Nilotinib

The dosage of Nilotinib depends heavily on the stage of the disease and whether the patient has received prior treatment for CML. It is vital to adhere to the specific dose prescribed by your hematologist/oncologist.

• Newly Diagnosed Chronic Phase Ph+ CML: The standard recommended dose is 300 mg taken orally twice daily (approximately 12 hours apart).
• Resistant or Intolerant Chronic Phase or Accelerated Phase Ph+ CML: The standard recommended dose is 400 mg taken orally twice daily (approximately 12 hours apart).

Treatment is typically continued as long as the patient continues to benefit and does not experience unacceptable toxicity. In some cases, if a patient achieves a deep and sustained molecular response for at least 3 years, a physician may consider a supervised 'Treatment-Free Remission' (TFR) attempt, though this requires extremely frequent monitoring.

Nilotinib is approved for use in pediatric patients 1 year of age and older who have newly diagnosed or resistant/intolerant Ph+ CML in the chronic phase. The dosage for children is based on Body Surface Area (BSA).

• Standard Pediatric Dose: The recommended dose is 230 mg/m² orally twice daily, rounded to the nearest 50 mg dose (up to a maximum single dose of 400 mg).
• Administration in Children: For children unable to swallow capsules, the contents of the capsule may be mixed with one teaspoon of applesauce. This mixture must be consumed immediately (within 15 minutes) and should not be stored.

Renal Impairment

Clinical studies did not specifically include patients with significant kidney disease. However, since Nilotinib is primarily eliminated via the liver and feces, dose adjustments for renal impairment are generally not required. Nevertheless, patients with severe renal disease should be monitored closely.

Hepatic Impairment

Because Nilotinib is metabolized by the liver, patients with hepatic impairment (liver dysfunction) will have higher levels of the drug in their system.

• Mild to Moderate Impairment: Caution is advised.
• Severe Impairment: A lower starting dose is recommended. For example, a starting dose of 200 mg twice daily followed by 300 mg twice daily may be considered for those otherwise requiring 400 mg doses.

Elderly Patients

No specific dose adjustments are required for patients over age 65. However, older adults may be more susceptible to side effects, particularly cardiovascular issues and fluid retention, and should be monitored accordingly.

Nilotinib must be taken with extreme care regarding timing and food intake. This is known as the 'fasting requirement.'

1. 1The Empty Stomach Rule: Do not eat any food for at least 2 hours before taking your dose and for at least 1 hour after taking your dose.
2. 2Swallow Whole: Capsules should be swallowed whole with water. Do not chew or crush the capsules.
3. 3Consistency: Take the doses approximately 12 hours apart at the same times each day (e.g., 8:00 AM and 8:00 PM).
4. 4Avoid Grapefruit: Do not consume grapefruit, grapefruit juice, or starfruit, as these inhibit the enzymes that break down Nilotinib, leading to toxic levels.
5. 5Storage: Store at room temperature (20°C to 25°C / 68°F to 77°F) in the original container to protect from moisture.

If you miss a dose of Nilotinib, skip the missed dose and take your next scheduled dose at its usual time. Do not take a double dose to make up for the one you missed. Taking extra doses increases the risk of serious heart rhythm problems.

Signs of a Nilotinib overdose may include severe nausea, vomiting, and significant changes in blood cell counts (neutropenia). Most critically, an overdose can cause life-threatening heart rhythm disturbances (QT prolongation). In case of a suspected overdose, contact your local poison control center or seek emergency medical attention immediately. An ECG (electrocardiogram) must be performed to monitor the heart's electrical activity.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking Nilotinib without medical guidance, as this can cause your leukemia to return or become resistant to treatment.

Most patients taking Nilotinib will experience some level of side effects. While many are manageable, they require consistent communication with your medical team. Common side effects include:

• Nausea and Vomiting: Often mild but can be persistent. Taking the medication on a strictly empty stomach as directed actually helps minimize some GI distress compared to taking it with small amounts of food.
• Rash and Pruritus (Itching): A maculopapular rash (flat and raised red spots) is very common. It usually appears within the first month of treatment and may resolve over time or with topical steroid creams.
• Headache: Frequently reported, often managed with over-the-counter analgesics (after consulting your doctor).
• Fatigue: A general feeling of tiredness or lack of energy that does not improve with rest.
• Myalgia and Arthralgia: Muscle and joint pain are common, particularly in the legs and back.
• Constipation or Diarrhea: Changes in bowel habits are frequent as the body adjusts to the medication.

• 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.

