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NILO

Cancer Type: Hematologic, Leukemia - Chronic Myeloid (CML)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    niLOtinib - Chronic phase Ph+ CML, with specific criteria
Exceptional Access Program
    niLOtinib - Accelerated phase Ph+ CML with documented resistance or intolerance to imatinib therapy, with specific criteria
A - Regimen Name

NILO Regimen
Nilotinib


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

Treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) in chronic phase.

The treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in adult patients resistant to or intolerant of at least one prior therapy including imatinib.

Note
Approval for use in newly diagnosed patients was based on the observation of major molecular and cytogenetic responses; overall survival benefit has not been demonstrated.  Approval for imatinib resistant or intolerant patients was based on hematological and unconfirmed major cytogenetic response rates.

 


Supplementary Public Funding

niLOtinib
Exceptional Access Program (niLOtinib - Chronic phase Ph+ CML, with specific criteria) (EAP Website)

niLOtinib
Exceptional Access Program (niLOtinib - Accelerated phase Ph+ CML with documented resistance or intolerance to imatinib therapy, with specific criteria) (EAP Website)

 
B - Drug Regimen

Newly diagnosed Ph+ CML (chronic phase):

 

niLOtinib
300 mg PO BID (every 12 hours)

 

Resistant or Intolerant Ph+ CML (chronic phase) or CML (accelerated phase):

 

niLOtinib
400 mg PO BID (every 12 hours)

outpatient prescription available as 150 and 200 mg capsules

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C - Cycle Frequency

CONTINUOUS TREATMENT

To response; discontinue with disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

  • Use of allopurinol and hydration to reduce the risk of tumour lysis syndrome are recommended, especially in patients with high tumour load or renal impairment.
     
  • See Nilotinib monograph for possible drug interactions with antiemetics or other supportive medications.
  • 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.

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Dosage with toxicity

Dosage with hematologic toxicities:  Exclude underlying disease causality.

Dose

 Counts (X 109/L)

Action

 

Time required for recovery (Platelets > 50 X 109/L and/or ANC > 1 X 109/L)

Subsequent Dose

Newly diagnosed at 300 mg BID

OR

Resistant or intolerant at 400 mg BID 

ANC < 1 

and/or

Platelet counts <50

Hold and monitor counts

AND

≤ 2 weeks

Resume at prior dose

> 2 weeks

Restart at 400 mg once daily 

 

 

 

 

 

 

Dosage with QT prolongation:

QTc

Action

 

QTc monitoring

Subsequent Dose

QTc > 480 msec

Hold; correct hypokalemia and hypomagnesemia. Review concomitant medications.

AND

QTcF < 450 msec or within 20 msec of baseline within 2 weeks

Resume at prior dose

QTcF = 450 – 480 msec after 2 weeks

Restart at 400 mg once daily*

No recovery

Discontinue

QTc > 480 msec at 400 mg daily

Discontinue

    -

                            -

                 -

 *repeat ECG 7 days after any dosage adjustment

Dosage with non-hematologic toxicities:

Toxicity

Action

 

≥ Grade 3 LFTs or ↑ lipase / amylase

Hold; resume at 400 mg once daily when ≤ Grade 1

Symptomatic lipase or amylase ↑ Hold, investigate.  May resume at 400 mg once daily if  ≤ grade 1
Other clinically significant moderate, or severe (≥ Grade 3, including fluid retention) Hold; resume at 400 mg once daily when resolved.  Consider re-escalation to starting dose if clinically appropriate.



Hepatic Impairment

Increased nilotinib exposure was observed in patients with hepatic impairment. Clinical studies excluded patients with ALT/AST > 2.5 x ULN and total bilirubin > 1.5 x ULN. Dose adjustment is not required for mild to moderate hepatic impairment at baseline. Use with caution; monitor LFTs and QTc interval regularly. Consider dose reduction in patients with severe impairment and use with extreme caution.  Use the table above for hepatic toxicity.

 


Renal Impairment

Nilotinib and its metabolites are minimally excreted by the kidney. Although dose adjustments are not anticipated, patients with creatinine > 1.5 x ULN were excluded from clinical trials.  Patients with renal impairment may be at increased risk of TLS.


Dosage in the Elderly

No differences in safety and efficacy were observed in patients ≥ 65 years of age.


 
F - Adverse Effects

Refer to nilotinib drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

 

  • Rash (may be severe)
  • Headache
  • Nausea, vomiting
  • QT interval prolonged
  • Fatigue
  • Myelosuppression ± infection, bleeding (may be severe)
  • Musculoskeletal pain
  • Constipation
  • Abdominal pain
  • Alopecia

 

  • ↑ Lipase, amylase
  • Cardiotoxicity, arrhythmia
  • Hypersensitivity
  • Pneumonitis; Interstitial lung disease
  • Rhabdomyolysis
  • Sudden death
  • Arterial thromboembolism
    Venous thromboembolism
  • Hepatic failure
  • Renal failure
  • GI perforation
  • TLS
  • Vasculitis
  • Optic neuritis
  • Fluid retention
  • Pulmonary hypertension
  • Pancreatitis
  • Secondary malignancies
  • Atypical infections (including HBV reactivation)

 

 
G - Interactions

Refer to nilotinib drug monograph(s) for additional details


  • Nilotinib is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, UGT1A1 and inducer of CYP2B6, CYP2C8, and CYP2C9. This may result in interactions with substrates of these enzymes (i.e. increased exposure to HMG CoA reductase inhibitors, or statins).
     
