Nilotinib is a medication that belongs to a class of drugs known as tyrosine kinase inhibitors (TKIs). It is primarily used in the treatment of chronic myeloid leukemia (CML), a type of blood cancer.

CML is characterized by the uncontrolled growth of white blood cells in the bone marrow. It is caused by a genetic abnormality known as the Philadelphia chromosome, which leads to the production of an abnormal protein called BCR-ABL. This protein promotes the growth and survival of cancerous cells.

Nilotinib works by inhibiting the activity of the BCR-ABL protein, thereby slowing down or stopping the growth of cancer cells. It specifically targets and blocks the tyrosine kinase enzyme, which is involved in the signaling pathway of cancer cell growth.

Nilotinib (Tasigna) uses:

• Chronic myelogenous leukemia:
  • It is used for the treatment of chronic myelogenous leukemia (CML) Philadelphia chromosome-positive in the chronic phase in children ≥1 year and adults.
  • It is indicated in the treatment of  Philadelphia chromosome-positive CML (chronic accelerated phase) in children more than or equal to 1 year of age or adults who show resistance or intolerance to previous therapy that included imatinib.
• Off Label Use of Nilotinib (Tasigna) in Adults:
  • Philadelphia chromosome-positive (Ph+) Acute lymphoblastic leukemia (ALL)
  • Refractory Gastrointestinal stromal tumor (GIST)

Nilotinib (Tasigna) dosage in adults

Note: If necessary, nilotinib can be given together with other medications like erythropoietin or filgrastim, which are hematopoietic growth factors. It can also be combined with hydroxyurea or anagrelide if your doctor determines it is appropriate for your specific situation.

Nilotinib (Tasigna) dose for the treatment of newly-diagnosed Philadelphia chromosome-positive Acute lymphoblastic leukemia:

• In the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL), nilotinib is sometimes used off-label.
• The recommended dose is 400 mg taken orally twice a day.
• It is typically started on day 8 of induction chemotherapy, along with daunorubicin, vincristine, and prednisolone.
• Nilotinib should be continued until the beginning of stem cell transplant conditioning or until the end of consolidation therapy.
• For patients who have completed five cycles of consolidation treatment, they may receive two years of nilotinib maintenance therapy.
• However, patients who have undergone an allogeneic stem cell transplant will not receive nilotinib after the transplant.

Nilotinib (Tasigna ) dose for the treatment of Philadelphia chromosome-positive relapsed or refractory ALL (Acute lymphoblastic leukemia):

• In the treatment of relapsed or refractory Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL), nilotinib may be used off-label.
• The recommended dose is 400 mg taken orally twice a day.

Nilotinib (Tasigna) dose for Philadelphia chromosome-positive (Ph+) Newly-diagnosed CML (Chronic myeloid leukemia) in Chronic phase:

• In the treatment of newly-diagnosed Chronic Myeloid Leukemia (CML) in the chronic phase with the Philadelphia chromosome (Ph+), nilotinib is typically administered orally at a dose of 300 mg twice daily.

Discontinuation of nilotinib therapy (following a sustained molecular response):

• For patients who have achieved a sustained molecular response (MR) and meet specific criteria, discontinuation of nilotinib therapy may be considered.
• These criteria include receiving at least three years of nilotinib treatment, maintaining an MR for one year prior to discontinuation (BCR-ABL/ABL ≤0.01% IS), achieving an MR (BCR-ABL/ABL ≤0.0032% IS) in the last assessment before discontinuation, expressing the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), having no history of accelerated phase or blast crisis, and no relapse from prior attempts at treatment-free remission discontinuation.

The reinitiation of therapy:

• If a patient loses the major molecular response after discontinuing nilotinib, it is necessary to restart treatment within four weeks at the dose used prior to discontinuation.
• BCR-ABL transcript levels should be monitored monthly until a major molecular response is re-established, and then every 12 weeks thereafter.
• BCR-ABL kinase domain mutation testing should be performed if a major molecular response is not achieved after three months of therapy reinitiation.

Philadelphia chromosome-positive (Ph+) CML in accelerated phase:

• In the treatment of Chronic Myeloid Leukemia (CML) with the Philadelphia chromosome (Ph+), specifically in patients who are resistant or intolerant to previous treatments and have progressed to the accelerated phase, nilotinib is typically administered orally at a dose of 400 mg twice daily.

