Nilotinib
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Ph+ CML in chronic phase — newly diagnosed | Adults and pediatrics ≥1 year | Monotherapy | FDA Approved |
| Ph+ CML-CP and CML-AP — resistant or intolerant to imatinib | Adults | Monotherapy | FDA Approved |
| Ph+ CML-CP and CML-AP — resistant or intolerant to prior TKI | Pediatrics ≥1 year | Monotherapy | FDA Approved |
| Treatment-free remission (TFR) — discontinuation after sustained MR4.5 | Eligible adults with typical BCR-ABL transcripts | Discontinuation pathway | FDA Approved |
Nilotinib is a second-generation BCR-ABL kinase inhibitor structurally derived from imatinib, designed to fit more tightly into the ATP-binding pocket of BCR-ABL and achieving approximately 30-fold greater potency against unmutated BCR-ABL compared with imatinib. In the ENESTnd trial, nilotinib 300 mg twice daily demonstrated higher rates of major molecular response (73% vs 53%) and deep molecular response (MR4.5: 54% vs 31%) compared with imatinib at 5 years. Uniquely among TKIs, nilotinib carries an FDA Boxed Warning for QT prolongation and sudden deaths, requires strict fasting administration, and has an FDA-approved treatment-free remission pathway for eligible patients who achieve sustained deep molecular response. Its metabolic side-effect profile — including hypercholesterolaemia and hyperglycaemia — and increased cardiovascular/arterial vascular occlusive events distinguish it from both imatinib and dasatinib.
Dosing
Adult Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Ph+ CML-CP — newly diagnosed | 300 mg twice daily | 300 mg BID | 400 mg BID | EMPTY STOMACH: no food 2 h before or 1 h after dose ~12-hour dosing intervals |
| Ph+ CML-CP or CML-AP — imatinib-resistant or -intolerant | 400 mg twice daily | 400 mg BID | 400 mg BID | EMPTY STOMACH: no food 2 h before or 1 h after dose Higher dose reflects more advanced disease |
| With strong CYP3A4 inhibitor (newly diagnosed 300 mg BID) | 200 mg once daily | 200 mg QD | 200 mg QD | Avoid if possible; washout period before upward adjustment Monitor QTc closely |
| With strong CYP3A4 inhibitor (resistant/intolerant 400 mg BID) | 300 mg once daily | 300 mg QD | 300 mg QD | Avoid if possible; washout period before upward adjustment Monitor QTc closely |
| Hepatic impairment — newly diagnosed (all Child-Pugh) | 200 mg twice daily | 200–300 mg BID | 300 mg BID | Increase to 300 mg BID based on tolerability |
| Hepatic impairment — resistant/intolerant, severe (Child-Pugh C) | 200 mg twice daily | 200–400 mg BID | 400 mg BID | Titrate: 200 → 300 → 400 mg BID based on tolerability |
Pediatric Dosing (≥1 year, CML-CP and CML-AP)
| Body Surface Area | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| ≤0.32 m² | 50 mg BID | 50 mg BID | 50 mg BID | 230 mg/m² BID, rounded to nearest 50 mg. Max single dose 400 mg. Combine capsule strengths as needed. Same fasting rules apply Capsules may be dispersed in applesauce |
| 0.55–0.76 m² | 150 mg BID | 150 mg BID | 150 mg BID | |
| 0.98–1.19 m² | 250 mg BID | 250 mg BID | 250 mg BID | |
| ≥1.64 m² | 400 mg BID | 400 mg BID | 400 mg BID |
Nilotinib MUST be taken on an empty stomach — no food for at least 2 hours before and 1 hour after the dose. Food significantly increases nilotinib bioavailability, which raises plasma concentrations and exacerbates QT prolongation. This fasting requirement is directly linked to the Boxed Warning for QT prolongation and sudden deaths. Capsules should be swallowed whole with water. For patients unable to swallow capsules, contents may be dispersed in 1 teaspoon of pureed applesauce and taken immediately (within 15 minutes).