  • Avoid concomitant use with CYP3A4 inhibitors and inducers; consider dose adjustment for substrates with narrow therapeutic index.
     
  • Caution with p-glycoprotein substrates and inhibitors, acid reducing agents, alcohol, CYP2D6 substrates, CYP 2B6 substrates, UGT1A1 substrates, CYP 2C9 substrates, CYP 2C8 substrates, and drugs that can affect electrolyte levels.
     
  • Nilotinib absorption is increased when taken with food, which can result in higher serum concentrations and toxicity
     
  • Yogurt has been shown to result in significant increases in nilotinib bioavailability.  Do not use yogurt to disperse the capsule contents.
     
  • Concomitant use of antiemetics, including metoclopramide, prochlorperazine, ondansetron, dolasetron and others may have additive effects on QT interval prolongation.
 
H - Drug Administration and Special Precautions

Refer to nilotinib drug monograph(s) for additional details


Administration:

  • Nilotinib should be swallowed whole with a glass of water on an empty stomach, at least 1 hour before and 2 hours after food. 
  • If patient has trouble swallowing the capsules, may open the capsule and mix the content of each capsule in 1 teaspoon of applesauce and swallow immediately. Do not mix with other foods or liquids or use more applesauce than described above. 
  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
  • If a dose is missed, take the next dose as scheduled.  Do not replace missed doses.
  • Store at room temperature (15-30°C) in the original package

Special Precautions

Contraindications:

  • Patients who have a hypersensitivity to nilotinib or to any of its excipients
  • Long QT syndrome, persistent QTc > 480 msec
  • Uncorrectable hypokalemia or hypomagnesemia

Other Warnings/Precautions:

  • Consultation with a liver disease expert is recommended prior to starting nilotinib in chronic HBV carriers (including those with active disease), and for patients who test positive for HBV infection while on treatment
  • The risk of QT prolongation is increased when nilotinib is taken with food, in patients who have had high-dose anthracyclines, patients with uncontrolled or significant cardiac disease (i.e. MI, CHF, unstable angina, etc) or with hypokalemia or hypomagnesemia.
  • Avoid drugs that can prolong QT including antiemetics, antiarrhythmics and strong CYP3A4 inhibitors (Refer to Interactions section).
  • Exercise caution in patients with risk factors for atherosclerosis.
  • Use with caution in patients with risk of tumour lysis (high tumour burden or decreased renal function).
  • Contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
  • Patients with Gilbert's Syndrome may experience an ↑ in indirect bilirubin levels.
  • Caution is recommended in patients with hepatic impairment or a previous history of pancreatitis.

Pregnancy and Lactation:

  • Nilotinib should not be used during pregnancy.  Patients of both sexes should use adequate contraception during treatment and for at least 4 weeks after nilotinib cessation.
  • Excretion into breast milk: Yes
  • Breastfeeding is not recommended.
  • Fertility effects: Probable
 
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

  • CBC; baseline and regular; every 2 weeks for the first 2 months and then monthly, or as clinically indicated thereafter
  • ECG; baseline, seven days after initiation and following dose adjustments, then periodically thereafter
  • Electrolytes, including phosphorus, potassium, calcium and magnesium; baseline and regular
  • Fasting blood glucose and creatine kinase (CK); baseline and regular
  • Lipase, amylase; baseline and regular; also monitor following dose adjustments or as clinically indicated
  • Liver function tests; baseline and regular, also monitor following dose adjustments or as clinically indicated
  • Monitoring for tumor lysis syndrome (including phosphate, uric acid, LDH); baseline and initial treatment period until tumour burden significantly reduced
  • Renal function tests; baseline and regular
  • Weight and other signs and symptoms of fluid retention; baseline and regular
  • HBV infection status: Prior to starting treatment; consult infectious disease if positive
  • For carriers of HBV:  signs and symptoms of active HBV infection; At each visit during treatment and for several months after treatment discontinues
  • Clinical assessment of toxicity (e.g. GI effects, fluid retention, rash, hemorrhage, cardiovascular effects, infections, hyperglycemia, pneumonitis, etc.); regular
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Close INR monitoring for patients on warfarin; baseline and as clinically indicated

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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

Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27(1):107-12.

Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51.

Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012 Oct;26(10):2197-203.

Le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated phase chronic myelogenous leukemia. Blood 2008; 111 (4): 1834-9.

Le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia. 2012 Jun;26(6):1189-94.

Nilotinib drug monograph, Cancer Care Ontario.

Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid myeloma. N Engl J Med 2010; 362: 2251-9.

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.
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