Nilotinib

+ 7 more variants

• Fluid Retention: Swelling of the eyelids, feet, or lower legs (peripheral edema).
• Electrolyte Imbalances: Low levels of magnesium, potassium, or calcium in the blood. These are dangerous because they increase the risk of heart rhythm problems.
• Hyperglycemia: Increased blood sugar levels, which may require the initiation or adjustment of diabetes medications.
• Hyperlipidemia: Increased cholesterol and triglyceride levels.
• Pancreatitis: Inflammation of the pancreas, characterized by severe upper abdominal pain radiating to the back.

• Peripheral Arterial Occlusive Disease (PAOD): A serious condition where blood flow to the legs or arms is restricted. Symptoms include leg pain while walking (claudication), cool extremities, or sores that do not heal.
• Ischemic Heart Disease: Reduced blood flow to the heart muscle, potentially leading to a heart attack.
• Ischemic Cerebrovascular Events: Strokes or 'mini-strokes' (TIAs) caused by narrowed arteries to the brain.

> Warning: Stop taking Nilotinib and call your doctor immediately or seek emergency care if you experience any of the following:

• Chest Pain or Pressure: Could indicate a heart attack or severe vascular restriction.
• Shortness of Breath: Especially when lying down, which could indicate fluid in the lungs or heart failure.
• Palpitations or Fainting: Feeling like your heart is skipping a beat, racing, or fluttering. This may be a sign of QT prolongation.
• Sudden Weakness or Numbness: Especially on one side of the body, or difficulty speaking (signs of a stroke).
• Yellowing of the Skin or Eyes (Jaundice): Along with dark urine, this indicates serious liver toxicity (hepatotoxicity).
• Severe Abdominal Pain: Specifically in the upper left or middle abdomen, suggesting pancreatitis.
• Unusual Bleeding or Bruising: Signs of severely low platelets (thrombocytopenia).
• Fever and Chills: Signs of a low white blood cell count (neutropenia) and potential infection.

With prolonged use, Nilotinib can cause cumulative damage to the vascular system. Patients may develop atherosclerosis (hardening of the arteries) at a faster rate than normal. Long-term monitoring of lipid profiles and cardiovascular health is essential. Additionally, some patients may experience persistent mild elevations in liver enzymes or bilirubin (UGT1A1 inhibition).

Nilotinib carries a FDA Black Box Warning for two critical risks:

1. 1QT Prolongation: Nilotinib can prolong the QT interval, an electrical measurement of the heart's rhythm. This can lead to a life-threatening arrhythmia called Torsades de Pointes.
2. 2Sudden Death: Cases of sudden death have been reported in patients receiving Nilotinib. This is often linked to the heart rhythm issues mentioned above.

To mitigate these risks, Nilotinib should not be used in patients with low potassium or magnesium levels, or those with 'Long QT Syndrome.' ECGs must be performed at baseline, seven days after starting, and regularly thereafter.

Report any unusual symptoms or side effects to your healthcare provider immediately. Dose interruptions or reductions are often used to manage these effects successfully.

• Cardiovascular Events: There is a significant risk of 'ischemic' events, including heart attacks, strokes, and severe leg artery blockages. Patients with existing heart disease or high blood pressure must be monitored with extreme caution.
• Hepatotoxicity: Nilotinib can cause severe liver damage. Liver function tests (LFTs) must be checked monthly.
• Pancreatitis: If a patient develops unexplained abdominal pain, Nilotinib should be interrupted to check lipase levels. A history of pancreatitis is a major precaution.
• Myelosuppression: Nilotinib frequently causes grade 3 or 4 neutropenia (low white cells) or thrombocytopenia (low platelets). This usually occurs within the first two months of treatment.
• Tumor Lysis Syndrome (TLS): In the first few weeks of treatment, the rapid breakdown of cancer cells can release toxins into the blood, potentially causing kidney failure. Hydration and uric acid monitoring are necessary.
• Total Gastrectomy: Patients who have had their entire stomach removed may not absorb Nilotinib effectively due to changes in gastric pH.

Patients on Nilotinib require a rigorous schedule of laboratory tests:

• ECG: Baseline, Day 7, and then periodically (e.g., every 3-6 months).
• CBC (Complete Blood Count): Weekly for the first month, then monthly.
• Electrolytes (K, Mg, Ca): Regularly to ensure they are within normal limits.
• Liver Function (ALT, AST, Bilirubin): Monthly.
• Lipid Profile and Glucose: Checked at baseline and every 3-6 months due to the risk of metabolic changes.
• Molecular Monitoring (BCR-ABL PCR): Every 3 months to track the effectiveness of the treatment.

Nilotinib can cause dizziness, fatigue, and blurred vision. Patients should observe how the medication affects them before driving or operating heavy machinery. If you feel lightheaded or excessively tired, avoid these activities.

There is no direct contraindication for moderate alcohol use, but alcohol can stress the liver. Since Nilotinib is hepatotoxic, it is generally advised to limit alcohol consumption to avoid compounding liver strain. Discuss your alcohol intake with your doctor.

Never stop taking Nilotinib suddenly. This can cause a 'rebound' effect where the leukemia cells begin to multiply rapidly again. If discontinuation is necessary (e.g., for a TFR attempt), it must be done under strict medical supervision with frequent blood tests to ensure the cancer remains in remission.

> Important: Discuss all your medical conditions, especially heart, liver, or pancreas problems, with your healthcare provider before starting Nilotinib.

