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niLOtinib
The Philadelphia chromosome is created by a reciprocal translocation between chromosomes 9 and 22, and results in production of a constitutively activated kinase (Bcr-Abl tyrosine kinase). Nilotinib is an inhibitor of Bcr-Abl in Philadelphia-chromosome positive (Ph+) leukemia cells. It is an aminopyrimidine derivative of imatinib, and is approximately 30 times more potent than imatinib. Nilotinib also inhibits the tyrosine kinase of platelet-derived growth factor (PDGF) receptor, c-KIT and DDR. It maintains activity against 32 of 33 imatinib-resistant mutant forms of Bcr-Abl, except for T315I.
Peak concentrations are reached at 3 hours with steady state achieved by day 8. Higher exposure in females has been observed (20% higher than males.)
| Bioavailability |
The bioavailability is approximately 30%, reduced by 48% in patients with total gastrectomy. When administered 30 min after food, the bioavailability increased by 29%. |
Mainly distributed to liver, adrenal cortex, small intestine, uveal tract
| Cross blood brain barrier? | Minimal |
| PPB | 98 % |
Extensive metabolism by CYP3A4, also a substrate for P-glycoprotein (Pgp).
| Active metabolites | None |
| Inactive metabolites |
Carboxylic acid derivative and other metabolites |
| Urine |
Parent drug and metabolites: minimal |
| Feces | >90% of the dose within 7 days |
| Half-life | 17 hours |
- Treatment of adult patients with newly diagnosed 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.
Emetogenic Potential:
Extravasation Potential: Not applicable
The following table contains adverse effects reported mainly in patients with newly diagnosed CML, receiving nilotinib 300 mg BID.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (<5%) | E | |||
| Arterial thromboembolism (3%) | E | ||||
| Cardiotoxicity (<5%) | E D | ||||
| Hypertension (<5%) | E | ||||
| Pulmonary hypertension (rare) | E | ||||
| QT interval prolonged (14%) (QT>450msec) | E | ||||
| Sudden death (rare) | E | ||||
| Venous thromboembolism (<1%) | E | ||||
| Dermatological | Alopecia (10%) | E | |||
| Photosensitivity (rare) | E | ||||
| Rash (33%) (may be severe) | E | ||||
| Gastrointestinal | Abdominal pain (10%) | E | |||
| Anorexia (4%) | E | ||||
| Constipation (10%) | E | ||||
| Diarrhea (9%) | E | ||||
| Dyspepsia (5%) | E | ||||
| GI perforation (rare) | E D | ||||
| Mucositis (<1%) | E | ||||
| Nausea, vomiting (14%) | E | ||||
| General | Fatigue (13%) | E | |||
| Fever (<5%) | E | ||||
| Fluid retention (5%) (may be severe, including effusions 1%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (grade 3-4; 12%) (including GI/CNS bleeding) | E | |||
| Hepatobiliary | ↑ Amylase / lipase (grade 3-4: 8%) | E | |||
| ↑ LFTs (4%) (grade 3-4, may be severe) | E | ||||
| Pancreatitis (2%) | E | ||||
| Hypersensitivity | Hypersensitivity (rare) | E | |||
| Immune | Other Atypical infections including HBV reactivation | D | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (5%) (grade 3-4, for ↑ / ↓ K, Na, Ca, Mg, Phosphate) | E | |||
| ↑ Cholesterol (3%) | E | ||||
| Hyperglycemia (6%) (grade 3/4) | E | ||||
| Hyperlipidemia (<5%) (<1% severe with 400mg daily) | E | ||||
| Hyperthyroidism (<1%) | E D | ||||
| Hypothyroidism (<1%) | E D | ||||
| Tumor lysis syndrome (rare) | E | ||||
| Musculoskeletal | Musculoskeletal pain (10%) | E | |||
| ↑CPK (<5%) | E | ||||
| Rhabdomyolysis (rare) | E | ||||
| Neoplastic | Secondary malignancy (rare; GI, ovarian, pNET, skin) | ||||
| Nervous System | Dizziness (<5%) | E | |||
| Dysgeusia (<5%) | E | ||||
| Headache (16%) | E | ||||
| Insomnia (<5%) | E | ||||
| Mood changes (<5%) | E | ||||
| Neuropathy (<5%) | E | ||||
| Optic neuritis (rare) | E | ||||
| Vertigo (<5%) | E | ||||
| Ophthalmic | Conjunctivitis (<5%) | E | |||
| Renal | Creatinine increased (rare, may be severe) | E | |||
| Respiratory | Cough, dyspnea (<5%) | E | |||
| Interstitial lung disease (rare) | E | ||||
| Pneumonitis (<1%) | E | ||||
| Urinary | Urinary symptoms (<5%) | E | |||
| Vascular | Vasculitis (rare) | 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 frequently reported drug-related adverse events are myelosuppression, headache, fatigue, myalgia, rash, pruritus, GI side effects. Myelosuppression is more frequent in patients with advanced or refractory disease.