Philadelphia chromosome-positive (Ph+) CML in Chronic phase resistant or intolerant to first-line therapy:

• In the treatment of Chronic Myeloid Leukemia (CML) with the Philadelphia chromosome (Ph+), specifically in patients who are resistant or intolerant to prior imatinib therapy and are in the chronic phase, nilotinib is typically administered orally at a dose of 400 mg twice daily.

Discontinuation of therapy (following a sustained molecular response [MR ]):

• For patients who have achieved a sustained molecular response (MR) and meet specific criteria, discontinuation of nilotinib therapy may be considered.
• These criteria include receiving at least three years of nilotinib treatment, being treated with imatinib alone before starting nilotinib, achieving an MR (BCR-ABL/ABL ≤0.0032% IS), maintaining a sustained MR for at least one year prior to discontinuation, expressing the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), having no history of accelerated phase or blast crisis, and no relapse from prior attempts at treatment-free remission discontinuation.

Reinitiation of therapy:

• If a patient experience confirmed loss of MR (two consecutive readings separated by at least four weeks showing loss of MR) or loss of major molecular response after discontinuing nilotinib, it is necessary to restart treatment within four weeks at the dose used prior to discontinuation.
• BCR-ABL transcript levels should be monitored monthly until the previous major molecular response or MR is re-established, and then every 12 weeks thereafter.
• BCR-ABL kinase domain mutation testing should be performed if a major molecular response is not achieved after three months of therapy reinitiation.

Nilotinib (Tasigna) dose for the treatment of refractory Gastrointestinal stromal tumor (GIST):

• In the treatment of refractory Gastrointestinal Stromal Tumor (GIST), nilotinib is sometimes used off-label.
• The recommended dose is 400 mg taken orally twice daily until disease progression or unacceptable toxicity.

Missed doses:

• If a dose of nilotinib is missed, it should not be made up, and the patient should resume with the next scheduled dose as directed.

Dosage adjustment for concomitant CYP3A4 inhibitors and inducers:

It's important to consider potential interactions with other medications that affect the activity of the enzyme CYP3A4.

CYP3A4 inhibitors:

• In the case of strong CYP3A4 inhibitors, it is generally advised to avoid concurrent use with nilotinib.
• If it is necessary to use a strong CYP3A4 inhibitor, nilotinib treatment should be interrupted.
• If interruption is not feasible and concurrent use with a strong CYP3A4 inhibitor cannot be avoided, the nilotinib dose should be reduced to 300 mg once daily for patients with resistant or intolerant Ph+ CML (chronic or accelerated phase) or to 200 mg once daily for newly diagnosed chronic phase Ph+ CML.
• Close monitoring, especially of the QT interval, is recommended in these situations.
• When discontinuing a strong CYP3A4 inhibitor, a washout period should be allowed before adjusting the nilotinib dose upward.

CYP3A4 inducers:

• Regarding strong CYP3A4 inducers, it is generally recommended to avoid their concurrent use with nilotinib.
• Increased nilotinib dosage is unlikely to compensate for the decreased exposure resulting from the induction of CYP3A4.

Nilotinib (Tasigna) dosage in Children:

Tasigna (Nilotinib) dose in the treatment of Newly diagnosed Chronic myeloid leukemia (CML) who are Philadelphia chromosome-positive (Ph+) and in chronic phase:

• In the treatment of newly diagnosed Chronic Myeloid Leukemia (CML) in the chronic phase, specifically in children and adolescents with Philadelphia chromosome-positive (Ph+) CML, nilotinib is administered orally.
• The recommended dose is calculated based on body surface area, with a dosage of 230 mg per square meter (m²) of body surface area per dose, given twice daily.
• The dose should be rounded to the nearest 50 mg increment, and the maximum dose per administration is 400 mg.
• It's important to continue the therapy as long as clinical benefit is observed and until unacceptable toxicity occurs.
• The duration of treatment may vary depending on the individual patient's response and circumstances

Tasigna (Nilotinib) dose in Philadelphia chromosome-positive (Ph+) CML who are resistant or intolerant to first-line treatment and in the chronic phase:

• In the treatment of Chronic Myeloid Leukemia (CML) with Philadelphia chromosome-positive (Ph+) in children and adolescents who are resistant or intolerant to prior therapy and are in the chronic phase, nilotinib is administered orally.
• The recommended dose is determined based on the patient's body surface area, with a dosage of 230 mg per square meter (m²) of body surface area per dose, given twice daily.
• The dose should be rounded to the nearest 50 mg increment, with a maximum dose of 400 mg per administration.
• The therapy should be continued as long as there is clinical benefit observed and until unacceptable toxicity occurs.
• The duration of treatment will depend on the individual patient's response and circumstances, which should be monitored and assessed by a healthcare professional.

Nilotinib Dosing adjustment for concomitant CYP3A4 inhibitors/inducers:

When it comes to concomitant use of medications that affect the activity of the enzyme CYP3A4, dosing adjustments may be necessary:

CYP3A4 inhibitors:

• It is generally recommended to avoid the concurrent use of strong CYP3A4 inhibitors with nilotinib in children and adolescents.
• If a strong CYP3A4 inhibitor is required, it may be necessary to interrupt nilotinib treatment.
• If interruption is not feasible and concurrent use with a strong CYP3A4 inhibitor cannot be avoided, experience in adult patients suggests that reduced dosing is necessary.
• However, there are no specific pediatric recommendations available.
• Close monitoring, especially of the ECG (QT interval), should be conducted.
• When discontinuing a strong CYP3A4 inhibitor, a washout period should be allowed before adjusting the nilotinib dose upward.

CYP3A4 inducers:

• It is generally advised to avoid the concomitant use of strong CYP3A4 inducers with nilotinib in children and adolescents.
• Increasing the nilotinib dose is unlikely to compensate for the decreased exposure caused by CYP3A4 induction.

Nilotinib (Tasigna) Dosage adjustment for toxicity unrelated to underlying leukemia:

In children and adolescents receiving nilotinib, dosage adjustments may be necessary in the presence of toxicity unrelated to the underlying leukemia. Here are the recommended adjustments for specific toxicities:

Hematologic toxicity (unrelated to underlying leukemia):

• If absolute neutrophil count (ANC) is less than 1,000/mm³ and/or platelets are less than 50,000/mm³, treatment should be withheld and blood counts monitored.
• If ANC is greater than 1,500/mm³ and/or platelets are greater than 75,000/mm³ within 2 weeks, treatment can be resumed at the prior dose.
• If blood counts remain low for more than 2 weeks, a dose reduction to 230 mg/m² once daily may be necessary.
• If toxicity occurs after the dose reduction, discontinuing treatment should be considered.

Nonhematologic toxicity:

• For amylase or lipase elevation of grade 3 or higher, treatment should be withheld and serum amylase or lipase levels monitored. Once lipase or amylase returns to grade 1 or lower, treatment can be resumed at 230 mg/m² once daily (if the previous dose was 230 mg/m² twice daily). If the previous dose was 230 mg/m² once daily, treatment should be discontinued.
• If lipase increases along with abdominal symptoms, treatment should be withheld, and diagnostic tests should be considered to exclude pancreatitis.

Clinically significant moderate or severe nonhematologic toxicity (including medically severe fluid retention):

• Treatment should be withheld, and upon resolution of toxicity, it can be resumed at 230 mg/m² once daily (if the previous dose was 230 mg/m² twice daily).
• If clinically appropriate, the dose can be escalated back to the initial dose of 230 mg/m² twice daily. Treatment should be discontinued if the previous dose was 230 mg/m² once daily.

QT prolongation:

• If QTc (corrected QT interval) is greater than 480 msec, treatment should be withheld. Serum potassium and magnesium levels should be monitored and corrected if necessary, and concurrent medications should be reviewed.
• If QTcF (QTc corrected using Fridericia's formula) returns to less than 450 msec and to within 20 msec of the baseline within 2 weeks, treatment can be resumed at the prior dose.
• If QTcF returns to a range of 450 to 480 msec after 2 weeks, the dose should be reduced to 230 mg/m² once daily, and an ECG should be repeated in approximately 7 days.
• If QTcF is still greater than 480 msec after reducing the dose to 230 mg/m² once daily, treatment should be discontinued.

