Nilotinib

Oral
Chronic phase Philadelphia chromosome positive chronic myelogenous leukaemia
Adult: In patients with newly-diagnosed case: 300 mg bid. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Child: In paediatric patients with newly diagnosed case, resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy: 230 mg/m² bid rounded to the nearest 50 mg dose. Max: 400 mg as single dose. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Hepatic impairment: In patients with newly-diagnosed case Mild to severe: 200 mg bid, may increase to 300 mg bid based on tolerability.

Oral
Chronic phase Philadelphia chromosome positive chronic myelogenous leukaemia
Adult: With resistance to prior treatment or intolerance to other therapy: 400 mg bid. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Hepatic impairment: With resistance to prior treatment or intolerance to other therapy Mild to moderate (Child-Pugh A or B): 300 mg bid, may increase to 400 mg bid based on tolerability. Severe (Child-Pugh C): 200 mg bid, may increase to 300 mg bid up to 400 mg bid based on tolerability.

Oral
Accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia
Adult: With resistance to prior treatment or intolerance to other therapy: 400 mg bid. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Hepatic impairment: With resistance to prior treatment or intolerance to other therapy Mild to moderate (Child-Pugh A or B): 300 mg bid, may increase to 400 mg bid based on tolerability. Severe (Child-Pugh C): 200 mg bid, may increase to 300 mg bid up to 400 mg bid based on tolerability.

Special Populations: Pharmacogenomics: Uridine diphosphate glucuronosyl-transferase 1A1 (UGT1A1) Bilirubin is glucuronidated by Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) and polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinaemia during treatment of some drugs including nilotinib. Polymorphisms of UGT1A1*28 allele may be at risk of hyperbilirubinaemia. A pharmacogenetic analysis was conducted to evaluate the polymorphisms of UGT1A1. Studies showed that the largest increases in bilirubin were observed among patients with (TA)₇/(TA)₇ genotype relative to (TA)₆/(TA) ₆ and (TA) ₆/(TA) ₇ genotypes. Caution is recommended in patients with (TA) ₇/(TA) ₇ genotype (UGT1A1*28).

Should be taken on an empty stomach. Avoid food at least 2 hr before & at least 1 hr after a dose. Swallow whole, do not chew/crush. Avoid grapefruit products.

Patients with hypokalaemia, hypomagnesaemia or long QT syndrome. Concomitant use with potent CYP3A4 inhibitors or inducers, antiarrhythmics and other QT prolonging drugs.

Patients with pre-existing risk factors of CV disease, electrolyte imbalance, history of pancreatitis and total gastrectomy. Maintain adequate hydration and correct uric acid levels, hypomagnesaemia, hypokalaemia and other electrolyte imbalances prior to therapy. Hepatic impairment. Pregnancy and lactation. Monitoring Parameters Monitor Philadelphia chromosome status, ECG, QTc, CBC, electrolytes (e.g. K, Ca, Mg), lipid profile, blood glucose, hepatic function (ALT/AST, bilirubin, alkaline phosphatase), serum lipase and amylase, uric acid, and bone marrow assessments at baseline, periodically thereafter or as clinically indicated. Monitor growth and development of paediatric patients.

Significant: Bone marrow suppression (e.g. myelosuppression, thrombocytopenia, neutropenia, anaemia), cardiovascular and arterial vascular-occlusive events, electrolyte imbalance (e.g. hypophosphataemia, hyper/hypokalaemia, hypocalcaemia, hyponatremia), hepatotoxicity, fluid retention (e.g. pleural and pericardial effusions, ascites, pulmonary oedema), tumor lysis syndrome. Ear and labyrinth disorders: Vertigo. Eye disorders: Eye pruritus, conjunctivitis, dry eye, xerophthalmia. I>Gastrointestinal disorders: Nausea, constipation, diarrhoea, vomiting, abdominal pain, dyspepsia. General disorders and administration site conditions: Fatigue, pyrexia, asthenia, peripheral oedema. Hepatobiliary disorders: Abnormal hepatic function. Infections and infestations: Folliculitis, upper respiratory tract infection. Musculoskeletal and connective tissue disorders: Myalgia, arthralgia, muscle spasms, bone pain, pain in extremity, back pain. Nervous system disorders: Headache, dizziness. Psychiatric disorders: Insomnia. Respiratory, thoracic and mediastinal disorders: Cough, dyspnoea. Skin and subcutaneous tissue disorders: Rash, pruritis, alopecia, dry skin, erythema. Vascular disorders: Hypertension.
Potentially Fatal: Haemorrhage, QT prolongation, sudden death.

Neutropenia, vomiting and drowsiness. Management: Monitor patient and give appropriate supportive treatment.

May decrease nilotinib efficacy with PPIs.
Potentially Fatal: Concomitant use with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, telithromycin) may increase nilotinib serum concentrations. Antiarrhythmics (e.g. amiodarone, disopyramide, procainamide, quinidine, sotalol) and other QT prolonging drugs (e.g. chloroquine, halofantrine, clarithromycin, haloperidol, methadone and moxifloxacin) may increase the risk of prolonged QT interval. Concomitant use with CYP3A4 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) may decrease nilotinib serum concentrations.

Bioavailability is increased with food. Avoid grapefruit juice as it may increase nilotinib serum levels. Avoid St. John's wort as it may decrease nilotinib serum levels.

Nilotinib selectively inhibits tyrosine kinase that targets BCR-ABL kinase, c-KIT and platelet derived growth factor receptor (PDGFR). It binds to the ATP-binding site of BCR-ABL to inhibit BCR-ABL mediated proliferation of leukemic cell lines, thereby inhibiting tyrosine kinase activity. Nilotinib does not have an activity against SRC family but has an activity in imatinib resistance BCR-ABL kinase mutations.
Absorption: Bioavailability: Approx 50%. High-fat meal increases bioavailability. Time to peak plasma concentration: Approx 3 hours.
Distribution: Plasma protein binding: Approx 98%.
Metabolism: Undergoes hepatic oxidation and hydroxylation via CYP3A4 to inactive metabolites.
Excretion: Via faeces (93%, 69% as parent drug). Elimination half-life: Approx 17 hours.

Oral: Store below 30°C.

Targeted Cancer Therapy

L01EA03 - nilotinib