Pharmacological Class
- Tyrosine kinase inhibitor (TKI)
- Second-generation BCR-ABL inhibitor (more potent and selective than imatinib)
Mechanism of Action
- Inhibits BCR-ABL tyrosine kinase by binding to the ATP-binding site.
- Effective against many imatinib-resistant BCR-ABL mutations (but not T315I).
Indications (FDA-approved)
- Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML):
- Newly diagnosed, chronic phase (first-line).
- Chronic or accelerated phase after resistance or intolerance to prior therapy, including imatinib.
Dosing
- Newly diagnosed CP-CML:
- 300 mg orally twice daily.
- Resistant/intolerant CP or AP-CML:
- 400 mg orally twice daily.
- Take on an empty stomach (≥1 hr before or ≥2 hrs after food).
- Food increases absorption → risk of toxicity (especially QT prolongation).
Adverse Effects
Boxed Warning:
- QT prolongation and sudden death
- Must monitor ECG and electrolytes before and during therapy.
Other common/serious toxicities:
- Metabolic: hyperglycemia, hyperlipidemia, pancreatitis
- Cardiovascular: arterial occlusive events (ischemic heart disease, PAD, stroke)
- Hematologic: cytopenias (neutropenia, thrombocytopenia, anemia)
- Rash, pruritus, alopecia
- Elevated LFTs, bilirubin, lipase/amylase
Monitoring
- ECG: baseline, 7 days after starting, then periodically
- Electrolytes (K⁺, Mg²⁺): correct abnormalities before starting, monitor during treatment
- CBC: every 2 weeks × 2 months, then monthly
- LFTs, lipase/amylase, glucose, lipid panel: periodically
- Cardiovascular risk assessment before and during therapy
Drug Interactions
- CYP3A4 substrate → avoid strong inhibitors (e.g., ketoconazole, clarithromycin) and inducers (e.g., rifampin, carbamazepine, St. John’s wort)
- Avoid QT-prolonging agents (risk of torsades)
- Acid-reducing agents:
- PPIs: avoid (reduce absorption)
- H2 blockers/antacids: separate dosing by several hours
Dose Adjustments
- Hepatic impairment: reduce starting dose to 200 mg BID (mild–moderate).
- QT prolongation or myelosuppression: hold or reduce dose as per labeling.
- Renal impairment: no adjustment, but caution (not primarily renally cleared).
Clinical Pearls
- Must be taken fasting → critical counseling point.
- Less pleural effusion risk compared with dasatinib.
- More metabolic/cardiovascular toxicity than imatinib/dasatinib.
- Not effective against T315I mutation (ponatinib or asciminib preferred).
- Can be considered for treatment-free remission (TFR) in eligible CML patients achieving deep, sustained molecular response.
High-yield exam point:
Nilotinib = 2nd-gen TKI, fasting administration, QT prolongation boxed warning, higher risk of CV/metabolic toxicities, but less pleural effusion than dasatinib.
Links