NILOTINIB HYDROCHLORIDE DIHYDRATE
Clinical safety rating: avoid
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause QT prolongation and sudden death.
Nilotinib is a BCR-ABL tyrosine kinase inhibitor that binds to and stabilizes the inactive conformation of the ABL kinase domain, thereby inhibiting proliferation and inducing apoptosis in Philadelphia chromosome-positive (Ph+) leukemic cells.
| Metabolism | Nilotinib is primarily metabolized by CYP3A4, with minor contributions from CYP2C8 and flavin-containing monooxygenases (FMO). |
| Excretion | Fecal (93%), renal (3%; unchanged nilotinib appears minimal, mostly metabolites) |
| Half-life | Approximately 17 hours (terminal elimination half-life; supports once-daily or twice-daily dosing; extensive accumulation with daily dosing, steady state by day 8) |
| Protein binding | 98% (bound to albumin and alpha-1-acid glycoprotein) |
| Volume of Distribution | Large (estimated 2.1–4.9 L/kg; extensive tissue distribution, including accumulation in tumors) |
| Bioavailability | Oral: approximately 30% (increased by high-fat meal; avoid food for 2 hours before and 1 hour after dose) |
| Onset of Action | Oral: 2 hours (time to peak plasma concentration); pharmacodynamic effects on BCR-ABL activity occur within hours but clinical response requires days to weeks. |
| Duration of Action | 24 hours (once-daily dosing maintains therapeutic levels throughout interval; due to prolonged half-life, effect persists for several days after discontinuation) |
| Molecular Weight | 529.5 |
400 mg orally twice daily, approximately 12 hours apart, without food (at least 2 hours before or 1 hour after a meal).
| 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; no specific dose recommendation available. |
| Liver impairment | Child-Pugh A (mild): No dose adjustment. Child-Pugh B (moderate): Reduce starting dose to 200 mg orally twice daily. Child-Pugh C (severe): Not recommended. |
| Pediatric use | Approved for pediatric patients ≥1 year with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. For BSA ≥0.9 m²: 230 mg/m² orally twice daily; for BSA <0.9 m²: 460 mg/m² orally twice daily, rounded to nearest 50 mg increment. Administer without food. |
| Geriatric use | No specific age-based dose adjustment; however, elderly patients (≥65 years) may have higher risk of adverse events (e.g., QT prolongation, myelosuppression). Monitor ECG, electrolytes, and blood counts regularly. Consider dose reduction if tolerance issues arise. |
| 1st trimester | Avoid use due to teratogenic risk; based on animal studies and its mechanism of action (tyrosine kinase inhibitor), there is potential for fetal harm. |
| 2nd trimester | Avoid use; limited human data but animal studies show embryotoxicity and fetotoxicity. |
| 3rd trimester | Avoid use; risk of fetal harm and potential for neonatal myelosuppression and hypotension. |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause QT prolongation and sudden death.
| FDA category | Contraindicated |
| Placental transfer | Crosses placenta in humans; based on molecular weight (529.5 Da) and animal studies showing fetal exposure. |
| Breastfeeding |
■ FDA Black Box Warning
QT prolongation and sudden death: Nilotinib prolongs the QT interval. Prior to initiation, monitor for hypokalemia or hypomagnesemia and correct. Use caution in patients with or at risk for QT prolongation, including those with electrolyte abnormalities, congenital long QT syndrome, or taking other QT-prolonging drugs. Avoid use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
| Common Effects | Myelosuppression |
| Serious Effects |
HypokalemiaHypomagnesemiaLong QT syndrome or QTc > 480 msecConcomitant use with strong CYP3A4 inhibitors or inducersConcomitant use with drugs known to prolong QT interval
| Precautions | QT prolongation and sudden death: monitor ECG and electrolytes before and during treatment., Hepatotoxicity: monitor liver function tests regularly., Pancreatitis: monitor serum lipase., Cardiovascular events: arterial occlusive events including stroke and myocardial infarction have been reported., Fluid retention: can cause pleural effusion, pericardial effusion, and ascites., Electrolyte abnormalities: monitor potassium, magnesium, and calcium., Tumor lysis syndrome: ensure hydration and monitor uric acid., Interaction with strong CYP3A4 inhibitors/inducers: adjust dose or avoid., Food effect: avoid food within 2 hours before and 1 hour after dose., Pregnancy: can cause fetal harm; advise contraception. |
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| Nilotinib is excreted into human milk. Because of the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Nilotinib is embryotoxic and fetotoxic in animal studies at exposures lower than human therapeutic doses. In humans, there is a risk of fetal harm if used during pregnancy, particularly during the first trimester. It is classified as Pregnancy Category D. Congenital anomalies and spontaneous abortions have been reported. Use only if benefit outweighs risk, and effective contraception must be used during treatment and for at least 14 days after the last dose. |
| Fetal Monitoring | Monitor complete blood count (CBC) with differential, hepatic function (ALT, AST, bilirubin), pancreatic enzymes (lipase, amylase), serum electrolytes (including potassium, magnesium, calcium), and glucose levels at baseline and periodically. Monitor ECG for QTc prolongation. Assess for signs of cardiac failure, hypertension, and arterial thrombotic events. During pregnancy, monitor fetal growth by ultrasound and consider fetal echocardiography due to potential cardiac effects. |
| Fertility Effects | Nilotinib may impair fertility in males and females based on animal studies. In humans, no specific fertility studies have been conducted. Reversible effects on spermatogenesis have been observed in animal models. Women of childbearing potential should use effective contraception during treatment and for at least 14 days after the last dose. |
| Food/Dietary | Avoid grapefruit, grapefruit juice, and Seville oranges (inhibit CYP3A4, increase nilotinib levels). Take on an empty stomach; do not consume food for at least 2 hours before and 1 hour after dosing. High-fat meals increase absorption and risk of toxicity. |
| Clinical Pearls | Administer on empty stomach (1 hour before or 2 hours after food); avoid grapefruit products; monitor QT interval, electrolytes, liver function, and lipase; caution with strong CYP3A4 inhibitors/inducers; dose reduction required in hepatic impairment (Child-Pugh A/B/C). |
| Patient Advice | Take nilotinib on an empty stomach: 1 hour before or 2 hours after a meal. · Swallow capsules whole with water, do not crush or open. · Avoid grapefruit, grapefruit juice, and Seville oranges. · Report symptoms like fast or irregular heartbeat, fainting, or jaundice. · Do not stop or change dose without consulting your doctor. · Women of childbearing age must use effective contraception during treatment and for at least 14 days after last dose. · Avoid breastfeeding while on nilotinib and for 2 weeks after last dose. |