Nilotinib (Tasigna) pregnancy Risk Category: D

• Nilotinib may harm the developing fetus if used during pregnancy, based on studies in animals and how the medication works.
• Before starting nilotinib treatment, it is important to confirm if a female of reproductive age is pregnant.
• Women who can become pregnant should use reliable contraception while taking nilotinib and for at least 14 days after stopping the medication to prevent pregnancy.

Use of Nilotinib while breastfeeding

• It is unknown if nilotinib secretes in breast milk.
• The manufacturer does not recommend breastfeeding during therapy or for more than 2 weeks following the last dose.

Nilotinib (Tasigna) dose adjustment in renal disease:

• The manufacturer's labeling does not provide specific dosage adjustments for nilotinib based on renal dysfunction.
• Nilotinib and its metabolites are primarily eliminated through processes other than renal excretion.

Nilotinib (Tasigna) dose adjustment in liver disease:

In patients with hepatic impairment at baseline, the recommended dosing of nilotinib may vary depending on the indication.

Patients with Hepatic impairment at baseline:

• For newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, if the patient has mild, moderate, or severe impairment, the initial dose is 200 mg twice daily. This dose may be increased to 300 mg twice daily based on the patient's tolerability.
• For patients with resistant or intolerant Ph+ CML in chronic or accelerated phase, if they have mild to moderate impairment, the initial dose is 300 mg twice daily. This may be increased to 400 mg twice daily based on tolerability. In patients with severe impairment, the initial dose is 200 mg twice daily, which may be increased to 300 mg twice daily and further increased to 400 mg twice daily based on patient tolerability.

Hepatotoxicity occurring during treatment:

• If hepatotoxicity occurs during treatment and the bilirubin level is grade 3 or higher, treatment should be withheld.
• Bilirubin levels should be monitored, and treatment can be resumed at a dose of 400 mg once daily when the bilirubin level returns to grade 1 or lower.
• Similarly, if the ALT or AST levels are grade 3 or higher, treatment should be withheld, transaminase levels should be monitored, and treatment can be resumed at a dose of 400 mg once daily when the ALT or AST levels return to grade 1 or lower.
• It is important to consult with a healthcare professional for individualized dosing recommendations and monitoring in patients with hepatic impairment.

Common Side Effects of Nilotinib (Tasigna):

• Cardiovascular:
  • Prolonged QT Interval On ECG
  • Occlusive Arterial Disease
  • Peripheral Edema
  • Hypertension
• Central Nervous System:
  • Headache
  • Fatigue
  • Dizziness
  • Insomnia
• Dermatologic:
  • Skin Rash
  • Pruritus
  • Night Sweats
  • Alopecia
  • Xeroderma
• Endocrine & Metabolic:
  • Hyperglycemia
  • Hypophosphatemia
  • Increased HDL Cholesterol
  • Increased VLDL
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Increased Serum Lipase
  • Diarrhea
  • Constipation
  • Upper Abdominal Pain
  • Decreased Appetite
  • Abdominal Pain
• Hematologic & Oncologic:
  • Decreased White Blood Cell Count
  • Neutropenia
  • Thrombocytopenia
  • Decreased Absolute Lymphocyte Count
  • Anemia
• Hepatic:
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Hyperbilirubinemia
• Infection:
  • Influenza
• Neuromuscular & Skeletal:
  • Arthralgia
  • Limb Pain
  • Myalgia
  • Back Pain
  • Asthenia
  • Ostealgia
  • Muscle Spasm
  • Musculoskeletal Pain
• Respiratory:
  • Cough
  • Nasopharyngitis
  • Upper Respiratory Tract Infection
  • Dyspnea
  • Oropharyngeal Pain
• Miscellaneous:
  • Fever

Rare Side Effects Of Nilotinib (Tasigna):

