NILOTINIB HYDROCHLORIDE
Clinical safety rating: avoid
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause QT prolongation and sudden death.
Bcr-Abl tyrosine kinase inhibitor; specifically binds to and inhibits the kinase activity of Bcr-Abl, leading to inhibition of proliferation and induction of apoptosis in Bcr-Abl positive cells.
| Metabolism | Primarily metabolized by CYP3A4; also a substrate of CYP2C8, CYP2C9, CYP2D6, and UGT1A1. |
| Excretion | Primarily fecal (≥90%); renal excretion accounts for <5% as unchanged drug and metabolites. |
| Half-life | Terminal elimination half-life is approximately 17 hours (range 15-22 hours), supporting twice-daily dosing. |
| Protein binding | Approximately 98-99% bound to human serum albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Steady-state volume of distribution is about 2.2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 30% (range 20-40%) when taken on an empty stomach; food increases exposure. |
| Onset of Action | Not applicable; clinical effect (e.g., hematologic response) typically observed after 1-2 months of continuous oral therapy. |
| Duration of Action | Duration of cytogenetic response persists with continued dosing; effect wanes upon discontinuation. |
| Molecular Weight | 565.98 |
400 mg orally twice daily, approximately 12 hours apart, with food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CLcr ≥30 mL/min). For severe renal impairment (CLcr <30 mL/min), use with caution and reduce dose to 300 mg twice daily. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce initial dose to 300 mg twice daily. Child-Pugh C: Reduce initial dose to 200 mg twice daily. |
| Pediatric use | Not approved for use in pediatric patients. |
| Geriatric use | No specific dose adjustment required, but monitor for adverse effects (e.g., QT prolongation, electrolyte disturbances) due to increased sensitivity. |
| 1st trimester | Avoid use; embryotoxic and teratogenic in animal studies. Human data limited. Consider alternative therapy. |
| 2nd trimester | Avoid use; potential for fetal harm. No adequate human studies; animal studies show adverse effects. |
| 3rd trimester | Avoid use; may cause fetal harm. Use only if benefit outweighs risk; monitor for fetal effects. |
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 | Evidence suggests placental transfer in animals; human data lacking. Likely crosses human placenta due to molecular weight and lipophilicity. |
| Breastfeeding |
■ FDA Black Box Warning
Corrected QT interval (QTc) prolongation and sudden death; do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Avoid strong CYP3A4 inhibitors and grapefruit products.
| Common Effects | Myelosuppression |
| Serious Effects |
HypokalemiaHypomagnesemiaLong QT syndromeConcomitant use with strong CYP3A4 inhibitors
| Precautions | QTc prolongation; myelosuppression; hepatotoxicity; pancreatitis; fluid retention; elevated lipase; electrolyte abnormalities; tumor lysis syndrome; fetal harm. |
| Food/Dietary | Avoid grapefruit, grapefruit juice, pomelos, Seville oranges, and pomegranates due to CYP3A4 inhibition and increased nilotinib exposure. Avoid high-fat meals as they increase drug absorption and risk of adverse effects. Take on empty stomach (1 hour before or 2 hours after food). |
Loading safety data…
| Excreted in animal milk; not known in humans. Discontinue breastfeeding or drug due to potential for serious adverse reactions in nursing infants. |
| Lactation Rating | L5 (Contraindicated; risk outweighs benefit) |
| Teratogenic Risk | Based on animal studies, nilotinib is embryotoxic and fetotoxic. Use in pregnant women may cause fetal harm, including increased risk of fetal death, skeletal anomalies, and reduced fetal weight. There are no adequate human studies. Risk cannot be excluded in the first trimester. Second and third trimester exposure may also pose risks of growth restriction and developmental abnormalities. |
| Fetal Monitoring | Monitor complete blood count (CBC), liver function tests (LFTs), serum lipase, and electrocardiogram (ECG) for QTc prolongation. Perform fetal ultrasound for growth and anatomy if exposure occurs. Closely monitor for pleural effusions, pulmonary arterial hypertension, and bleeding events in the mother. |
| Fertility Effects | Nilotinib may impair male and female fertility based on animal studies. In males, reversible oligospermia and testicular atrophy have been observed. In females, reversible ovarian effects including delayed ovulation and reduced fertility have been noted. The clinical significance in humans is unknown. |
| Clinical Pearls | Nilotinib requires ECG monitoring for QTc prolongation; avoid use with hypokalemia, hypomagnesemia, or drugs that prolong QT. Administer on empty stomach (1 hour before or 2 hours after food) to avoid food-induced absorption variability. Monitor serum lipase and amylase due to risk of pancreatitis. Dose reduction needed for hepatic impairment (Child-Pugh B/C) and strong CYP3A4 inhibitors. Assess for pleural effusions and tumor lysis syndrome in CML treatment initiation. |
| Patient Advice | Take nilotinib on an empty stomach, one hour before or two hours after a meal. · Do not eat grapefruit, pomegranate, or Seville oranges while taking this medication. · Avoid medications that can increase QT interval without doctor approval. · Report symptoms of pancreatitis such as severe abdominal pain, nausea, vomiting, or fever. · Use effective contraception during treatment and for at least 2 weeks after stopping. · Do not crush or cut capsules; swallow whole with water. |