Ponaxen

Approved Indications:

• Chronic Myeloid Leukemia (CML):
• Chronic phase (CP-CML)
• Accelerated phase (AP-CML)
• Blast phase (BP-CML)
• Especially indicated for patients with T315I-positive CML or resistance/intolerance to prior tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, and nilotinib.
• Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL):
• For adult patients with T315I mutation or who are resistant or intolerant to prior TKIs.

Important Off-label/Clinically Accepted Uses:

• Relapsed/refractory Ph+ leukemias with compound BCR-ABL1 mutations.
• Post-transplant relapse of Ph+ ALL or CML (as salvage or maintenance therapy under hematologist supervision).

Adults:

• Initial Dose:
• 45 mg orally once daily, with or without food.
• Dose Adjustments:
• May be reduced to 30 mg or 15 mg daily based on response or adverse effects.
• Reduction recommended upon achieving major cytogenetic or molecular response to minimize vascular risk.

Pediatric Use:

• Safety and efficacy in pediatric patients have not been established.

Elderly:

• No specific dose adjustment solely based on age; however, use with caution due to increased risk of vascular events.

Renal Impairment:

• No adjustment required in mild to moderate renal impairment.
• Use with caution in severe renal dysfunction due to limited data.

Hepatic Impairment:

• Mild to moderate impairment: No dosage adjustment recommended.
• Severe impairment: Use with caution; monitor liver function tests regularly.

Administration:

• Administer orally once daily at the same time each day.
• Tablets should be swallowed whole; do not crush or dissolve.
• Continue until disease progression or unacceptable toxicity.

Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) that potently inhibits BCR-ABL1, including the T315I mutation, which is resistant to other TKIs. It binds to the ATP-binding site of the BCR-ABL1 fusion protein, thereby blocking phosphorylation and subsequent signal transduction pathways involved in cell proliferation and survival. Beyond BCR-ABL1, ponatinib also inhibits other kinases such as VEGFR, FGFR, PDGFR, SRC, and KIT, contributing to both its antileukemic effects and toxicity profile. Its broad kinase inhibition disrupts leukemic cell growth and induces apoptosis in malignant hematopoietic cells.

• Absorption:
• Rapidly absorbed; peak plasma concentrations achieved in 4 to 6 hours.
• Oral bioavailability is estimated to be high; food does not significantly affect absorption.
• Distribution:
• Highly protein-bound (~99%)
• Volume of distribution: ~1,229 L, indicating extensive tissue distribution.
• Metabolism:
• Primarily metabolized in the liver via CYP3A4, with minor contributions from CYP2C8, CYP2D6, and esterases.
• Elimination:
• Half-life: ~24 hours
• Excreted mainly via feces (~87%), minimal urinary excretion (<5%)
• Steady-State:
• Reached within 1 week of daily dosing.

• Pregnancy:
• Not assigned a formal FDA pregnancy category under the PLLR system.
• Animal studies demonstrate embryotoxicity, teratogenicity, and fetal mortality.
• Use only if potential benefit justifies potential fetal risk. Effective contraception required during treatment and for 3 weeks after the last dose.
• Lactation:
• Unknown whether ponatinib is excreted in human breast milk.
• Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for 6 days after the final dose.

• Primary Class: Tyrosine Kinase Inhibitor (TKI)
• Subclass: Third-generation BCR-ABL TKI
• Target Specificity: Active against wild-type and mutated BCR-ABL1, including T315I mutation

• Known hypersensitivity to ponatinib or any excipients in the formulation.
• History of arterial thromboembolic events (in patients where risks outweigh benefits)
• Uncontrolled hypertension
• Active or recent hemorrhage (clinically significant)

• Vascular Occlusion:
• Arterial and venous thrombosis can occur at any dose. Events may be fatal and affect multiple vascular beds (coronary, cerebral, peripheral).
• Heart Failure:
• Ponatinib may cause or exacerbate congestive heart failure. Monitor for signs/symptoms.
• Hypertension:
• Common and may be severe; requires regular monitoring and control before and during therapy.
• Hepatotoxicity:
• May cause liver enzyme elevation or hepatic failure. Monitor LFTs regularly.
• Pancreatitis:
• Dose-dependent; monitor serum lipase/amylase and clinical symptoms.
• Myelosuppression:
• Includes neutropenia, thrombocytopenia, and anemia. Frequent CBC monitoring required.
• Hemorrhage Risk:
• Serious or fatal hemorrhagic events may occur, especially in thrombocytopenic patients.
• Tumor Lysis Syndrome:
• Use caution in patients with rapidly proliferating disease or high tumor burden.

Common Adverse Effects (≥10%):

• Hematologic:
• Thrombocytopenia, neutropenia, anemia
• Gastrointestinal:
• Diarrhea, abdominal pain, nausea
• General:
• Fatigue, fever, edema
• Skin:
• Rash, dry skin
• Metabolic:
• Hyperlipidemia, hyperglycemia

Serious/Rare Side Effects:

• Arterial thrombosis (e.g., myocardial infarction, stroke)
• Venous thromboembolism
• Congestive heart failure
• Hepatic failure
• Pancreatitis
• Gastrointestinal perforation
• Retinal vascular occlusion

• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin):
• May increase ponatinib exposure and toxicity risk. Avoid if possible.
• CYP3A4 Inducers (e.g., rifampin, carbamazepine):
• May reduce ponatinib effectiveness. Avoid concomitant use.
• Antiplatelets/Anticoagulants (e.g., aspirin, warfarin):
• Increased risk of bleeding; use with caution, particularly in thrombocytopenic patients.
• Grapefruit juice:
• May increase plasma concentration; avoid.
• QT-prolonging agents:
• Additive effect possible; monitor ECG if used concurrently.

• Dose Optimization Update:
• Regulatory agencies now recommend starting at 45 mg/day with early reduction to 15–30 mg/day upon achieving response to reduce vascular risks.
• Black Box Warning Reinforcement:
• Strengthened warnings for vascular occlusion, heart failure, and hepatotoxicity.
• NCCN Guidelines:
• Ponatinib remains recommended for T315I-positive or resistant CML/Ph+ ALL as part of second- or third-line strategies.

• Storage Temperature:
• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Humidity/Light Protection:
• Store in original container; protect from excessive moisture and light.
• Handling Precautions:
• Wash hands after handling. Use gloves if tablets are broken or crushed.
• Reconstitution:
• Not applicable. Do not crush or dissolve tablets.