Nilotinib is available by the brand name of Tasigna (manufactured by Novartis Pharmaceuticals). It belongs to the second generation of tyrosine kinase inhibitors used to treat various leukemias.

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: It can be given concurrently with hematopoietic growth factors such as erythropoietin/ filgrastim and with hydroxyurea or anagrelide.

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

• 400 mg bi.d per oral daily starting on day 8 of induction chemotherapy in addition to with daunorubicin, vincristine, and prednisolone.
• Therapy should be continued up to the initiation of stem cell transplant conditioning or until the end of consolidation therapy.
• Patients receive two years of maintainance therapy of nilotinib after completing 5 cycles of consolidation treatment.
• Patients who underwent allogeneic stem cell transplant did not receive nilotinib after transplant.

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

• 400 mg per oral b.i.d daily.

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

• 300 mg per oral b.i.d daily.

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

  • Nilotinib can be discontinued in patients who have been
    • resistant or intolerant to previous nilotinib therapy.
    • Treated with nilotinib for at least 3 years
    • Maintained a molecular response (corresponding to BCR-ABL/ABL ≤0.01% IS) for 1 year before discontinuation or  achieved a molecular response (corresponding to BCR-ABL/ABL ≤0.0032% IS) for the last assessment done immediately before discontinuation
    • Confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no evidence of accelerated phase/ blast crisis
    • No evidence of previous attempts of treatment-free remission discontinuation resulted in relapse.

• The reinitiation of therapy:

  • Patients who lose major molecular response after stopping nilotinib must reinitiate treatment within one month at the dose used before discontinuation.
  • BCR-ABL transcript levels should be monitored every 4 weeks until a major molecular response is achieved and every 12 weeks thereafter.
  •  If a major molecular response is not achieved after 3 months of therapy reinitiation, BCR-ABL kinase domain mutation testing should be done.

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

• 400 mg per oral b.i.d daily.

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

• 400 mg per oral b.i.d daily.

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

• 400 mg per oral b.i.d daily until disease progression or unacceptable toxicity.

• Missed doses:

  • In case of a missed dose, do not makeup, resume with the next scheduled dose.

Dosage adjustment for concomitant CYP3A4 inhibitors and inducers:

• CYP3A4 inhibitors:

  • Concomitant use of a strong CYP3A4 inhibitor with nilotinib should be avoided.
  • Nilotinib treatment should be interrupted if a strong CYP3A4 inhibitor is required.
  • If interruption is not possible and combination with a strong CYP3A4 inhibitor is necessary,nilotinib dose should be reduced to 300 mg once daily in patients with resistant or intolerant Ph+ CML (chronic or accelerated phase) or to 200 mg once daily in newly diagnosed chronic phase Ph+ CML, with regular monitoring, especially of the QT interval. When a strong CYP3A4 inhibitor is discontinued, a washout period is recommended before adjusting nilotinib dose

• CYP3A4 inducers:

  • Combination therapy with strong CYP3A4 inducer should be avoided(based on pharmacokinetic parameters, an increased nilotinib dose is not likely to compensate for decreased exposure).

Nilotinib (Tasigna) dosage in Childerns

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

• • 230 mg/m² per oral b.i.d daily (round the dose to the nearest 50 mg increment)
  • The maximum dose is 400 mg/dose.
  • Therapy should be continued until positive clinical benefit or until unacceptable toxicity.

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

• 230 mg/m² per oral b.i.d daily (round dose to the nearest 50 mg increment)
• The maximum dose is 400 mg/dose.
• Therapy should be continued until positive clinical benefit or until unacceptable toxicity.

Nilotinib Dosing adjustment for concomitant CYP3A4 inhibitors/inducers:

• CYP3A4 inhibitors:

  • concurrent use of a strong CYP3A4 inhibitor with nilotinib. should be avoided.
  • If a strong CYP3A4 inhibitor is unavoidable, nilotinib treatment should be interrupted.
  • If the interruption is not possible and combination with a strong CYP3A4 inhibitor cannot be avoided, reduced dosing is advised in adults but there are no pediatric-specific recommendations.
  • Close monitoring, especially for QT interval, should be done.
  • When a strong CYP3A4 inhibitor is stopped, a washout period is recommended before adjusting the nilotinib dose upward.

• CYP3A4 inducers:

  • A combination of a strong CYP3A4 inducer with nilotinib is better avoided (based on pharmacokinetic parameters, an increased nilotinib dose is not likely to compensate for decreased exposure).

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

• Hematologic toxicity (unrelated to underlying leukemia):

  • Absolute neutrophil count <1,000/mm³ and/or platelets <50,000/mm³:

    • Withhold treatment and monitor blood counts

  • If Absolute neutrophil count >1,500/mm³ and/or platelets >75,000/mm³ within 14 days:

    • Resume at the previous dose

  • If blood counts remain low for >14 days:

    • May need to reduce dose to 230 mg/m² once daily
    • If toxicity occurs after dose reduction, therapy should be discontinued.