Nilotinib is the first TKI with an FDA-approved pathway for treatment discontinuation. Eligible patients must have been on nilotinib for ≥3 years, achieved sustained MR4.5, have typical BCR-ABL transcripts, and no history of AP/BC or prior failed TFR attempt. After discontinuation, monitor BCR-ABL monthly for 1 year, every 6 weeks for year 2, then every 12 weeks. Reinitiate within 4 weeks if MMR is lost. Musculoskeletal symptoms (arthralgia, myalgia, bone pain) are commonly reported in the first year after discontinuation (28–45%) and should be anticipated.
Pharmacology
Mechanism of Action
Nilotinib is a selective, second-generation BCR-ABL kinase inhibitor designed through rational modification of the imatinib molecule to improve binding affinity and selectivity. It binds exclusively to the inactive (DFG-out) conformation of BCR-ABL, achieving approximately 30-fold greater potency against unmutated BCR-ABL compared with imatinib. Nilotinib retains activity against most imatinib-resistant BCR-ABL mutations but, like imatinib, is inactive against the T315I gatekeeper mutation. Its kinase selectivity profile is narrower than dasatinib — it does not inhibit SRC family kinases — which results in a distinct toxicity pattern with lower rates of pleural effusion but higher cardiovascular and metabolic events. Nilotinib also inhibits c-KIT and PDGFR, though its clinical use is focused on CML. Notably, nilotinib is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, P-glycoprotein, and UGT1A1, giving it a broad perpetrator drug interaction profile.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~3 h; ~30% absolute bioavailability; less than dose-proportional at doses >400 mg; food dramatically increases bioavailability and QT risk | MUST take on empty stomach (2 h before, 1 h after food). Total gastrectomy reduces exposure — consider dose increase or alternative |
| Distribution | ~98% plasma protein bound | High protein binding |
| Metabolism | Primarily CYP3A4; also oxidation and glucuronidation (UGT1A1). Nilotinib itself INHIBITS CYP3A4, CYP2C8, CYP2C9, CYP2D6, P-gp, and UGT1A1; may INDUCE CYP2B6, CYP2C8, CYP2C9 | Broad perpetrator: raises levels of many co-medications. Also a CYP3A4 substrate (victim). Gilbert syndrome patients may have higher bilirubin elevations due to UGT1A1 inhibition |
| Elimination | t½ ~17 h; >90% fecal (primarily as metabolites); <5% renal | Predominantly hepatic elimination; supports twice-daily dosing; no renal dose adjustment needed |
Side Effects
Side effect data below are from the ENESTnd trial (newly diagnosed CP-CML, nilotinib 300 mg BID, N=279 vs imatinib 400 mg QD, N=280, 60-month analysis; FDA PI Table 7) unless otherwise stated.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Rash | 38% | Much higher than imatinib (19%); Grade 3/4 in <1% |
| Headache | 32% | Higher than imatinib (23%); Grade 3/4 in 3% |
| Nasopharyngitis | 27% | Higher than imatinib (21%) |
| Fatigue | 23% | Similar to imatinib (20%); Grade 3/4 in 1% |
| Nausea | 22% | Much lower than imatinib (41%); a tolerability advantage |
| Arthralgia | 22% | Higher than imatinib (17%); Grade 3/4 in <1% |
| Pruritus | 21% | Much higher than imatinib (7%) |
| Constipation | 20% | Much higher than imatinib (8%); Grade 3/4 in <1% |
| Diarrhea | 19% | Much lower than imatinib (46%); a key advantage |
| Myalgia | 19% | Similar to imatinib (19%) |
| Back pain | 19% | Similar to imatinib (17%) |
| Upper abdominal pain | 18% | Higher than imatinib (14%); Grade 3/4 in 1% |
| Upper respiratory infection | 17% | Higher than imatinib (14%) |
| Cough | 17% | Higher than imatinib (13%) |
| Vomiting | 15% | Much lower than imatinib (27%) |
| Abdominal pain | 15% | Higher than imatinib (12%); Grade 3/4 in 2% |
| Pain in extremity | 15% | Similar to imatinib (16%) |
| Asthenia | 14% | Similar to imatinib (12%) |
| Pyrexia | 14% | Similar to imatinib (13%) |
| Alopecia | 13% | Higher than imatinib (7%) |
| Influenza | 13% | Higher than imatinib (9%) |
| Dry skin | 12% | Higher than imatinib (6%) |
| Dizziness | 12% | Similar to imatinib (11%) |
| Muscle spasms | 12% | Much lower than imatinib (34%); a key advantage |
| Oropharyngeal pain | 12% | Higher than imatinib (6%) |
| Insomnia | 11% | Higher than imatinib (9%) |
| Dyspnea | 11% | Higher than imatinib (6%); Grade 3/4 in 2% |
| Hypertension | 10% | Higher than imatinib (4%); Grade 3/4 in 1% |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Peripheral edema | 9% | Much lower than imatinib (20%); a key advantage |
| Dyspepsia | 10% | Similar to imatinib (12%) |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| QT prolongation (QTcF >60 ms from baseline) | 0.4% (newly diagnosed, 300 mg BID); 4.1% (resistant/intolerant, 400 mg BID) | Concentration-dependent; can occur early | ECG at baseline, day 7, then periodically. Hold if QTcF >480 ms; reduce dose if QTcF 450–480 ms after 2 weeks; permanently discontinue if QTcF >480 ms on reduced dose |
| Sudden deaths | 0.3% of 5,661 patients in clinical studies | Some relatively early after initiation | Pre-treatment ECG and electrolyte correction mandatory. May be related to ventricular repolarization abnormalities |
| Cardiovascular/arterial vascular occlusive events | 9% (300 mg BID) vs 3.2% (imatinib) at 60 months | During treatment; cumulative risk | IHD: 5%; PAOD: 3.6%; cerebrovascular: 1.4% (all nilotinib 300 mg BID). Evaluate cardiovascular status before starting; actively manage CV risk factors |
| Grade 3/4 thrombocytopenia | 10% (newly diagnosed); 30% (resistant/intolerant CP); 42% (AP) | First weeks of therapy | Hold until recovery; reduce to 400 mg QD if low >2 weeks |
| Grade 3/4 neutropenia | 12% (newly diagnosed); 31% (resistant/intolerant CP); 42% (AP) | First weeks of therapy | Hold until ANC ≥1.0×10&sup9;/L; reduce to 400 mg QD if low >2 weeks |
| Grade 3/4 elevated lipase | 9% (newly diagnosed); 18% (resistant/intolerant) | Variable | Hold if ≥Grade 3 with abdominal symptoms; exclude pancreatitis. Resume at 400 mg QD once resolved to ≤Grade 1 |
| Hyperglycemia (all grades) | 50% (nilotinib) vs 31% (imatinib); Grade 3/4: 7% | During treatment | Assess glucose before starting and monitor periodically. Treat per guidelines if warranted |
| Hypercholesterolaemia (all grades) | 28% (nilotinib) vs 4% (imatinib) | During treatment | Monitor lipid profiles periodically; consider statin (note CYP3A4 interaction for some statins). Contributes to cardiovascular risk |
| Hepatotoxicity (Grade 3/4 bilirubin or ALT) | 4% each (newly diagnosed) | Variable | Hold if bilirubin or transaminases ≥Grade 3; resume at reduced dose once ≤Grade 1. Hyperbilirubinemia often reflects UGT1A1 inhibition (Gilbert-like) |
| Hemorrhage (Grade 3/4) | 1.1% (300 mg BID) vs 0.4% (imatinib) | Any time | GI hemorrhage reported in 2.9% (300 mg BID) vs 1.4% (imatinib). Fatal events reported. Monitor and manage |
| Fluid retention (Grade 3/4) | 3.9% (300 mg BID) vs 2.5% (imatinib) | Variable | Effusions (pleural, pericardial, ascites) in 2.2% (300 mg BID); severe effusions in 0.7%. Much lower than dasatinib |
| Growth retardation in children | 5% (3/58 pediatric patients) | During prolonged treatment | Monitor growth; more pronounced in children <12 years at baseline. Growth deceleration crossing ≥2 percentile lines in 14% (8/58) |
Nilotinib carries the highest cardiovascular/arterial vascular occlusive event risk among the approved TKIs for CML. At 60 months in ENESTnd, cardiovascular events occurred in 9% of nilotinib 300 mg BID patients versus 3.2% with imatinib. This includes ischaemic heart disease (5%), peripheral arterial occlusive disease (3.6%), and ischaemic cerebrovascular events (1.4%). The metabolic profile — hyperglycaemia (50%), hypercholesterolaemia (28%), and hypertriglyceridaemia (12%) — likely contributes to the vascular risk. Cardiovascular status should be evaluated before starting and risk factors actively managed throughout treatment. Patients with pre-existing cardiovascular disease or diabetes require especially careful monitoring.
Drug Interactions
Nilotinib has an exceptionally broad drug interaction profile. It is both a CYP3A4 substrate (victim) and an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, P-glycoprotein, and UGT1A1 (perpetrator). It may also induce CYP2B6, CYP2C8, and CYP2C9. These dual properties make comprehensive medication review essential before and during therapy. The food interaction is also critical — food must be strictly avoided around dosing.
Monitoring
- ECG / QTcBaseline, day 7, periodically thereafter, and after dose adjustments
RoutineBoxed Warning requirement. QTcF >60 ms in 0.4% (newly diagnosed) and 4.1% (resistant/intolerant). Sudden deaths in 0.3%. Hold if QTcF >480 ms. Correct electrolytes before and during treatment. - Complete Blood CountEvery 2 weeks × 2 months, then monthly
RoutineGrade 3/4 neutropenia 12%, thrombocytopenia 10%, anemia 4% in newly diagnosed. Much higher in resistant/intolerant CML (neutropenia 31%, thrombocytopenia 30%). - Electrolytes (K+, Mg2+, Ca2+)Baseline, then periodically
RoutineHypokalemia and hypomagnesemia are CONTRAINDICATIONS. Must be corrected before starting nilotinib and monitored throughout to prevent QT prolongation. - Liver FunctionMonthly or as clinically indicated
RoutineGrade 3/4 bilirubin elevation 4%, ALT 4%. Hyperbilirubinemia common (59% all grades) partly due to UGT1A1 inhibition (Gilbert-like). Higher rates in pediatric patients. - LipaseMonthly or as clinically indicated
RoutineGrade 3/4 lipase elevation 9% (newly diagnosed), 18% (resistant/intolerant). If elevated with abdominal symptoms, exclude pancreatitis. - Lipid Profile & GlucoseBaseline, periodically during first year, then annually
RoutineHypercholesterolaemia 28%, hyperglycaemia 50% (all grades). These metabolic effects contribute to cardiovascular risk. Use non-CYP3A4 statins if treatment needed. - Cardiovascular StatusBaseline evaluation; monitor risk factors throughout
RoutineArterial vascular occlusive events in 9% (300 mg BID) vs 3.2% (imatinib) at 60 months. Actively manage hypertension, diabetes, dyslipidaemia. Report acute CV symptoms immediately. - Molecular Response (CML)Q3 months until MMR; then Q3–6 months
RoutineBCR-ABL1 transcript levels by qRT-PCR (IS). Nilotinib achieves deeper molecular responses than imatinib. Monitor for TFR eligibility (MR4.5 sustained ≥1 year). - Growth (Pediatric)Every 3–6 months
RoutineGrowth deceleration crossing ≥2 percentile lines in 14% (8/58). More pronounced in children <12 years. Monitor height, weight, and growth velocity.
Contraindications & Cautions
Absolute Contraindications
- Hypokalemia. Must be corrected before initiating nilotinib (FDA PI Section 4).
- Hypomagnesemia. Must be corrected before initiating nilotinib (FDA PI Section 4).
- Long QT syndrome. Nilotinib prolongs QT in a concentration-dependent manner; congenital or acquired long QT is an absolute contraindication (FDA PI Section 4).
Relative Contraindications (Specialist Input Recommended)
- Pre-existing cardiovascular disease or multiple CV risk factors. Arterial vascular occlusive events in 9% (300 mg BID) vs 3.2% (imatinib) at 5 years. Particular caution with IHD, PAOD, or cerebrovascular disease.
- Pregnancy. Nilotinib causes embryo-fetal toxicity in animals. Effective contraception required during treatment and for 14 days after the last dose.
- Concomitant strong CYP3A4 inhibitors or QT-prolonging drugs. Substantially increases QT risk. If unavoidable, dose reduction and strict ECG monitoring required.
- Total gastrectomy. Reduced nilotinib exposure; more frequent monitoring needed; consider dose increase or alternative therapy.