Nilotinib is a high-risk medication that requires specialized handling by a hematologist. The most critical safety aspect is the avoidance of food around the time of dosing. Because food significantly increases the concentration of the drug in the blood, failing to follow the fasting requirement can lead to fatal heart arrhythmias. Patients must also be aware that Nilotinib can suppress the bone marrow, making them more susceptible to infections and bleeding.

WARNING: QT PROLONGATION AND SUDDEN DEATH

• Tasigna (Nilotinib) prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib.
• Tasigna should not be used in patients with hypokalemia (low potassium), hypomagnesemia (low magnesium), or long QT syndrome.
• Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored.
• Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors.
• ECGs should be obtained to monitor the QT interval at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

• 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.

Certain drugs must NEVER be used with Nilotinib because the risk of fatal heart rhythm disturbances or extreme toxicity is too high:

• Strong CYP3A4 Inhibitors: Drugs like Ketoconazole, Itraconazole, Voriconazole, Clarithromycin, and Ritonavir. These block the breakdown of Nilotinib, causing levels to skyrocket.
• QT-Prolonging Drugs: Antiarrhythmics like Amiodarone, Sotalol, and Quinidine; certain antipsychotics like Haloperidol or Ziprasidone; and certain antibiotics like Moxifloxacin.
• St. John’s Wort: This herbal supplement is a powerful inducer of CYP3A4 and can lower Nilotinib levels so much that the treatment fails.

• Moderate CYP3A4 Inhibitors: Examples include Erythromycin and Fluconazole. These can increase Nilotinib exposure and may require a dose reduction.
• Strong CYP3A4 Inducers: Drugs like Rifampin, Phenytoin, Carbamazepine, and Phenobarbital. These speed up the metabolism of Nilotinib, potentially making it ineffective against the leukemia.
• UGT1A1 Substrates: Nilotinib inhibits UGT1A1 (an enzyme that processes bilirubin). Taking it with other drugs processed by this enzyme (like Irinotecan) can lead to severe toxicity.

• 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.

Conditions where Nilotinib must NEVER be used due to an unacceptable risk of death or permanent injury:

1. 1Hypokalemia or Hypomagnesemia: Low levels of potassium or magnesium in the blood. These electrolytes are essential for the heart's electrical stability. Taking Nilotinib with these imbalances creates a 'perfect storm' for Torsades de Pointes (a fatal heart rhythm).
2. 2Long QT Syndrome: A congenital (from birth) or acquired heart condition where the heart takes longer than normal to recharge between beats. Nilotinib will dangerously extend this window.
3. 3Hypersensitivity: A known severe allergy to Nilotinib or any of the inactive ingredients in the capsule (such as lactose monohydrate).

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 classified as having significant reproductive risk (formerly FDA Category D). Based on its mechanism of action and animal studies, Nilotinib can cause fetal harm when administered to a pregnant woman.

• Teratogenicity: In animal studies, Nilotinib caused embryo-fetal toxicity, including skeletal anomalies and reduced fetal body weight at doses lower than the human equivalent.
• Contraception: Females of reproductive potential must use highly effective contraception during treatment and for at least 14 days after the final dose.
• Pregnancy Testing: A pregnancy test must be performed before starting Nilotinib.

It is not known if Nilotinib is excreted in human milk. However, because many drugs are excreted in milk and because of the potential for serious adverse reactions in nursing infants (including heart and blood count issues), breastfeeding is not recommended during treatment and for at least 14 days after the final dose.

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.

Nilotinib is a selective and potent inhibitor of the Bcr-Abl tyrosine kinase. It functions by binding to the inactive conformation of the Bcr-Abl protein, specifically at the ATP-binding site. By occupying this site, Nilotinib prevents the enzyme from binding with ATP, which is necessary for the phosphorylation of tyrosine residues on substrate proteins. This inhibition blocks the downstream signaling pathways (such as PI3K/Akt and STAT5) that lead to the uncontrolled proliferation and impaired apoptosis (programmed cell death) of leukemic cells. Nilotinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGFR) and stem cell factor (c-Kit), though its affinity for Bcr-Abl is significantly higher.

The pharmacodynamic effect of Nilotinib is measured by the reduction in the number of cells containing the Philadelphia chromosome (Cytogenetic Response) and the reduction in the amount of BCR-ABL1 mRNA in the blood (Molecular Response). There is a clear dose-response relationship; however, increasing the dose beyond 400 mg twice daily does not significantly increase efficacy but does dramatically increase the risk of QT prolongation and vascular events.

| Parameter | Value |

|---|---|

| 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).