• Non-hematologic toxicity :

  • Amylase or lipase elevation ≥ grade 3:

    • Withhold treatment, monitor serum amylase or lipase.
    • When lipase or amylase returns to ≤ grade 1, resume treatment 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, therapy should be stopped

  • Lipase increases in conjunction with abdominal symptoms:

    • Withhold treatment and rule out for pancreatitis,

• Clinically significant moderate or severe non-hematologic toxicity (including medically severe fluid retention):

  • Treatment should be withheld.
  • Upon resolution of toxicity, resume at 230 mg/m² once daily (if the previous dose was 230 mg/m² twice daily), may escalate back to initial dose (230 mg/m² twice daily) if clinically appropriate.
  • Discontinue if the previous dose was 230 mg/m² once daily.

• QT prolongation:

Note: Repeat electrocardiogram one week after any dosage adjustment

• Withhold treatment and monitor serum potassium and magnesium if QTc >480 msec.
• If QTcF returns to <450 msec and to within 20 msec of baseline within 14 days:
  • Resume at the previous dose
• If QTcF returns to 450 to 480 msec after 14 days, dose reduction to 230 mg/m² once daily, an electrocardiogram should be repeated in one week.
• Treatment should be stopped if QTcF >480 msec after dosage reduction to 230 mg/m² once daily.

Nilotinib (Tasigna) pregnancy Risk Category: D

• Studies on animal reproduction and the mechanism of action have shown that nilotinib can cause teratogenecity in pregnant animals.
• Before starting therapy, it is important to get rid of any pregnancy.
• Effective contraception should be used by women of childbearing years during treatment, and at least for 2 weeks following the last dose.

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:

• There are no dosage adjustments provided in the manufacturer's labeling (has not been studied.
• Dosage adjustments for renal dysfunction is not required as nilotinib and its metabolites have minimal renal excretion.

Nilotinib (Tasigna) dose adjustment in liver disease:

• Patients with Hepatic impairment at baseline:

  • Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase:

    • • Mild, moderate, and severe impairment (Child-Pugh class A, B, or C)

        • An Initial dose of 200 mg b.i.d daily.
        • The dose may be increased to 300 mg b.id daily depending on patient tolerability.

  • Resistant or intolerant Ph+ CML in chronic or accelerated phase:

    • Mild to moderate impairment (Child-Pugh class A or B):

      • An initial dose of 300 mg b.i.d daily.
      • The dose may be increased to 400 mg bi.d daily depending on patient tolerability.

    • Severe impairment (Child-Pugh class C):

      • An initial dose of 200 mg b.i.d daily,
      • The dose may be increased to 300 mg b.i.d daily and then further increase to 400 mg b.i.d daily depending on patient tolerability.

• Hepatotoxicity occurring during treatment:

  • If elevated bilirubin ≥ grade 3:

    • Withhold treatment/ monitor bilirubin resume treatment at 400 mg once daily when bilirubin returns to ≤ grade 1.

  • If elevated ALT or AST ≥ grade 3:

    • Withhold treatment/ monitor transaminases, resume treatment at 400 mg once daily when ALT or AST returns to ≤ grade 1.

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):

These include:

• Hypokalemia
• Hypomagnesemia
• Long QT syndrome
• Hypersensitivity to nilotinib and any component of the formulation
• Persistent QTc >480msec

Warnings and precautions

• Suppression of bone marrow

  • Reversible myelosuppression can occur, including grade 3 and 4 thrombocytopenias, neutropenia and anemia.
  • Treatment delay and dose reduction may be necessary. For the first two months, monitor blood counts every 14-days and then monthly.

• Cardiovascular:

  • There are many possible cardiovascular events, including MI, arterial, or vascular occlusion and peripheral arterial occlusive diseases.
  • Patients with pre-existing risk factors should be treated with caution. You should monitor for any new or worsening symptoms related to cardiovascular events.

• Inadequate electrolyte levels:

  • Before treatment, it is important to correct hypophosphatemia, hypokalemia and hypokalemia. Also, be sure to monitor your progress monthly.

• Fluid retention

  • Monitor fluid retention for pleural/pericardial effusions/ascites/pulmonary embolisms closely
  • Signs such as rapid weight gain/ swelling/shortness should be immediately noted and treated.

• Hemorrhage

  • Patients with chronic myelogenous Leukemia treated with Nilotinib have experienced life-threatening hemorhagic events.
  • A clinical trial comparing imatinib with nilotinib was conducted to determine which treatment is more effective in treating chronic phase CML in Philadelphia chromosome-positive patients.
  • It was found that gastrointestinal hemorhage, including grade 3 and 4, was more common in the nilotinib group.

• Hepatotoxicity

  • Hepatotoxicity may include raised bilirubin/transaminitis or alkaline phosphatase.
  • These elevations were more common in children than in adults.
  • It is important to monitor the liver function every month.