Increases in serum lipase/amylase have been observed, in which a few were associated with abdominal pain or pancreatitis. Increases in LFTs have been reported, and rarely, fatal hepatic failure. Patients with Gilberts may have increases in their unconjugated bilirubin.
Nilotinib may prolong the QT interval, and should be used with caution in patients at risk, such as those with hypokalemia, hypomagnesemia, those on antiarrhythmic therapy or other medications that may prolong the QT interval, or patients who have received cumulative high-dose anthracyclines. Administering with meals or strong CYP3A4 inhibitors significantly increases the risk. Hypokalemia or hypomagnesemia must be corrected prior to nilotinib therapy. Patients with uncontrolled or significant cardiac disease were excluded from clinical trials; there was no clinically significant change in LVEF from baseline in previously untreated patients. (See Special Precautions and Interactions sections.)
Peripheral arterial occlusive disease, ischemic heart disease and ischemic cerebrovascular events have been reported, may be fatal, and are more common in patients with risk factors. Patients should be monitored for signs and symptoms of atherosclerosis, including monitoring lipid and glucose profiles (see Monitoring). Peripheral arterial occlusive disease can be severe, rapidly progressing, affect more than one site and require repeated revascularization procedures.
Severe fluid retention, including pleural and pericardial effusion/tamponade and pulmonary edema has been reported. Unexpected, rapid weight gain should be investigated and treated appropriately.
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. Patients should be tested for HBV infection prior to initiating treatment. Consult hepatology/infectious disease if seropositive. Carriers of HBV must be monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Refer to protocol by which 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.
Hypokalemia and hypomagnesemia must be corrected prior to starting treatment with nilotinib. Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.
Avoid concomitant use of antiemetics. BID doses should be taken at approximately 12 hour intervals, 1 hour before or 2 hours after food.
Newly diagnosed Ph+ CML-CP:
Oral: 300 mg BID
Resistant or Intolerant Ph+ CML-CP or CML-AP:
Oral: 400 mg BID
Dosage with hematologic toxicities: Exclude underlying disease causality.
|
Counts (X 109/L) |
Action |
|
Time required for recovery (Platelets > 50 X 109/L and/or ANC > 1 X 109/L) |
Subsequent Dose |
|
ANC < 1 and/or Platelet counts <50 |
Hold and monitor counts |
AND |
≤ 2 weeks |
Resume at prior dose |
|
> 2 weeks |
Restart at 400mg 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 400mg once daily* |
|||
| No recovery |
Discontinue |
|||
|
QTc > 480 msec at 400mg daily |
Discontinue |
- |
- |
- |
Dosage with non-hematologic toxicities:
|
Toxicity
|
Action
|
|
≥ Grade 3 LFTs or ↑ lipase / amylase |
Hold; resume at 400mg once daily when ≤ Grade 1 |
| Symptomatic lipase or amylase ↑ | Hold, investigate. May resume at 400mg once daily if ≤ grade 1 |
| Other clinically significant moderate, or severe (≥ Grade 3, including fluid retention) |
Hold; resume at 400mg once daily when resolved. Consider re-escalation to starting dose if clinically appropriate. |
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.
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.
No differences in safety and efficacy were observed in patients ≥ 65 years of age.
The safety and effectiveness of nilotinib in children and adolescents have not been studied.
- 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
- Patients who have a hypersensitivity to nilotinib or to any of its excipients
- Long QT syndrome, persistent QTc > 480 msec
- Uncorrectable hypokalemia or hypomagnesemia
- 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.
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Mutagenicity:
No
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
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
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).
Nilotinib absorption is increased when taken with food, which can result in higher serum concentrations and toxicity (e.g. prolonged QT interval; see Administration section)
Yogurt has been shown to result in significant increases in nilotinib bioavailability. Do not use yogurt to disperse the capsule contents (see Administration Guidelines section).