• Cardiovascular:
  • Ischemic Heart Disease
  • Peripheral Arterial Disease
  • Cerebral Ischemia
  • Pericardial Effusion
  • Angina Pectoris
  • Cardiac Arrhythmia
  • Chest Discomfort
  • Chest Pain
  • Flushing
  • Palpitations
• Central Nervous System:
  • Anxiety
  • Depression
  • Flank Pain
  • Hypoesthesia
  • Malaise
  • Myasthenia
  • Pain
  • Paresthesia
  • Peripheral Neuropathy
  • Vertigo
  • Voice Disorder
• Dermatologic:
  • Acne Vulgaris
  • Dermatitis
  • Eczema
  • Erythema Of Skin
  • Folliculitis
  • Hyperhidrosis
  • Urticaria
• Endocrine & Metabolic:
  • Decreased Serum Albumin
  • Fluid Retention
  • Diabetes Mellitus
  • Electrolyte Disorder
  • Hypercalcemia
  • Hypercholesterolemia
  • Hyperkalemia
  • Hyperlipidemia
  • Hyperphosphatemia
  • Hypertriglyceridemia
  • Hypocalcemia
  • Hypokalemia
  • Hypomagnesemia
  • Hyponatremia
  • Increased Gamma-Glutamyl Transferase
  • Weight Gain
  • Weight Loss
• Gastrointestinal:
  • Dyspepsia
  • Gastroenteritis
  • Gastrointestinal Hemorrhage
  • Abdominal Distension
  • Abdominal Distress
  • Dysgeusia
  • Flatulence
  • Increased Serum Amylase
  • Pancreatitis
• Genitourinary:
  • Pollakiuria
• Hematologic & Oncologic:
  • Hemorrhage
  • Bruise
  • Change In Serum Protein
  • Cutaneous Papilloma
  • Eosinophilia
  • Febrile Neutropenia
  • Hemophthalmos
  • Leukopenia
  • Lymphocytopenia
  • Pancytopenia
• Hepatic:
  • Ascites
  • Hepatic Insufficiency
  • Increased Serum Alkaline Phosphatase
• Neuromuscular & Skeletal:
  • Increased Creatine Phosphokinase In Blood Specimen
  • Musculoskeletal Chest Pain
  • Neck Pain
• Ophthalmic:
  • Eyelid Edema
  • Conjunctivitis
  • Eye Pruritus
  • Xerophthalmia
• Respiratory:
  • Pleural Effusion
  • Dyspnea On Exertion
  • Epistaxis

Side effects of Tasigna (Nilotinib) with frequency not known:

• Cardiovascular:
  • Hypotension
  • Pericarditis
  • Reduced Ejection Fraction
  • Shock (Hemorrhagic)
  • Thrombosis
  • Ventricular Dysfunction
• Central Nervous System:
  • Amnesia
  • Breast Induration
  • Cerebral Edema
  • Confusion
  • Disorientation
  • Dysesthesia
  • Dysphoria
  • Lethargy
  • Restless Leg Syndrome
• Dermatologic:
  • Cutaneous Nodule (Sebaceous Hyperplasia)
  • Dermal Ulcer
  • Erythema Multiforme
  • Erythema Nodosum
  • Exfoliation Of Skin
  • Furuncle
  • Hyperkeratosis
  • Palmar-Plantar Erythrodysesthesia
  • Psoriasis
  • Skin Atrophy
  • Skin Blister
  • Skin Discoloration
  • Skin Hyperpigmentation
  • Skin Hypertrophy
  • Skin Photosensitivity
  • Tinea Pedis
• Endocrine & Metabolic:
  • Altered Hormone Level (Insulin C-Peptide Decreased)
  • Secondary Hyperparathyroidism
  • Hyperuricemia
  • Hypoglycemia
  • Thyroiditis
• Gastrointestinal:
  • Cholestasis
  • Enterocolitis
  • Gastric Ulcer (Perforation Possible)
  • Gingivitis
  • Hematemesis
  • Hemorrhoids
  • Hiatal Hernia
  • Intestinal Obstruction
  • Oral Lesion (Papilloma)
  • Ulcerative Esophagitis
• Genitourinary:
  • Dysmenorrhea
  • Hematuria
  • Urinary Incontinence
  • Urine Discoloration
• Hematologic & Oncologic:
  • Leukocytosis
  • Paraproteinemia
  • Petechia
  • Rectal Hemorrhage
  • Retroperitoneal Hemorrhage
  • Thrombocythemia
• Hepatic:
  • Hepatomegaly
• Hypersensitivity:
  • Hypersensitivity
• Infection:
  • Abscess (Subcutaneous)
  • Anal Abscess
  • Reactivation Of HBV
  • Sepsis
• Local:
  • Local Swelling (Nipple)
  • Localized Edema
• Neuromuscular & Skeletal:
  • Arthritis
• Ophthalmic:
  • Allergic Conjunctivitis
  • Blepharitis
  • Diplopia
  • Eye Pain
  • Optic Neuritis
  • Papilledema
  • Photophobia
  • Retinopathy (Chorioretinopathy)
  • Swelling Of Eye
• Otic:
  • Auditory Impairment
  • Otalgia
  • Tinnitus
• Renal:
  • Renal Failure Syndrome
• Respiratory:
  • Pulmonary Hypertension
  • Wheezing
• Miscellaneous:
  • Cyst (Dermal)
  • Troponin Increased In Blood Specimen