• QT prolongation/sudden Death: [US Boxed Warn]

  • Reports of QT interval prolongation, sudden deaths and sudden death have been made.
  • Patients with hypokalemia, hypomagnesemia or long QT syndrome are not advised to take it.
  • Before starting therapy, it is important to correct electrolyte anomalies and monitor them regularly.
  • Monitoring QTc and ECG (baseline, at 7-days, with dose change and periodically).
  • Antiarrhythmics that combine QT-prolonging drugs and strong CYP3A4 inhibitors should be avoided. This can increase the risk of fatal arrhythmias.
  • These sudden deaths may be due to dose-dependent ventricular abnormalities.
  • A prolonged QT interval can lead to torsade des pointes. This may cause syncope, seizure and death.
  • Studies excluded patients with significant or uncontrolled cardiovascular disease.

• Tumor lysis syndrome

  • In chronic mylogenus patients with intolerant or resistant disease, tumor lysis syndrome (TLS), was reported.
  • It was more common in patients with malignant diseases progression/higher white blood cell counts/dehydration. 
  • Before starting nilotinib, ensure that you are adequately hydrated and have a treatment for high levels of uric acid.

• Gastrectomy

  • Patients undergoing total gastrectomy may need to be treated with alternative therapy, or higher doses and more frequent monitoring.

• Hepatic impairment

  • Patients with hepatic impairment should reduce their dosage and keep an eye on the QT interval.
  • Because Nilotinib metabolism occurs primarily in the liver, it is more likely that you will be exposed to it.

• Pancreatitis

  • Patients with a history or pancreatitis should be cautious as it can raise serum lipase or amylase.
  • Patients with abdominal symptoms and raised lipase should be withheld from treatment and checked for pancreatitis.
  • Monitor serum lipase levels at least once a month or as required by the doctor.

Monitoring parameters while using Tasigna (Nilotinib):

These include:

• Status of Philadelphia's chromosomes before treatment
• For the first two months, complete blood count with differential every 2 week. Then, monthly
• At baseline, serum electrolytes such as potassium, calcium, magnesium, and periodically thereafter.
• Baseline glucose and lipid profile at baseline, and then periodically for the first year. Then, at least annually thereafter.
• Liver function ALT/AST and bilirubin at baseline, monthly thereafter.
• Serum lipase and amylase (baseline, monthly or as clinically necessary).
• Assessments of bone marrow with urac acid (baseline).
• Before starting therapy, you should have a pregnancy test
• ECG and QTc (baseline/one-week after treatment initiation/dosage adjustments and monthly).
• Signs and symptoms of bleeding, cardiovascular events, and fluid retention
• Monitoring children's growth and development
• After a sustained molecular response to nilotinib, it is recommended that you monitor BCR-ABL transcripts and your full blood count with differential every month for 1 year. Then, every 6 weeks for the 2nd year. Finally, every 12 weeks.
• Monitor BCR/ABL transcript levels for 2 weeks after treatment stops to ensure that the BCR/ABL levels are not lower than the major molecular reaction (MMR) and continue to do so until 4 therapy cycles.
• The patient can then return to their original monitoring program.
• Patients who have re-initiated nilotinib following a loss of molecular reaction should monitor their complete blood count and BCR–ABL transcript levels for at least one month, then for 12 weeks.

• Thyroid function testing

  • Pre-existing levothyroxine therapy should be monitored for baseline levels of thyroid-stimulatinghormone (TSH), then monitor every month until the levels and levothyroxine dosage are stable. Then monitor every 2 months.

  • Without the need for thyroid hormone replacement

    • TSH at baseline, then once a month for 4 months, and then every 2 to three months thereafter
• You must ensure that you adhere to the rules.

How to administer Nilotinib (Tasigna)?

You should take it orally two times daily, with doses at least one hour apart.

Notification:

• You should avoid eating for 2 hours or more before, and for 1 hour after, the nilotinib treatment.
• Capsules are best taken whole and diluted with water.
• You can swallow the contents whole if you are unable to swallow.

Mechanism of action of Nilotinib (Tasigna):

• Nilotinib, a selective inhibitor of tyrosine-kinase kinase (PTK), targets BCR-ABL, cKIT and platelet derived growth factor receptors (PDGFR).
• It is not clear that Nilotinib has any activity against the SRC family. 
• After binding to the Adenosine Triphosphate binding site of BCR–ABL, Nilotinib inhibits leukemic cell proliferation and inhibits Tyrosine Kinase activity. Nilotinib is active in imatinib resistant BCR-ABL mutations.

Protein binding:

• 98%

Metabolism:

• Obtains its metabolism from liver via oxidation or hydroxylation. CYP3A4 is used to identify primarily inactive metabolites.

Bioavailability

• The Capsules have a 50% reduction in the pH (compared to an oral solution of pH 1.2 to 1.3). Two 200mg capsules sprinkled over applesauce were found to be bioequivalent in size to two intact 200mg capsules. When taken half an hour after eating a high-fat meal, bioavailability increases 82%.

Half-life elimination:

• 17 hours

Time to peak:

• 3 hours

Excretion:

• Feces (93%; 69% as parent drug)

Nilotinib Brand Name (International):

• Tasigna (Novartis Pharmaceuticals PVT Ltd)

Nilotinib Brand Names (Availability) in Pakistan: