drug-monograph

ponatinib

Cancer Type

Hematologic, Leukemia - Chronic Myeloid (CML), Leukemia - Acute Lymphoblastic (ALL)

Other Names

Iclusig™

Appearance

tablet

Funding Program

Exceptional Access Program

A - Drug Name

ponatinib

COMMON TRADE NAME(S): Iclusig®

B - Mechanism of Action and Pharmacokinetics

Ponatinib is a potent BCR-ABL tyrosine kinase inhibitor that binds to native BCR-ABL and mutant forms, including T315I.

Absorption

Dose proportional increases in C_max and AUC between 15 to 60 mg.

Bioavailability

Absolute bioavailability unknown.

Peak plasma levels

6 hours

Distribution

PPB

> 99%

Metabolism

Main enzymes involved

Esterases and/or amidases and by CYP3A4

Active metabolites

Inactive metabolites

Yes

Elimination

Feces

87% (24% unchanged)

Urine

5% (<1% unchanged)

Half-life

22 hours

C - Indications and Status

Health Canada Approvals:

Chronic myeloid leukemia (CML),
Acute lymphoblastic leukemia (ALL)

Refer to the product monograph for a full list and details of approved indications.

D - Adverse Effects

Emetogenic Potential:

Minimal – No routine prophylaxis; PRN recommended

Extravasation Potential: Not applicable

The following adverse effects were reported mainly in chronic phase CML patients or in pooled safety analyses. The table also includes severe or life-threatening adverse effects from other sources.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Arrhythmia (<5%) (including atrial fibrillation)	E
	Arterial thromboembolism (14%)	E
	Artery aneurysm (rare)	E D L
	Artery dissection (rare)	E D L
	Cardiotoxicity (5%) (cardiac failure)	E D
	Hypertension (23%) (severe 7%)	E
	Pulmonary hypertension (<5%)	E
	Venous thromboembolism (6%)	E
Dermatological	Alopecia (7%)	E
	Rash (42%) (4% severe)	E
	Skin discolouration (<5%) (also hyperpigmentation)	E
Gastrointestinal	Abdominal pain (29%)	E
	Anorexia, weight loss (6%)	E
	Constipation (21%)	E
	Diarrhea (9%)	E
	Dry mouth (6%)	E
	GI perforation (rare)	E
	Nausea, vomiting (16%)	I E
General	Fatigue (21%)	E
	Fluid retention (including effusions) (32%) (4% severe)	E
Hematological	Myelosuppression ± infection, bleeding (42%) (32% severe)	E
Hepatobiliary	↑ Amylase / lipase (26%) (12% severe)	E
	↑ LFTs (15%) (4% severe)	E
	Pancreatitis (7%) (severe)	E
Immune	Other - Atypical infections (including HBV reactivation)	D
Metabolic / Endocrine	Hyperglycemia (<5%)	E
	Hyperuricemia (7%)	E
	Hypothyroidism (rare)	D
	↓ PO4 (<5%)	E
	Tumour lysis syndrome (<1%)	E
Musculoskeletal	Musculoskeletal pain (19%)	E
Nervous System	Cranial neuropathy (3%)	E
	Dizziness (7%)	E
	Headache (26%)	E
	Insomnia (<5%)	E
	Peripheral neuropathy (20%) (2% severe)	E
	Posterior reversible encephalopathy syndrome (PRES) (rare)	E
Ophthalmic	Eye disorders (30%) (including blurred vision, cataract, dry eye, eye pain, blurred vision)	E
	Retinal vascular disorder (3%) (retinal vein occlusion, retinal hemorrhage)	E
Respiratory	Cough, dyspnea (8%)	E
Vascular	Peripheral ischemia (3%)	E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

The most common side effects for ponatinib include myelosuppression ± infection/bleeding, rash, fluid retention (including effusions), eye disorders, abdominal pain, ↑ amylase / lipase, headache, hypertension, constipation and fatigue.