Contraindications to Nilotinib (Tasigna):

Nilotinib has certain contraindications that should be considered before initiating treatment. These contraindications include:

• Hypokalemia (low potassium levels)
• Hypomagnesemia (low magnesium levels)
• Long QT syndrome (a heart rhythm disorder)

In the Canadian labeling, there are additional contraindications not mentioned in the US labeling. These include hypersensitivity (allergic reaction) to nilotinib or any component of the formulation, as well as persistent QTc interval prolongation greater than 480 msec, which is a measure of the electrical activity of the heart.

Warnings and precautions

Suppression of bone marrow

• Treatment with nilotinib may lead to bone marrow suppression, which can cause a decrease in the production of blood cells.
• This can result in grades 3 and 4 thrombocytopenia (low platelet count), neutropenia (low neutrophil count), and anemia (low red blood cell count).
• In such cases, dose reductions or treatment delays may be necessary.
• It is important to regularly monitor blood counts every 2 weeks for the first 2 months of treatment and then monthly thereafter to assess the impact on blood cell levels.
• Close monitoring allows for timely adjustments in treatment and appropriate management of bone marrow suppression.

Cardiovascular:

• Nilotinib treatment has been associated with cardiovascular events, including ischemic heart disease-related events, arterial vascular occlusive events, peripheral arterial occlusive disease, and ischemic cerebrovascular accident (stroke).
• It is important to exercise caution when administering nilotinib to patients who have preexisting risk factors for cardiovascular disease.
• Additionally, patients should be monitored closely for any new or worsening symptoms that may indicate the occurrence of cardiovascular events.
• Prompt identification and management of such symptoms are essential to ensure patient safety.

Inadequate electrolyte levels:

• During treatment with nilotinib, there is a risk of electrolyte imbalances, which can include hypophosphatemia (low phosphate levels), hyperkalemia or hypokalemia (high or low potassium levels), hypocalcemia (low calcium levels), and hyponatremia (low sodium levels).
• It is important to correct any existing electrolyte abnormalities before initiating treatment with nilotinib.
• Regular monitoring of electrolyte levels should be performed periodically to ensure that any new imbalances are detected and promptly addressed.
• This helps maintain the proper functioning of the body's electrolyte balance and supports the safe and effective use of nilotinib.

Fluid retention

• During treatment with nilotinib, fluid retention is a possible side effect and can manifest as pleural and pericardial effusions (build-up of fluid around the lungs or heart), ascites (abdominal fluid accumulation), and pulmonary edema (fluid in the lungs).
• These cases of fluid retention can be severe.
• It is crucial to closely monitor patients for any signs or symptoms of fluid retention, such as rapid weight gain or swelling.
• Additionally, watch out for respiratory or cardiac distress symptoms, including shortness of breath.
• If any of these symptoms occur, it is important to evaluate the patient promptly and manage the condition appropriately.
• Timely intervention can help mitigate the impact of fluid retention and ensure patient safety.

Hemorrhage

• Hemorrhage, which refers to serious bleeding events, including some that have been fatal, has been reported in patients with chronic myelogenous leukemia (CML) who were treated with nilotinib.
• In a clinical study comparing nilotinib to imatinib for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase CML, hemorrhagic events, including gastrointestinal hemorrhage, occurred more frequently in the nilotinib group, some of which were classified as grade 3 or 4 severity.
• It is important to closely monitor patients for any signs or symptoms of bleeding and manage them appropriately based on the clinical situation.
• Prompt identification and management of bleeding events are crucial for patient safety and well-being.