Use with Caution
- Hepatic impairment. Dose reduction required for all severity levels; monitor QTc closely.
- History of pancreatitis. Higher risk of elevated serum lipase; monitor monthly.
- Lactose intolerance. Capsules contain lactose; not recommended for patients with severe lactase deficiency, galactose intolerance, or glucose-galactose malabsorption.
- Lactation. Present in rat milk; do not breastfeed during treatment or for 14 days after the last dose.
Nilotinib prolongs the QT interval in a concentration-dependent manner. Prior to administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs at baseline, 7 days after initiation, and periodically thereafter, and following any dose adjustments. Sudden deaths have been reported in 0.3% of 5,661 patients. Do not administer to patients with hypokalemia, hypomagnesemia, or long QT syndrome. Avoid concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking the dose (FDA PI Boxed Warning).
In the ENESTnd trial at a median of 60 months, cardiovascular events including arterial vascular occlusive events occurred in 9% (300 mg BID) and 15% (400 mg BID) of nilotinib patients, compared with 3.2% with imatinib. This included ischaemic heart disease (5% and 9%), peripheral arterial occlusive disease (3.6% and 2.9%), and ischaemic cerebrovascular events (1.4% and 3.2%). Evaluate cardiovascular status before starting and monitor and manage risk factors during therapy (FDA PI Section 5.4).
Patient Counselling
Purpose of Therapy
Nilotinib is a targeted medicine that blocks the abnormal BCR-ABL protein responsible for your chronic myeloid leukaemia. It is more potent than imatinib and achieves deeper responses, which means eligible patients may be able to stop treatment entirely and remain in remission (treatment-free remission). However, nilotinib requires strict fasting rules and careful heart monitoring because it can affect your heart rhythm.
How to Take
Take nilotinib exactly 12 hours apart (e.g., 8 AM and 8 PM). You MUST take it on an empty stomach — do not eat anything for at least 2 hours before and 1 hour after each dose. Swallow the capsules whole with water. If you cannot swallow capsules, the contents may be mixed in one teaspoon of applesauce and taken immediately (within 15 minutes). Never take nilotinib with food — this is a safety requirement, not just a preference.
Sources
- TASIGNA (nilotinib) Capsules. Full Prescribing Information. Novartis Pharmaceuticals Corporation. Revised 02/2024. FDA LabelPrimary regulatory source for all dosing, pharmacokinetics, adverse reaction rates, contraindications, boxed warning, and drug interaction data.
- Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–2259. DOIENESTnd initial results demonstrating superior MMR rates with nilotinib vs imatinib at 12 months.
- Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–1054. DOIENESTnd 5-year analysis confirming superior molecular responses and characterizing long-term cardiovascular safety signal.
- Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance. Blood. 2011;117(4):1141–1145. DOIPhase 2 study establishing nilotinib efficacy in imatinib-resistant/intolerant CP-CML (400 mg BID).
- Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525–1531. DOIENESTfreedom trial demonstrating feasibility of treatment-free remission after frontline nilotinib; 51.6% maintained MMR at 48 weeks.
- Hughes TP, Leber B, Engert A, et al. Critical factors for treatment-free remission in patients with CML: results of a subanalysis of ENESTfreedom. Blood. 2016;128(22):791. DOITFR subanalysis identifying sustained MR4.5 duration and Sokal score as predictors of successful treatment discontinuation.
- Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–984. DOIELN 2020 CML management guideline positioning nilotinib as a first-line TKI option with cardiovascular risk considerations.
- Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129–141. DOIPreclinical characterization of nilotinib showing 30-fold greater potency than imatinib and activity against most imatinib-resistant mutations.
- Tanaka C, Yin OQP, Sethuraman V, et al. Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib. Clin Pharmacol Ther. 2010;87(2):197–203. DOIPK study characterizing nilotinib absorption, metabolism, food effect, and dose-exposure relationships.
- Abruzzese E, Bocchia M, Trawinska MM, et al. Cardiovascular events and deep molecular response in patients treated with nilotinib for CML. Eur J Clin Invest. 2021;51(2):e13418. DOIReal-world study examining association between nilotinib use, cardiovascular events, and molecular response depth.