Avoid concomitant use of antiemetics, including metoclopramide, prochlorperazine, ondansetron, dolasetron and others that may prolong the QT interval.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ nilotinib concentration, increase risk of QT prolongation (up to 3-fold) | ↓ metabolism | Avoid concomitant use – interrupt nilotinib; if not feasible, monitor QTc closely |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ nilotinib concentration (up to 80%) | ↑ metabolism | Avoid concomitant use |
| CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↑ plasma concentration of CYP3A4 substrates (up to 3-fold) | Nilotinib is moderate CYP3A4 inhibitor | Monitor; consider dose adjustment for CYP3A4 substrates with narrow therapeutic index |
| P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) | ↑ concentration of Pgp substrates | Pgp inhibition by nilotinib | Caution; consider use of alternative medications |
| P-glycoprotein inhibitors (i.e. quinidine, cyclosporine) | ↑ nilotinib concentration and/or toxicity | nilotinib is a Pgp substrate | Caution |
| Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of QT prolongation | Additive | Avoid; monitor closely if must use |
| Proton Pump Inhibitors, prior gastrectomy | ↓ nilotinib concentration | Suppression of gastric acid decreases bioavailability of nilotinib | Use proton inhibitors as needed with caution |
| Non absorbable Antacids (aluminum hydroxide/magnesium hydroxide/simethicone) | ↓ nilotinib concentration | Suppression of gastric acid decreases bioavailability of nilotinib | Administer ≥ 2 hours before or after nilotinib |
| H2 blockers | ↓ nilotinib concentration | Suppression of gastric acid decreases bioavailability of nilotinib | Give H2 blockers 10 hours before or 2 hours after nilotinib |
| Alcohol | One report of reduced efficacy with concomitant use | Unknown | Avoid |
| CYP2D6 substrates (e.g. beta-blockers, tramadol, nortriptyline, mirtazapine, serotonin-H3 antagonists) | ↑ plasma concentration of CYP2D6 substrates | nilotinib appears to inhibit CYP2D6 enzymes | Caution |
| CYP 2B6 substrates (i.e. bupropion, cyclophosphamide, selegiline) | ↓ plasma concentration of CYP2B6 substrates | Nilotinib appears to induce CYP2B6 enzymes | Caution |
| UGT1A1 substrates (i.e. estradiol, irinotecan) | ↑ concentration of UGT1A1 substrates | Nilotinib appears to inhibit UGT1A1 | Caution |
| CYP 2C9 substrates (e.g. warfarin, glyburide, losartan, diclofenac) | ↑ plasma concentration of CYP2C9 substrates (e.g. enhanced warfarin effect) or ↓ plasma concentration of CYP2C9 substrates | Nilotinib appears to inhibit CYP2C9 and/or induce CYP2C9 | Caution; monitor carefully and adjust warfarin dose accordingly closely |
| CYP 2C8 substrates (i.e. paclitaxel, sorafenib, amiodarone) | ↓ (or ↑) plasma concentration of CYP2C8 substrates | Nilotinib appears to induce (and/or inhibit) CYP2C8 | Caution |
| Drugs that may alter electrolyte levels (e.g. diuretics, laxatives, amphotericin B, high dose corticosteroids) | ↑ risk of QT prolongation | altered electrolyte levels | Caution; monitor closely |
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.
| Monitor Type | Monitor Frequency |
|---|---|
| Fasting blood glucose, lipid profile and creatine kinase (CK) | baseline, regular, and as clinically indicated |
| Renal function tests | baseline and regular |
| Electrolytes, including phosphorus, potassium, calcium and magnesium | baseline and regular |
| Liver function tests | baseline and regular, also monitor following dose adjustments or as clinically indicated |
| Lipase, amylase; baseline and regular | also monitor following dose adjustments or as clinically indicated |
| ECG | baseline, seven days after initiation and following dose adjustments, then periodically thereafter |
| CBC | Baseline and regular; every 2 weeks for the first 2 months and then monthly, or as clinically indicated |
| Monitoring for tumor lysis syndrome (including phosphate, uric acid, LDH) | baseline and initial treatment period until tumour burden significantly reduced |
| Weight and other signs and symptoms of fluid retention | Baseline and regular |
Clinical assessment of toxicity (e.g. GI effects, fluid retention, rash, hemorrhage, cardiovascular, infection, hyperglycemia, pneumonitis, etc.) |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| Close INR monitoring for patients on warfarin | Baseline and as clinically indicated |
Exceptional Access Program (EAP Website)
- niLOtinib - Accelerated phase Ph+ CML with documented resistance or intolerance to imatinib therapy, with specific criteria
- niLOtinib - Chronic phase Ph+ CML, with specific criteria
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
Jarkowski A, Sweeney RP. Nilotinib: A New Tyrosine Kinase Inhibitor for the Treatment of Chronic Myelogenous Leukemia. Pharmacotherapy 2008;28(11):1374-82.
Plosker GL, Robinson DM. Nilotinib. Drugs 2008;68 (4):449-59.
Product Monograph: Gleevec® (imatinib). Novartis Pharmaceuticals Canada, August 25, 2016.
December 2023 Added information on hepatitis B testing
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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