Ponatinib

ICLUSIG

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What it isOral pan-BCR-ABL tyrosine-kinase inhibitor for resistant CML and Ph-positive ALL.

Why this oneIt retains activity against the T315I gatekeeper mutation that defeats most other BCR-ABL inhibitors.

What limits itArterial occlusion, venous thrombosis, heart failure, and hepatotoxicity demand aggressive cardiovascular selection and monitoring.

FDA label

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BOXED WARNING Arterial occlusive events incl. fatal MI/stroke (in patients with and without CV risk factors, incl. age ≤50), venous thromboembolic events, heart failure incl. fatal, and hepatotoxicity/liver failure — monitor; interrupt or discontinue based on severity

FDA dosing	Population	Start	Target	Max
Newly diagnosed Ph+ ALL (with chemotherapy)	adults	30 mg QD	reduce to 15 mg QD upon MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at end of induction; continue up to 20 cycles	30 mg QD
Ph+ ALL monotherapy (no other kinase inhibitors indicated, or T315I-positive)	adults	45 mg QD	45 mg QD until loss of response or unacceptable toxicity (optimal dose not identified)	45 mg QD
CP-CML	adults	45 mg QD	reduce to 15 mg QD upon ≤1% BCR::ABL1IS; may re-escalate to previously tolerated 30 or 45 mg QD on loss of response	45 mg QD
AP-CML and BP-CML	adults	45 mg QD	45 mg QD until loss of response or unacceptable toxicity; consider dose reduction in AP-CML on major cytogenetic response	45 mg QD

Renal Undefined

Hepatic Monotherapy (CP/AP/BP-CML, Ph+ ALL): reduce starting dose 45→30 mg QD for pre-existing impairment (Child-Pugh A, B, or C). Newly diagnosed Ph+ ALL: no adjustment for Child-Pugh A; monitor closely in B/C

Instructions

With or without food; swallow tablets whole — do not crush, break, cut, or chew
Missed dose: take next dose at regularly scheduled time next day
Consider discontinuing if no response by 3 months (monotherapy indications)
Toxicity dose reductions: CP-CML 45→30→15→10 mg QD; AP/BP-CML and Ph+ ALL monotherapy 45→30→15 mg QD; newly diagnosed Ph+ ALL 30→15→10 mg QD; discontinue if lowest step not tolerated
If strong CYP3A inhibitor unavoidable: 45→30, 30→15, 15→10 mg QD (avoid if on 10 mg)
Withhold ≥1 week before elective surgery; do not give for ≥2 weeks after major surgery and until adequate wound healing

Cautions

Arterial occlusive events, VTE, heart failure, hepatotoxicity (boxed)
Hypertension incl. renal artery stenosis — monitor BP; interrupt/reduce/stop if not controlled
Pancreatitis and lipase elevation — monitor serum lipase
Peripheral and cranial neuropathy
Ocular toxicity — comprehensive eye exams at baseline and periodically
Hemorrhage
Fluid retention
Cardiac arrhythmias
Myelosuppression — CBC every 2 weeks x3 months, then monthly
Tumor lysis syndrome — hydrate, correct uric acid before starting
Reversible posterior leukoencephalopathy syndrome
Impaired wound healing and GI perforation

Adverse reactions

Single agent (>20%): rash, arthralgia, abdominal pain, fatigue, headache, constipation, hypertension, dry skin, hepatotoxicity, fluid retention/edema, pyrexia, pancreatitis/lipase elevation, nausea, hemorrhage, anemia, arterial occlusive events, cardiac arrhythmias
Grade 3/4 labs (>20%): decreased platelets, neutrophils, WBC

Pregnancy Can cause fetal harm — adverse developmental effects in rats at exposures below human exposure at 45 mg/day

Lactation Do not breastfeed during treatment and for 1 week after last dose

NO BOXED WARNINGS