Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
PNAT
Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR). Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.
For the treatment of patients with Philadelphia chromosome positive (Ph+) chronic, accelerated or blast phase chronic myeloid leukemia (CML), with documented T315i mutation, or where there is resistance, disease progression, or intolerance to at least 2 prior tyrosine kinase inhibitors.
(Refer to EAP criteria.)
ponatinib
Exceptional Access Program
(ponatinib - For the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia, according to specific clinical criteria)
(EAP Website)
| ponatinib | 45 mg | PO | Daily |
Ponatinib is only prescribed and dispensed through a controlled distribution program. For more information, visit www.iclusigcdp.ca.
See drug monograph; may consider lower starting dose in selected patients with hepatic impairment or those taking concomitant strong CYP3A4 inhibitors.
Consider reducing the dose of ponatinib from 45 mg to 15 mg once daily for chronic phase CML patients who have achieved a MCyR (major cytogenetic response). Consider discontinuation if a hematologic response has not been achieved by 3 months.
Minimal – No routine prophylaxis; PRN recommended
- Also refer to CCO Antiemetic Recommendations.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Other Supportive Care:
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Ensure adequate hydration and correct hyperuricemia before starting ponatinib.
Doses should be modified according to the protocol by which the patient is being treated.
Patients' cardiovascular status should be assessed and risk factors managed prior to starting treatment and monitored during treatment.
Dosage with toxicity
Dose levels: 45 mg, 30 mg, 15 mg (if further dose reduction indicated, discontinue)
Doses reduced for toxicity may be re-escalated after toxicity has resolved, if clinically appropriate.
|
Toxicity |
Severity |
Action/ponatinib dose |
|
Myelosuppression |
ANC < 1 x 109/L or platelets < 50 x 109/L (unrelated to disease) |
1st occurrence: Hold* until recovery, restart at the same dose. 2nd occurrence: Hold* until recovery, restart at ↓ 1 dose level from previous dose. 3rd occurrence: 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/ALT > 3 x ULN |
Hold until recovery to ≤ grade 1, restart at ↓ 1 dose level from previous dose. |
|
AST/ALT ≥ 3 x ULN AND total bilirubin > 2 x ULN AND ALP < 2 x ULN |
Discontinue` |
|
|
Suspected Pancreatitis
|
Asymptomatic Amylase/lipase > 2 x ULN |
Hold until recovery to ≤ grade 1 then restart at ↓1 dose level from previous dose. |
|
Amylase/Lipase elevations and symptomatic |
Hold and investigate for pancreatitis. |
|
|
Grade 3 pancreatitis |
Hold until recovery to < grade 2 then restart at ↓ 1 dose level from previous dose. |
|
|
Grade 4 pancreatitis |
Discontinue |
|
|
Hypertriglyceridemia |
Grade 3 or 4 |
Manage patient appropriately to reduce pancreatitis risk. |
|
Cardiac/ATE/VTE
|
Arterial or venous thromboembolic event |
Discontinue unless benefit outweighs risk |
|
Blurred or decreased vision |
Hold and refer for ophthalmic examination for suspected vascular occlusion. Consider the risk vs. benefit of restarting. |
|
|
LVEF < 50% and > 10% below baseline and asymptomatic |
Hold until recovery. Discontinue if does not resolve within 4 weeks or is ≥ grade 3. |
|
|
Symptomatic CHF |
Discontinue |
|
|
Arrhythmias |
Hold and investigate. |
|
|
Hypertension |
Treat to normalize blood pressure. Hold if not medically controlled and evaluate for renal artery stenosis. |
|
|
Fluid retention |
|
Hold, reduce or discontinue ponatinib as clinically indicated. |
| RPLS /PRES | Any |
Hold if suspected.
|
|
Other non-hematologic toxicity |
Grade 3 or 4 |
Hold until recovery. Restart at ↓ 1 dose level from previous dose. If grade 4, consider discontinuation. |
|
Major surgical procedures |
|
Consider hold prior to surgery. Restart based on clinical judgement of adequate wound healing. |
|
*Restart once ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L |
||
Hepatic Impairment
The recommended starting dose is 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B or C). There was an increase in adverse effects in patients with severe hepatic impairment.
Renal Impairment
Renal excretion is not a major route of elimination. Dosage adjustment is not recommended, but ponatinib has not been studied in patients with CrCl < 50 ml/min or end-stage renal disease.
Dosage in the Elderly
Patients aged 65 and older were more likely to experience reduced efficacy and adverse effects compared to younger patients. The dose should be selected with caution given the greater frequency of decreased hepatic, renal and cardiac function, other diseases and drug therapies in older patients.
Refer to ponatinib drug monograph(s) for additional details of adverse effects.
|
Common (25-49%) |
Less common (10-24%) |
Uncommon (< 10%), but may be severe or life-threatening |
|
|
|
Refer to ponatinib drug monograph(s) for additional details.
- Ponatinib is metabolized by CYP3A4 and is susceptible to drug interactions with inducers and inhibitors of this isoenzyme.
- Consider reducing the starting dose of ponatinib when co-administered with strong CYP3A4 inhibitors.
- Avoid strong CYP3A4 inducers if possible. Caution and monitor if used together.
- Drugs that raise gastric pH may result in lower ponatinib Cmax, but no change in systemic exposure. No need to adjust dose or separate admin.
- Ponatinib is an inhibitor of P-gp and BCRP and may increase substrate concentration and/or toxicity.
Refer to ponatinib drug monograph(s) for additional details.
Administration:
- Ponatinib should be swallowed whole with or without food.
- Tablets should not be crushed, chewed or dissolved.
- 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 (15oC to 30oC) in the original package.
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 a history of myocardial infarction, prior revascularization or stroke unless the potential benefit outweighs the risk
- Patients with dehydration or untreated hyperuricemia
Warnings/Precautions:
- Patients aged 65 and older experienced reduced efficacy and increased adverse effects.
- Use with caution 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 with hepatic impairment.
- 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; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Pregnancy/lactation
- Ponatinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose. It is unknown whether ponatinib affects the effectiveness of oral contraceptives. An alternative method of contraception should be used.
- Breastfeeding is not recommended.
- Fertility effects: Likely
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
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Blood pressure; Baseline and as clinically indicated; ensure hypertension is controlled to minimize risk of arterial thromboembolism
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Calcium, phosphate; Baseline and as clinically indicated
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CBC; Baseline, every 2 weeks for the first 3 months, and then monthly and as clinically indicated
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Eye exam and fundoscopy; Baseline, with blurred vision and as clinically indicated
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Lipase, amylase; Baseline, every 2 weeks for the first 2 months, and then periodically or as clinically indicated
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Liver function tests; Baseline, at least monthly and as clinically indicated
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LVEF; Baseline, 3 months after treatment initiation, and as clinically indicated
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Clinical toxicity assessment for bleeding, infection, thromboembolism, fluid retention (including regular weight monitoring), hypertension, cardiac and GI effects, tumour lysis syndrome, ocular and neurologic effects; Baseline and at each visit
-
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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BCR-ABL Tyrosine Kinase Inhibitors [GLEEVEC (imatinib mesylate), TASIGNA (nilotinib), BOSULIF (bosutinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib hydrochloride)] - Risk of Hepatitis B Reactivation. Health Canada, May 4, 2016. [Accessed May 13, 2016]. Available from: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/58222a-eng.php
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.
Ponatinib drug monograph, Ontario Health (Cancer Care Ontario).
March 2023 Modified Rationale/uses and Pregnancy/lactation sections
Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph. Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.