least monthly or as clinically indicated. Depending on the recurrence or severity of the event, treatment may be resumed at a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued.

Hypertension

Severe or life - threatening hypertension (including hypertensive crisis) has been reported. Patients may present with confusion, headache, chest pain or shortness of breath, requiring emergency intervention to control hypertension. Blood pressure should be monitored at baseline and as clinically indicated, and managed according to clinical guidelines. If hypertension cannot be controlled with medications, ponatinib should be temporarily discontinued, the dose reduced or the drug permanently discontinued. For significant deterioration, blood pressure fluctuations or refractory hypertension, ponatinib should be temporarily discontinued and evaluation for renal artery stenosis should be considered.

Pancreatitis

Severe or life - threatening pancreatitis has been reported. Elevated lipase and amylase levels have also been observed. In most cases leading to dose adjustment or discontinuation, pancreatitis resolves within 2 - 3 weeks. Serum lipase should be monitored every 2 weeks during the first 2 months of treatment, and then monthly or as clinically indicated. Increased monitoring frequency should be considered for patients with a history of pancreatitis or alcohol abuse. Depending on the severity of the condition, treatment may be resumed at the same dose or a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued. When lipase elevation is accompanied by abdominal symptoms, pancreatitis should be evaluated.

Increased Toxicity in Patients with Newly Diagnosed Chronic - Phase Chronic Myeloid Leukemia (CP - CML)

In a prospective randomized clinical trial of first - line treatment for patients with newly diagnosed CP - CML, single - agent ponatinib treatment was associated with an increased risk of serious adverse reactions. The trial was terminated early due to safety concerns. Ponatinib is not indicated and is not recommended for the treatment of patients with newly diagnosed CP - CML.

Neuropathy

Peripheral neuropathy and cranial neuropathy (including grade 3 or 4 events) have been reported in patients receiving ponatinib treatment. Symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain or weakness need to be monitored. Depending on the recurrence or severity of the event, treatment may be resumed at the same dose or a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued.

Ocular Toxicity

Severe or life - threatening ocular toxicity leading to blindness and blurred vision has been reported. The most common ocular toxicities are dry eye, blurred vision and eye pain. Retinal toxicities include retinal vein occlusion, retinal hemorrhage, age - related macular degeneration, arteriosclerotic retinopathy, retinal vasculopathy, macular edema and vitreous floaters. Comprehensive ophthalmic examinations should be performed at baseline and regularly during treatment.

Hemorrhage

Fatal and severe hemorrhage events have been reported. Intracranial hemorrhage, gastrointestinal hemorrhage and subdural hematoma are the most commonly reported serious hemorrhage events. Most hemorrhage events occur in patients with grade 4 thrombocytopenia. Hemorrhage should be monitored and managed according to clinical indications. Depending on the recurrence or severity of the event, treatment may be resumed at the same dose or a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued.

Fluid Retention

Fatal and severe events have been reported, including 1 case of fatal cerebral edema, as well as serious events such as pleural effusion, pericardial effusion and angioedema. The most common manifestations of fluid retention in patients receiving ponatinib treatment are peripheral edema, pleural effusion, hydrothorax, pericardial effusion and peripheral swelling. Fluid retention should be monitored and managed according to clinical indications. Depending on the recurrence or severity of the event, treatment may be resumed at the same dose or a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued.

Arrhythmia

Arrhythmias have been reported, including ventricular and atrial arrhythmias, tachycardia, bradycardia, cardiorespiratory arrest, syncope, atrial fibrillation and supraventricular tachycardia. Some patients experience severe or life - threatening (grade 3 or 4) events requiring hospitalization. Signs and symptoms suggesting bradycardia (syncope, dizziness) or tachycardia (chest pain, palpitations or dizziness) should be monitored and managed according to clinical indications. Depending on the recurrence or severity of the event, treatment may be resumed at the same dose or a reduced dose after temporary discontinuation, or ponatinib may be permanently discontinued.

Myelosuppression

Grade 3 or 4 neutropenia, thrombocytopenia and anemia have been reported. Complete blood count should be performed every 2 weeks during the first 3 months of treatment, and then monthly or as clinically indicated. If the absolute neutrophil count (ANC) is < 1×10⁹/L or platelets are < 50×10⁹/L, ponatinib should be temporarily discontinued; treatment may be resumed at the same dose or a reduced dose when ANC ≥ 1.5×10⁹/L and platelets ≥ 75×10⁹/L.

Tumor Lysis Syndrome

Severe tumor lysis syndrome has been reported. Adequate hydration and treatment of hyperuricemia should be ensured before initiating ponatinib treatment.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cases of RPLS have been reported. Patients may present with hypertension, seizures, headache, decreased alertness, altered mental function, vision loss and other visual and neurological dysfunctions. Diagnosis should be confirmed by magnetic resonance imaging (MRI). If RPLS occurs, ponatinib should be temporarily discontinued until symptoms resolve. The safety of reinitiating ponatinib after RPLS resolution is unclear.

Impaired Wound Healing and Gastrointestinal Perforation

Impaired wound healing has been reported in patients receiving ponatinib treatment. The drug should be discontinued at least 1 week before elective surgery and at least 2 weeks after major surgery until the wound is fully healed. Gastrointestinal perforation or fistula has been reported. Patients with gastrointestinal perforation should permanently discontinue ponatinib.

Embryo - Fetal Toxicity

Ponatinib may cause fetal harm when administered to pregnant women. Pregnant women should be informed of the potential risks to the fetus. Females of reproductive potential should use effective contraception during ponatinib treatment and for 3 weeks after the last dose.

FDA,2022.02