• Warfarin: Nilotinib may affect the metabolism of Warfarin, increasing the risk of bleeding. Frequent INR monitoring is required.
• Statins: Nilotinib can increase the levels of certain cholesterol-lowering drugs (like Simvastatin), increasing the risk of muscle damage (rhabdomyolysis).

• High-Fat Meals: Taking Nilotinib with food increases its absorption by up to 82%. This is the most dangerous interaction and must be avoided by following the 2-hour-before/1-hour-after fasting rule.
• Grapefruit and Starfruit: These fruits contain compounds that inhibit CYP3A4 in the gut wall, leading to increased drug levels. They should be completely avoided.

• St. John's Wort: As mentioned, this will likely cause treatment failure.
• Antacids and Acid Reducers: Nilotinib requires an acidic environment in the stomach to dissolve.
• Proton Pump Inhibitors (PPIs): Drugs like Omeprazole or Esomeprazole should be avoided as they permanently raise stomach pH.
• H2 Blockers: Drugs like Famotidine should be taken 10 hours before or 2 hours after Nilotinib.
• Antacids: Should be taken 2 hours before or 2 hours after Nilotinib.

Nilotinib can cause significant changes in laboratory results that do not necessarily reflect organ damage but require monitoring:

• Bilirubin: Often elevated due to UGT1A1 inhibition (indirect hyperbilirubinemia).
• Lipase/Amylase: May be elevated without clinical pancreatitis.
• Glucose and Cholesterol: Frequently elevated.

For each major interaction, the management strategy usually involves either avoiding the combination, adjusting the Nilotinib dose, or increasing the frequency of ECG and blood monitoring.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter acid reducers.

Relative Contraindications

Conditions requiring a careful risk-benefit analysis by a specialist:

• Severe Hepatic Impairment: Because the liver is the primary route of metabolism, patients with Child-Pugh Class C liver disease are at high risk for toxicity. Doses must be significantly reduced.
• History of Pancreatitis: Nilotinib can trigger a recurrence of pancreatic inflammation.
• Severe Cardiovascular Disease: Patients with a history of heart attack, stroke, or peripheral artery disease are at much higher risk for the vascular complications associated with Nilotinib.
• Lactose Intolerance: The capsules contain lactose. While the amount is small, patients with severe intolerance or galactosemia should be aware.
• Total Gastrectomy: The lack of stomach acid in these patients significantly impairs the drug's ability to dissolve and enter the bloodstream.

While there is no documented cross-sensitivity between Nilotinib and other TKIs like Imatinib or Dasatinib, patients who have had severe skin reactions (like Stevens-Johnson Syndrome) to one kinase inhibitor should be started on another with extreme caution and dermatological oversight.

> Important: Your healthcare provider will evaluate your complete medical history, including an initial ECG and blood panel, before prescribing Nilotinib to ensure none of these conditions are present.

Nilotinib is approved for children 1 year of age and older.

• Growth Monitoring: There are concerns that TKIs can affect bone growth in children. Pediatric patients should have their growth (height and weight) monitored closely by a pediatrician.
• Dosing: Dosing is strictly based on Body Surface Area (BSA).
• Safety: The safety profile in children is generally similar to adults, though the incidence of certain lab abnormalities (like elevated bilirubin) may differ.

Clinical studies of Nilotinib included a sufficient number of patients aged 65 and over. While no overall differences in effectiveness were observed compared to younger patients, older adults are more likely to have underlying heart disease or reduced liver function.

• Cardiovascular Risk: Older patients should be screened more frequently for signs of peripheral artery disease or heart failure.
• Polypharmacy: Elderly patients are often on multiple medications (e.g., for blood pressure or cholesterol), increasing the risk of drug-drug interactions.

Nilotinib has not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min). However, since less than 7% of the drug is excreted by the kidneys, it is generally considered safe in patients with mild to moderate kidney disease without dose adjustment. Patients on dialysis should be treated with extreme caution.

Hepatic impairment has a significant effect on the pharmacokinetics of Nilotinib. In a study of subjects with mild, moderate, and severe hepatic impairment, the systemic exposure (AUC) of Nilotinib increased by 35%, 35%, and 19% respectively.

• Adjustment: A lower starting dose is required for patients with severe liver dysfunction (Child-Pugh Class C).

> Important: Special populations require individualized medical assessment. Always inform your doctor if you are planning to become pregnant or have underlying organ dysfunction.

|---|---|

| Bioavailability | ~30% (Increases to ~55% with food) |

| Protein Binding | 98% (primarily to albumin) |

| Half-life | ~17 hours |

| Tmax | ~3 hours |

| Metabolism | Hepatic (Primary: CYP3A4; Secondary: CYP2C8) |

| Excretion | Fecal 93%, Renal <7% |

• Molecular Formula: C28H22F3N7O · HCl · H2O
• Molecular Weight: 583.99 g/mol (hydrochloride monohydrate salt)
• Solubility: Nilotinib is practically insoluble in water and has pH-dependent solubility (more soluble at low pH/acidic environments).
• Structure: It is an aminopyrimidine derivative. Its structure was optimized from the imatinib scaffold to provide better binding to the Bcr-Abl kinase domain, even in the presence of most mutations that cause imatinib resistance.

Nilotinib is a second-generation Tyrosine Kinase Inhibitor (TKI). It is part of the larger therapeutic class of Antineoplastics and the specific subclass of Bcr-Abl Inhibitors. Related medications include Imatinib (1st gen), Dasatinib (2nd gen), Bosutinib (2nd gen), and Ponatinib (3rd gen).