Arterial and venous thromboembolism and occlusions (including stroke, renal artery stenosis, peripheral vascular events, myocardial infarction, ocular, pulmonary embolism, mesenteric occlusions) occurred in patients with and without cardiovascular risk factors, some of which required revascularization procedures. The median onset of arterial occlusive events was 13.4 months (range 3 days to 60 months). Recurrent or multi-site vascular occlusion has also been reported. Renal artery stenosis has been reported and may be associated with worsening or treatment-resistant hypertension.

Vascular occlusive events were more frequent in older patients and those with a history of ischemia, hypertension, diabetes or hyperlipidemia. Peripheral vascular events sometimes required amputation. Before starting treatment, the cardiovascular status of the patient should be assessed and risk factors managed, with monitoring during treatment.

Severe cases of artery dissection (with or without hypertension) and artery aneurysm (including rupture) have been reported in patients using VEGFR TKIs.

Congestive heart failure and reduced left ventricular ejection fraction (LVEF) have been reported, and may be fatal. LVEF should be evaluated prior to treatment. Symptomatic bradyarrhythmias and supraventricular tachyarrhythmias have been reported, with atrial fibrillation being the most common.

Severe hemorrhage (some fatal, including CNS, GI) occurred in 7% of patients with the incidence of this and severe neutropenia being higher in patients with acute or blast phase CML or Ph+ ALL compared to chronic phase CML patients.

Hepatotoxicity that may be severe and life-threatening occurred within a week of starting treatment.

Pancreatitis was reported more frequently within the first two months of therapy.

Reactivation of hepatitis B virus (HBV) has been reported in patients who received BCR-ABL TKI’s and are chronic carriers of HBV. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.

E - Dosing

Refer to protocol by which the patient is being treated.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Patients' cardiovascular status should be assessed and risk factors managed prior to starting treatment and monitored during treatment.

Ensure adequate hydration and correct hyperuricemia prior to starting treatment.

Consider temporary hold of ponatinib prior to undergoing major surgery.

Adults:

Concomitant use with strong CYP3A inducers or strong CYP3A inhibitors should be avoided. Also refer to Section H - Interactions for further details.

Oral: 45 mg Daily

Consider discontinuation if a hematologic response has not been achieved by 3 months.

Dosage with Toxicity:

Dose Level	Ponatinib Dose (mg/day)
0	45
-1	30
-2	15
-3	Discontinue

Toxicity	Severity	Action/Ponatinib Dose
Myelosuppression	ANC < 1 x 10⁹/L or platelets < 50 x 10⁹/L (unrelated to disease)	Hold* until recovery, restart at the same dose. If recurs, hold* until recovery, restart at ↓ 1 dose level from previous dose.
Hemorrhage	Grade 3 or 4	Hold and investigate. Consider the risk vs. benefit of restarting.
LFTs	AST or ALT > 3 x ULN	Hold until recovery to ≤ grade 1, restart at ↓ 1 dose level from previous dose.
LFTs	AST or ALT ≥ 3 x ULN AND total bilirubin > 2 x ULN AND ALP < 2 x ULN	Discontinue.
Pancreatitis and elevation of amylase / lipase	Asymptomatic grade 2 pancreatitis and/or amylase/lipase > 1.5 to 2 x ULN, or >2 to 5 x ULN and asymptomatic	Consider hold until resolution then restart at same dose level.
	Amylase/lipase > 5 x ULN and asymptomatic	Hold until amylase/lipase ≤ 1.5 x ULN, then restart at ↓ 1 dose level from previous dose.
	Grade 3 pancreatitis or amylase/lipase > 2 to 5 x ULN and symptomatic	Hold until resolution of symptoms and recovery of amylase/lipase to ≤ 1.5 x ULN, then restart at ↓ 1 dose level from previous dose.
	Grade 4 pancreatitis or amylase/lipase > 5 x ULN and symptomatic	Discontinue.
Hypertriglyceridemia	Grade 3 or 4	Manage patient appropriately to reduce pancreatitis risk.
Arterial Occlusive Events (AOE): cardiovascular or cerebrovascular	Grade 1	Hold until resolution, then restart at same dose level.
	Grade 2	Hold until ≤ grade 1, then restart by ↓ 1 dose level from previous dose Discontinue at recurrence.
	Grade 3 or 4	Discontinue.
AOE: peripheral or other or VTE	Grade 1	Hold until resolution, then restart at same dose level.
	Grade 2	Hold until ≤ grade 1, then restart at same dose level. If recurrence, hold until ≤ grade 1, then restart by ↓ 1 dose level from previous dose.
	Grade 3	Hold until ≤ grade 1, then restart by ↓ 1 dose level from previous dose. Discontinue at recurrence.
	Grade 4	Discontinue.
Heart failure	Grade 2 or 3	Hold until ≤ grade 1, then restart by ↓ 1 dose level from previous dose. Discontinue at recurrence.
Heart failure	Grade 4	Discontinue.
Hypertension	Any	Treat to normalize blood pressure. Hold, reduce dose, or discontinue (as clinically indicated) if not medically controlled, and evaluate for renal artery stenosis.
Fluid retention	Any	Hold, reduce or discontinue ponatinib as clinically indicated.
PRES	Any	Hold if suspected. Discontinue if confirmed. or Restart if resolved and only if benefits outweigh risks.
Other non-hematologic toxicity	Grade 2	Hold until ≤ grade 1, then restart at same dose level. If recurrence, hold until ≤ grade 1, then restart by ↓ 1 dose level from previous dose.
Other non-hematologic toxicity	Grade 3 or 4	Hold until recovery. Restart at ↓ 1 dose level from previous dose. If grade 4, consider discontinuation. Discontinue at recurrence.
*Restart once ANC ≥ 1.5 x 10⁹/L and platelets ≥ 75 x 10⁹/L.

Dosage with Hepatic Impairment:

The recommended starting dose is 30 mg once daily in patients with hepatic impairment (Child-Pugh classes A, B or C); use caution in these patients. There was an increase in adverse effects in patients with severe hepatic impairment. The safety of multiple ponatinib doses, or doses > 30 mg, has not been studied in patients with hepatic impairment.

Dosage with Renal Impairment:

Renal excretion is not a major route of elimination. There are no specific recommendations for dosage adjustment. Ponatinib has not been studied in patients with CrCl < 30 mL/min or end-stage renal disease; exercise caution if ponatinib is administered to these patients.

Dosage in the elderly:

Patients aged 65 and older (with chronic phase CML) are more likely to experience adverse effects and reduced efficacy compared to younger patients. Patients ≥ 65 years of age are more likely to experience adverse effects including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite.

Children:

The safety and efficacy of ponatinib in patients under 18 years have not been established.

F - Administration Guidelines

Ponatinib should be swallowed whole with or without food
Tablets should not be crushed, chewed or dissolved.
Grapefruit, starfruit, pomegranate, Seville oranges, their juices or products should be avoided during ponatinib treatment.
If a dose is missed, an additional dose should not be taken. Patients should take the next dose at the usual time.

Store at room temperature (15^oC to 30^oC) in the original package.

G - Special Precautions

Contraindications:

Patients who have a hypersensitivity to this drug or any of its components
Patients who have uncontrolled hypertension or other unmanaged cardiac risk factors
Patients with dehydration or untreated hyperuricemia

Other Warnings/Precautions:

Ponatinib should not be used in patients with a history of myocardial infarction, prior revascularization or stroke, unless the potential benefit outweighs the risk.
Use with caution and consider benefits vs risks in patients with a prior history of ischemia, hypertension, congestive heart failure or conditions that may impair left ventricular function, diabetes or hyperlipidemia.
Use with caution in patients at risk of bleeding, those receiving antiplatelets and/or anticoagulants.
Use with caution in patients with a history of pancreatitis or alcohol abuse.
Contains lactose; patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take ponatinib.
Use caution when driving or operating a vehicle or potentially dangerous machinery as dizziness, mental status changes and vision problems have been reported.

