NILOTINIB
Clinical safety rating: avoid
Contraindicated (not allowed)
Tyrosine kinase inhibitor targeting BCR-ABL, c-KIT, and PDGFR. Binds to inactive conformation of ABL kinase, preventing ATP binding and substrate phosphorylation.
| Metabolism | Primarily via CYP3A4; minor contributions from UGT1A3, UGT1A8, UGT1A9; active metabolite (minor); substrate of P-glycoprotein. |
| Excretion | Primarily fecal (93% of absorbed dose) via biliary excretion; renal excretion accounts for <1% of unchanged drug. |
| Half-life | Terminal elimination half-life approximately 17 hours (range 14-20 hours), supporting twice-daily dosing. |
| Protein binding | Approximately 98% bound to albumin and α1-acid glycoprotein. |
| Volume of Distribution | Steady-state volume of distribution (Vss) is 962 L (approximately 13.7 L/kg for a 70 kg person), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is about 50% (range 30-60%), increased by food (high-fat meal increases AUC by 82% and Cmax by 112%; thus should be taken on an empty stomach). |
| Onset of Action | Oral: Inhibition of BCR-ABL autophosphorylation detected within 1-2 hours after single dose. |
| Duration of Action | Clinically effective suppression of BCR-ABL activity persists for 8-12 hours, consistent with twice-daily dosing. |
300 mg orally twice daily for newly diagnosed chronic phase CML; 400 mg orally twice daily for resistant or intolerant CML. Take on an empty stomach (no food for 2 hours before and 1 hour after).
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl >30 mL/min). For severe renal impairment (CrCl <30 mL/min), use with caution and monitor QT interval; consider dose reduction to 300 mg twice daily for resistant/intolerant CML. No data for dialysis. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce starting dose to 300 mg twice daily for resistant/intolerant CML. Child-Pugh C: Contraindicated due to increased risk of QT prolongation and liver toxicity. |
| Pediatric use | Approved for pediatric patients 1 year and older with newly diagnosed or resistant/intolerant CML. Dose: 230 mg/m² orally twice daily, rounded to the nearest 50 mg (maximum 400 mg twice daily). For patients BSA <0.32 m², use 50 mg twice daily. |
| Geriatric use | No specific dose adjustment; pharmacokinetics similar to younger adults. Monitor renal and hepatic function, and correct electrolyte abnormalities more frequently due to higher risk of QT prolongation. Consider starting at 300 mg twice daily for newly diagnosed patients over 65 years. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause QT prolongation and sudden death.
| Breastfeeding | No human data on milk excretion. Nilotinib is highly protein bound (98%) and likely excreted into milk. M/P ratio unknown. Risk of severe adverse reactions in breastfed infant (myelosuppression, infection, gastrointestinal toxicity). Advise not to breastfeed during therapy and for at least 2 weeks after last dose. |
| Teratogenic Risk | Nilotinib is embryotoxic and fetotoxic in animal studies. In humans, there are no adequate studies; however, based on mechanism of action (BCR-ABL inhibitor) and animal data, it is expected to cause fetal harm when administered to pregnant women. First trimester exposure carries highest risk of major malformations (neural tube, cardiac, skeletal). Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and preterm labor. Avoid use in pregnancy unless no safer alternative. |
■ FDA Black Box Warning
QT interval prolongation and sudden death. Correct hypokalemia/hypomagnesemia prior to use. Avoid with long QT syndrome. Perform ECG at baseline, after 7 days, and periodically.
| Common Effects | Myelosuppression |
| Serious Effects |
["Hypokalemia or hypomagnesemia","Long QT syndrome or baseline QTc > 480 ms","Concurrent use of strong CYP3A4 inhibitors or inducers","Pregnancy"]
| Precautions | ["QT prolongation and risk of torsade de pointes; monitor electrolytes and ECG","myelosuppression (thrombocytopenia, neutropenia, anemia)","pancreatitis; monitor lipase and amylase","hepatotoxicity; monitor liver function tests","fluid retention (pleural/pericardial effusions, ascites)","femoral/hip avascular necrosis","growth retardation in children","embryofetal toxicity"] |
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| Fetal Monitoring | Pregnancy test before initiation in women of childbearing potential. Monthly complete blood count, liver function tests, serum lipase, and glucose monitoring. Fetal monitoring: serial ultrasounds for growth restriction and anatomy; fetal echocardiogram due to potential QT prolongation and cardiac effects. Monitor maternal ECG for QT interval prolongation (corrected QT >450 ms). |
| Fertility Effects | Animal studies show no impairment of male or female fertility. In humans, no specific data; however, nilotinib may affect spermatogenesis or oogenesis due to kinase inhibition. Men and women should consider fertility preservation before treatment. Use effective contraception during therapy and for 2 weeks after. |