Hepatotoxicity

• Hepatotoxicity, which refers to potential liver damage, is a known risk associated with nilotinib treatment.
• It can lead to elevated levels of bilirubin, transaminases (AST and ALT), and alkaline phosphatase in the blood.
• In pediatric patients, grade 3 or 4 elevations in bilirubin, AST, and ALT were observed more frequently compared to adult patients.
• To ensure the safety of patients, regular monitoring of liver function is recommended, typically on a monthly basis or as clinically indicated.
• By closely monitoring liver function, any potential hepatotoxicity can be detected early, allowing for appropriate management and intervention.

QT prolongation/sudden Death: [US Boxed Warn]

• Nilotinib carries a significant risk of prolonging the QT interval, which can lead to sudden death.
• Patients with hypokalemia, hypomagnesemia, or long QT syndrome should not use nilotinib due to the increased risk.
• Before starting treatment, any electrolyte imbalances should be corrected, and electrolyte levels should be periodically monitored.
• Electrocardiograms (ECGs) and QTc intervals should be assessed at baseline, after 7 days of treatment, with any dose changes, and periodically thereafter.
• It is important to avoid the use of medications that can prolong the QT interval, as well as strong CYP3A4 inhibitors.
• Concurrent use of antiarrhythmic drugs should also be avoided as it may increase the risk of potentially fatal arrhythmias.
• The reported cases of sudden death were related to dose-dependent abnormalities in ventricular repolarization.
• Prolonged QT interval can lead to a specific type of arrhythmia called torsade de pointes, which can cause fainting, seizures, and even death.
• Patients with uncontrolled or significant cardiovascular disease were not included in the clinical studies of nilotinib.

Tumor lysis syndrome

• Tumor lysis syndrome (TLS) has been observed in patients with resistant or intolerant chronic myeloid leukemia (CML) who were treated with nilotinib.
• Most cases occurred in patients with advanced disease, high white blood cell counts, and/or dehydration.
• To minimize the risk of TLS, it is important to ensure adequate hydration and address elevated levels of uric acid before starting nilotinib treatment.
• By maintaining proper hydration and managing uric acid levels, the incidence of TLS can be reduced.

Gastrectomy

• In patients who have undergone total gastrectomy, the exposure to nilotinib may be reduced.
• Therefore, it is recommended to consider alternative therapies or adjust the dosage of nilotinib in these patients.
• If nilotinib is still chosen as the treatment option, a dosage increase may be necessary, accompanied by more frequent monitoring to ensure appropriate drug levels and effectiveness.

Hepatic impairment

• In patients with hepatic impairment, it is recommended to reduce the dosage of nilotinib.
• This is because the metabolism of nilotinib primarily occurs in the liver, and patients with hepatic impairment may experience increased exposure to the medication.
• Along with dosage reduction, it is important to closely monitor the QT interval, as nilotinib has the potential to prolong it.
• By adjusting the dosage and monitoring the QT interval.

Pancreatitis

• Caution should be exercised when using nilotinib in patients with a history of pancreatitis.
• The medication may lead to elevated levels of serum lipase and amylase, which can limit the dosage.
• It is important to monitor these levels regularly.
• If patients experience abdominal symptoms along with increases in lipase, treatment should be temporarily discontinued, and further diagnostic tests may be necessary to rule out pancreatitis.
• Monthly monitoring of serum lipase levels or as clinically indicated can help ensure the safe use of nilotinib in patients with a history of pancreatitis.