Other Drug Properties:

Carcinogenicity: Documented in animals

Increased incidence of squamous cell carcinoma of the clitoral gland was observed in animals. Clinical relevance is unknown.

Pregnancy and Lactation:

Mutagenicity: Not observed in vitro
Clastogenicity:
- Not observed in in vitro and in vivo studies
Embryotoxicity: Documented in animals
Fetotoxicity: Documented in animals
Teratogenicity: Documented in animals
Pregnancy:
- Ponatinib is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 6 months after the last dose (general recommendation).
- It is unknown whether ponatinib affects the effectiveness of oral contraceptives. An alternative method of contraception should be used.
Breastfeeding:
- Breastfeeding is not recommended.
Fertility effects:
- Documented in studies with female animals

H - Interactions

Ponatinib is metabolized by CYP3A4 and is therefore susceptible to drug interactions with inducers and inhibitors.

Ponatinib may be given concurrently with proton pump inhibitors or other drugs that increase gastric pH without adjusting the ponatinib dose or separating the administration.

Ponatinib Dosage with Strong CYP3A4 Inhibitors

Current Ponatinib Dose (mg daily)	Ponatinib Dose^† (mg daily) with a Strong CYP3A4 Inhibitor
45	30
30	15
15	Discontinue

^†Resume previous dose after the inhibitor has been discontinued for 3 to 5 elimination half-lives.

AGENT	EFFECT	MECHANISM	MANAGEMENT
CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit)	↑ ponatinib concentration and/or toxicity (ketoconazole ↑ ponatinib exposure by 78%)	↓ metabolism of ponatinib	Avoid strong CYP3A4 inhibitors. If must co-administer, reduce ponatinib dose (see table above).
CYP3A4 inducers (e.g. phenytoin, rifampin, carbamazepine, phenobarbital, St. John’s Wort, etc.)	↓ ponatinib concentration and/or efficacy (rifampin ↓ ponatinib exposure by 62%)	↑ metabolism of ponatinib	Avoid strong CYP3A4 inducers if possible. If not possible, monitor for reduced efficacy of ponatinib.
P-glycoprotein substrates (e.g. digoxin, dabigatran, colchicine, pravastatin)	↑ substrate concentration and/or toxicity	Ponatinib is an inhibitor of P-gp	Caution and monitor.
BCRP substrates (e.g. sulfasalazine, methotrexate, rosuvastatin)	↑ substrate concentration and/or toxicity	Ponatinib is an inhibitor of BCRP	Caution and monitor.

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
Blood pressure	Baseline and as clinically indicated; ensure hypertension is controlled to minimize risk of arterial thromboembolism
CBC	Baseline, every 2 weeks for the first 3 months, and then monthly or as clinically indicated
Liver function tests	Baseline, at least monthly or as clinically indicated
Lipase, amylase	Baseline, every 2 weeks for the first 2 months, and then periodically or as clinically indicated
LVEF	Baseline, 3 months after treatment initiation, and as clinically indicated
Calcium, phosphate	Baseline and as clinically indicated
Eye exam and fundoscopy	Baseline, with blurred vision and as clinically indicated
Clinical toxicity assessment for bleeding, infection, arterial and venous thromboembolism, fluid retention (including regular weight monitoring), hypertension, cardiac and GI effects, tumour lysis syndrome, ocular, wound healing, and neurologic effects	Baseline and at each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

J - Supplementary Public Funding

Exceptional Access Program (EAP Website )

ponatinib - For the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia, according to specific criteria
ponatinib - For the treatment of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), according to specific criteria

K - References

Cortes J, Apperley J, Lomaia E, et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood 2021;138(21):2042-50.

Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood 2018;132(4):393-404.

Cortes JE, Kim DW, Pinilla-Ibarz J, et al; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96.

Product monograph: ponatinib (Iclusig). Paladin Labs Inc., February 24, 2025.

June 2026 Modified Adverse effects, Dosing, Dose modifications, Administration guidelines, Warnings and special precautions, Interactions, and Monitoring sections

L - Disclaimer

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Last Updated: July 27, 2026

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