Tasigna

Approved Indications:

• Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (Ph+ CML):
• Newly diagnosed chronic phase (CP) Ph+ CML in adults
• Chronic phase (CP) and accelerated phase (AP) Ph+ CML in adults resistant or intolerant to prior therapy including imatinib

Off-label/Clinically Accepted Uses:

• Pediatric patients with CP Ph+ CML (approved in select regions)
• Investigational use in other BCR-ABL–positive leukemias or tyrosine kinase–driven cancers (under study)

Route: Oral

Adults:

• Newly diagnosed CP Ph+ CML: 300 mg twice daily
• CP or AP Ph+ CML resistant/intolerant to prior therapy: 400 mg twice daily

Administration Notes:

• Take on an empty stomach (≥2 hours after food, wait ≥1 hour before next meal)
• Swallow capsules whole with water; do not crush or open

Pediatrics:

• Limited data support use in pediatric CP Ph+ CML; dosing individualized by body surface area

Elderly:

• No initial dose adjustment required, but monitor closely due to increased risk of adverse reactions

Renal Impairment:

• No specific dose adjustment needed, but use with caution and monitor renal function

Hepatic Impairment:

• Mild to moderate impairment: start with reduced dose
• Severe impairment: not recommended

Dose Adjustments:

• Based on hematologic toxicity, QT prolongation, or liver enzyme elevations
• Regular ECG, CBC, and liver function tests recommended

Nilotinib is a second-generation selective BCR-ABL tyrosine kinase inhibitor (TKI). It binds to the ATP-binding site of the BCR-ABL fusion protein with higher affinity than imatinib, inhibiting its phosphorylation activity. This blockade prevents activation of downstream signaling pathways essential for leukemic cell proliferation and survival. Additionally, it inhibits other kinases such as c-KIT and PDGF receptor, contributing to its antitumor activity.

• Absorption: Oral bioavailability ~30%; delayed and reduced by food
• Peak Plasma Time (Tmax): ~3 hours post-dose (fasted state)
• Distribution: ~98% protein-bound
• Metabolism: Extensively metabolized in the liver, primarily via CYP3A4; minor roles of CYP2C8, CYP2C9, CYP2D6
• Elimination Half-life: ~17 hours
• Excretion: ~93% in feces, <1% in urine
• Steady-State: Achieved within 8 days with twice-daily dosing

• Pregnancy:
• FDA Pregnancy Category: Not formally assigned (post-FDA letter system)
• Animal studies show fetal toxicity and teratogenicity. Use during pregnancy only if clearly needed and if benefits outweigh potential risks.
• Lactation:
• Unknown whether excreted in human milk; animal studies confirm excretion
• Breastfeeding not recommended during treatment and for 2 weeks after last dose
• Caution: Use effective contraception in women of childbearing potential

• Primary Class: Antineoplastic agent
• Subclass: BCR-ABL Tyrosine Kinase Inhibitor (Second Generation)

• Known hypersensitivity to nilotinib or any formulation component
• Long QT syndrome or baseline QTc >450 ms
• Uncorrected hypokalemia or hypomagnesemia
• Use with strong CYP3A4 inhibitors or inducers

• QT Prolongation and Sudden Death: Monitor ECG and electrolytes regularly
• Myelosuppression: Common in early treatment; monitor CBC and adjust dosage
• Hepatotoxicity: Monitor liver enzymes; dose interruption may be required
• Pancreatitis: Elevated lipase/amylase reported; monitor and manage as needed
• Hyperglycemia and Elevated Lipids: Monitor glucose and lipid profile
• Cardiovascular Events: Arterial occlusive events (e.g., stroke, MI) reported; monitor in high-risk patients
• Drug Interactions: Avoid concomitant use of QT-prolonging drugs, CYP3A4 modifiers
• Hepatitis B Reactivation: Screen before therapy; monitor HBV carriers

Common Side Effects (>10%):

• Gastrointestinal: Nausea, vomiting, constipation, abdominal pain
• Skin: Rash, pruritus, alopecia
• General: Fatigue, headache, fever
• Hematologic: Neutropenia, thrombocytopenia, anemia
• Hepatic: Elevated ALT, AST
• Metabolic: Hyperglycemia, hyperlipidemia, hyperbilirubinemia

Serious/Rare Side Effects:

• QT prolongation and sudden death
• Arterial thrombosis (MI, stroke)
• Pancreatitis
• Hepatic failure
• Pulmonary hypertension

• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): ↑ Nilotinib levels → ↑ risk of QT prolongation
• CYP3A4 Inducers (e.g., rifampin, phenytoin): ↓ Nilotinib levels → ↓ efficacy
• QT-Prolonging Agents (e.g., amiodarone, fluoroquinolones): ↑ QT risk
• Food: High-fat meals ↑ absorption → Avoid taking with food
• Acid-reducing agents (e.g., PPIs): Potential alteration in bioavailability

• NCCN (2024): Nilotinib remains a first-line option for CP Ph+ CML in adult patients; monitored use recommended in pediatric CML in select settings
• FDA (2023): Updated warning on arterial occlusive events and emphasized cardiovascular monitoring
• EMA (2024): Reinforced restrictions on co-administration with QT-prolonging drugs
• WHO Essential Medicines List: Nilotinib is included for treatment of chronic myeloid leukemia

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C
• Humidity: Store in a dry place; protect from moisture
• Light Protection: Keep in original container; protect from light
• Handling: Do not crush or open capsules; avoid exposure to skin or mucous membranes
• Disposal: Follow local regulations for hazardous waste disposal