Monitoring parameters while using Tasigna (Nilotinib):

• Philadelphia chromosome status (prior to treatment)
• Complete blood count (CBC) with differential:
  • Every 2 weeks for the first 2 months, then monthly
• Electrolytes (including potassium, calcium, and magnesium):
  • Baseline and periodic monitoring
• Lipid profile and glucose:
  • Baseline and periodic monitoring during the first year, then at least yearly
• Hepatic function (ALT/AST, bilirubin, alkaline phosphatase):
  • Baseline and monthly or as clinically indicated
• Serum lipase/amylase:
  • Baseline and monthly or as clinically indicated
• Uric acid:
  • Baseline assessment
• Bone marrow assessments
• Pregnancy test (in females of reproductive potential):
  • Prior to initiating therapy
• Electrocardiogram (ECG) and QTc interval:
  • Baseline, 7 days after treatment initiation or dosage adjustments, and periodically thereafter
• Monitor for signs/symptoms of cardiovascular events, hemorrhage, or fluid retention
• Monitor growth and development in pediatric patients

For patients who discontinue nilotinib after achieving sustained molecular response (MR):

• Monitor BCR-ABL transcript levels and CBC with differential:
  • Monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter
• Upon the loss of MR during the treatment-free phase:
  • Monitor BCR-ABL transcript levels every 2 weeks until the levels remain lower than major molecular response (MMR) for 4 consecutive measurements, then return to the original monitoring schedule
• For patients who reinitiate nilotinib after losing molecular response:
  • Monitor CBC and BCR-ABL transcript levels every 4 weeks until a major molecular response (MR) is re-established, and then every 12 weeks thereafter

Thyroid function testing (Hamnvik 2011):

• Preexisting levothyroxine therapy:
  • Obtain baseline thyroid-stimulating hormone (TSH) levels, then monitor every 4 weeks until levels and levothyroxine dose are stable, then monitor every 2 months
• Without preexisting thyroid hormone replacement:
  • Baseline TSH, then monthly for 4 months, then every 2 to 3 months

Additionally, it is important to monitor adherence to the prescribed treatment regimen.

How to administer Nilotinib (Tasigna)?

• Administer the oral medication twice daily, with doses approximately 12 hours apart.
• Take the medication on an empty stomach, at least 1 hour before or 2 hours after eating.
• It is important to follow the specific instructions regarding food consumption in relation to nilotinib. No food should be consumed for at least 2 hours before taking nilotinib and for at least 1 hour after the dose.
• Swallow the capsules whole with water. Do not chew, crush, or open the capsules.
• If swallowing the whole capsule is not possible, the contents can be emptied into 5 mL of applesauce (puréed apple) and taken within 15 minutes. Do not save the mixture for later use.

Mechanism of action of Nilotinib (Tasigna):

• Nilotinib is a medication that selectively inhibits certain enzymes called tyrosine kinases.
• It specifically targets BCR-ABL kinase, c-KIT, and platelet-derived growth factor receptor (PDGFR).
• It does not affect the SRC family of enzymes.
• By binding to the ATP-binding site of BCR-ABL, nilotinib blocks its tyrosine kinase activity, which is involved in the proliferation of leukemic cells.
• Nilotinib is effective against BCR-ABL kinase mutations that have developed resistance to another medication called imatinib.

Protein Binding:

• Nilotinib is bound to proteins in the blood at a rate of approximately 98%.

Metabolism:

• The liver is primarily responsible for metabolizing nilotinib.
• It undergoes oxidation and hydroxylation through a specific enzyme called CYP3A4.
• These processes convert nilotinib into mostly inactive substances.

Bioavailability:

• When taken in capsule form, about 50% of the drug is absorbed into the bloodstream.
• The bioavailability of nilotinib is influenced by factors such as the pH of the oral solution and whether it is taken with food.
• Sprinkling the contents of two 200 mg capsules on applesauce has been found to be equivalent to taking two intact capsules.
• The bioavailability of nilotinib is increased by 82% when it is taken 30 minutes after a high-fat meal.

Half-Life and Time to Peak:

• Nilotinib has an elimination half-life of approximately 17 hours, meaning it takes about 17 hours for half of the drug to be eliminated from the body.
• It reaches its peak concentration in the blood around 3 hours after administration.

Excretion:

• The majority of nilotinib and its metabolites are eliminated from the body through the feces.
• Approximately 93% of the drug is excreted in the feces, with 69% of it remaining in its original form (as the parent drug).

Nilotinib Brand Name (International):

• Tasigna

Nilotinib Brand Names (Availability) in Pakistan:

Nilotinib 150 mg Capsules
Tasigna	Novartis Pharma (Pak) Ltd

Nilotinib 200 mg Capsules
Tasigna	Novartis Pharma (Pak) Ltd