Nilotinib


Thông tin thuốc gốc
Chỉ định và Liều dùng
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).

Oral
Accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia, 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).
Special Patient Group
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 increase 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).
Hepatic Impairment
Chronic phase Philadelphia chromosome positive chronic myelogenous leukaemia:
In patients with newly-diagnosed case
Mild to severe: 200 mg bid, may increase to 300 mg bid based on tolerability.

Chronic phase Philadelphia chromosome positive chronic myelogenous leukaemia; Accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia:
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.
Cách dùng
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.
Chống chỉ định
Patients with hypokalaemia, hypomagnesaemia or long QT syndrome. Concomitant use with potent CYP3A4 inhibitors or inducers, antiarrhythmics and other QT prolonging drugs.
Thận trọng
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.
Phản ứng phụ
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.
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.
MonitoringParameters
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.
Quá liều
Symptoms: Neutropenia, vomiting and drowsiness. Management: Monitor patient and give appropriate supportive treatment.
Tương tác
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.
Food Interaction
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.
Tác dụng
Description: 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.
Pharmacokinetics:
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.
Đặc tính

Chemical Structure Image
Nilotinib

Source: National Center for Biotechnology Information. PubChem Database. Nilotinib, CID=644241, https://pubchem.ncbi.nlm.nih.gov/compound/Nilotinib (accessed on Jan. 22, 2020)

Bảo quản
Store below 30°C.
Phân loại MIMS
Phân loại ATC
L01EA03 - nilotinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.
References
Singer JB, Shou Y, Giles F et al. UGT1A1 Promoter Polymorphism Increases Risk of Nilotinib-induced Hyperbilirubinemia. Leukemia. 2007;21:2311–2315. Accessed 05/07/2019

Annotation of HCSC Label for Nilotinib and UGT1A1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 04/07/2019.

Anon. Nilotinib (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/07/2019.

Anon. Nilotinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/07/2019.

Anon. UGT1A1 - Nilotinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/07/2019.

Buckingham R (ed). Nilotinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/07/2019.

Clinical Annotation for rs8175347 (UGT1A1); Nilotinib; Leukemia, Myelogenous, Chronic, BCR-ABL Positive (Level 3 Toxicity/ADR). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 04/07/2019.

Joint Formulary Committee. Nilotinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/07/2019.

Tasigna (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/07/2019.

Tasigna (Novartis Pharmaceuticals Corporation). U.S. FDA. https://www.fda.gov/. Accessed 04/07/2019.

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