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PNAT

Cancer Type: Hematologic, Leukemia - Chronic Myeloid (CML)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    ponatinib - For the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia, according to specific clinical criteria
A - Regimen Name

PNAT Regimen
Ponatinib


Disease Site
Hematologic - Leukemia - Chronic Myeloid (CML)

Intent
Palliative

Regimen Category
Evidence-Informed :

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.


Rationale and Uses

For the treatment of patients with chronic, accelerated or blast phase chronic myeloid leukemia (CML) who are resistant or intolerant to prior tyrosine kinase inhibitors (dasatinib or nilotinib) or who are T315I mutation positive.


Supplementary Public Funding

ponatinib
Exceptional Access Program (ponatinib - For the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia, according to specific clinical criteria) (EAP Website)

 
B - Drug Regimen

Ponatinib is only prescribed and dispensed through a controlled distribution program. For more information, call 1-855-552-7423 or 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.

ponatinib
45 mg PO Daily

(available as 45 mg or 15 mg tablets)

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

  • Patients should be tested for HBV infection prior to initiating treatment.  Carriers of HBV must be monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

  • Ensure adequate hydration and correct hyperuricemia before starting ponatinib.

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

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

The following recommendations have been adapted from clinical trials or product monographs and could be considered.

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. 


Discontinue if confirmed 
or 
Restart if resolved and only if benefits outweigh risks 

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.

 


 
F - Adverse Effects

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

  • Increased amylase/lipase (may be severe)
  • Rash (may be severe)
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Abdominal pain
  • Fluid retention (may be severe, including effusions)

 

  • Headache
  • Constipation
  • Arterial thromboembolism (may be severe)
  • Fatigue
  • Increased LFTs (may be severe)
  • Musculoskeletal pain
  • Hypertension (may be severe)
  • Nausea, vomiting
  • Eye disorders (may be severe including retinal vascular disorders)
  • Peripheral neuropathy
  • Cardiotoxicity
  • Arrhythmia (atrial fibrillation)
  • Venous thromboembolism
  • Tumour lysis syndrome
  • GI perforation
  • Atypical infections (including HBV reactivation)
  • Hypothyroidism
  • Hyperglycemia
  • RPLS / PRES

 

 
G - Interactions

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
 
H - Drug Administration and Special Precautions

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

 

 
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.

Recommended Clinical Monitoring

  • Blood pressure; Baseline and as clinically indicated; ensure hypertension is controlled to minimize risk of arterial thromboembolism
  • Calcium, phosphate; Baseline and as clinically indicated
  • CBC; Baseline, every 2 weeks for the first 3 months, and then monthly and as clinically indicated
  • Eye exam and fundoscopy; Baseline, with blurred vision and as clinically indicated
  • For carriers of HBV:  signs and symptoms of active HBV infection; At each visit during treatment and for several months after treatment discontinues
  • HBV infection status; Prior to starting treatment and as clinically indicated during treatment; consult infectious disease if positive
  • Lipase, amylase; Baseline, every 2 weeks for the first 2 months, and then periodically or as clinically indicated
  • Liver function tests; Baseline, at least monthly and as clinically indicated
  • LVEF; Baseline, 3 months after treatment initiation, and as clinically indicated
  • 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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J - Administrative Information

Outpatient prescription for home administration


 
K - References

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, Cancer Care Ontario.

June 2019 Updated emetic risk category


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M - Disclaimer

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.