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. |
| Molecular Weight | 529.5 |
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 | Avoid use due to teratogenicity risk in animal studies; human data limited. |
| 2nd trimester | Avoid use; may cause fetal harm. If necessary, monitor pregnancy closely. |
| 3rd trimester | Avoid use; risks of fetal toxicity and adverse outcomes. |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause QT prolongation and sudden death.
| Placental transfer | Likely crosses placenta based on molecular weight and animal studies. |
| Breastfeeding | Excreted into human milk; potential for serious adverse reactions in nursing infants. Advise not to breastfeed during treatment and for at least 2 weeks after last dose. |
| Lactation Rating |
■ 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 |
HypokalemiaHypomagnesemiaLong QT syndromeKnown hypersensitivity to nilotinib
| 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 |
| Food/Dietary | Nilotinib absorption is increased with food, leading to higher plasma concentrations and risk of adverse effects. It must be taken on an empty stomach (at least 1 hour before or 2 hours after food). Grapefruit and grapefruit juice should be avoided as they inhibit CYP3A4 and may increase nilotinib levels. Avoid St. John's wort as it may decrease nilotinib efficacy. |
Loading safety data…
| L5 (Contraindicated) |
| 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. |
| 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. |
| Clinical Pearls | Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor with higher potency than imatinib. It is associated with QTc prolongation; baseline and periodic ECG monitoring is required, and electrolytes should be corrected before initiation. Nilotinib has a black box warning for sudden death. It is a substrate of CYP3A4; avoid strong inhibitors and inducers. Administer twice daily on an empty stomach (at least 1 hour before or 2 hours after a meal) due to food effect increasing absorption and risk of toxicity. Nilotinib can cause pancreatitis, so monitor lipase. Also monitor for hepatotoxicity and myelosuppression. Dose reduction may be needed in hepatic impairment. |
| Patient Advice | Take nilotinib exactly as prescribed, usually twice daily. · Take on an empty stomach: at least 1 hour before or 2 hours after a meal. · Do not eat grapefruit or drink grapefruit juice while taking nilotinib. · Avoid taking St. John's wort as it may decrease the effectiveness of nilotinib. · Report symptoms like fast or irregular heartbeat, fainting, or dizziness immediately. · Tell your doctor if you have a history of pancreatitis, liver problems, or electrolyte imbalances. · Do not change the dose or stop taking nilotinib without consulting your doctor. · Use effective contraception during treatment and for a period after treatment ends. |