|Systematic (IUPAC) name|
|4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||D (US)|
|Legal status||POM (UK) ℞-only (US)|
|Mol. mass||529.5245 g/mol|
| (what is this?)
Nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib (trade name: Gleevec [USA]/ Glivec [Europe/Australia/Latin America]), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study 92% of patients (already resistant or unresponsive to imatinib) achieved a normal white blood cell counts after five months of treatment. The drug carries a black box warning for possible heart complications. The use of low doses of nilotinib is being investigated for use for Parkinson's and Alzheimer's disease, as well as for ALS, dementia and Huntington's disease.
Nilotinib possesses an in vitro Bcr-Abl binding potency 30 times greater than imatinib in imatinib-resistant cells, and 5-7 times greater than imatinib in imatinib-susceptible leukemic cells. The clinical importance of nilotinib’s greater binding affinity is not established in patients with imatinib-susceptible disease. Nilotinib absorption greatly decreases with increasing dose above 400 mg. Absorption increases significantly in the presence of food. The clinical course of CML begins with an indolent chronic phase, but can quickly progress to the more aggressive accelerated, then blast phases if left untreated. Disease classification is based on the degree of cell abnormality in the blood and bone marrow. Nearly 85% of patients are diagnosed during the chronic stage, when treatment is most effective. Diagnosis is often made from a routine blood test wherein leukocytosis (up to 1000 × 109/L) is found. Disease staging is primarily based on percent of blasts in the blood and bone marrow. Staging criteria vary between guidelines. Most CML studies follow criteria established at M.D. Anderson Cancer Center. The World Health Organization (WHO) guidelines propose a lower threshold for the acute and blastic phases of CML. Other criteria such as clonal evolution and platelet abnormalities also contribute to disease staging. Patients in the blastic phase with symptoms of malaise, fever, and worsening splenomegaly are considered to be in blast crisis.
FDA (USA): 400 mg orally twice daily, approximately 12 hours apart and should not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after. Dose adjustment may be required for hematologic and non-hematologic toxicities, and drug interactions.
EMA (Europe): The recommended dose of nilotinib is 400 mg twice daily. Treatment should be continued as long as the patient continues to benefit. Nilotinib should be taken twice daily approximately 12 hours apart and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken. Nilotinib may be given in combination with haematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) if clinically indicated. Nilotinib may be given with hydroxyurea or anagrelide if clinically indicated.
Black Box Warning (USA)
Nilotinib prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to nilotinib administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.
US FDA: August 2007
Europe (EMEA): 19 November 2007
On 22 May 2006, orphan designation (EU/3/06/375) was granted by the European Commission to Novartis Europharm Limited, United Kingdom, for nilotinib for the treatment of chronic myeloid leukemia CML).
Europe (EMEA): EU/1/07/422/001-004
FDA (USA): Nilotinib, second generation oral kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia-chromosome-positive Chronic Myelogenous Leukemia (CML) in adult patients.
Europe (EMEA): Nilotinib is authorised in the European Union for the treatment of Philadelphia-chromosome-positive Chronic Myelogenous Leukaemia (CML).
USA (NCCN):The National Comprehensive Cancer Network (NCCN) recommends nilotinib for CML (grade 2A) as follows: Follow-up therapy after primary treatment with imatinib in patients with the following indications: no hematologic remission or in hematologic relapse at 3 months, no cytogenetic response at 6 months, minor or no cytogenetic response or in cytogenetic relapse at 12 months, partial, minor, or no cytogenetic response or in cytogentic relapse at 18 months; post-transplant follow-up treatment in patients with the following indications: molecular relapse (polymerase chain reaction positive) following cytogenetic remission, cytogenetic relapse or those who are not in cytogenetic remission; for the treatment of CML in accelerated phase in patients with disease progression on imatinib therapy; alternative treatment for patients with the following indications: severe hepatotoxicity due to imatinib therapy, severe nonhematologic toxicity due to imatinib or dasatinib therapy. The NCCN also recommends nilotinib for the treatment of GIST (grade 2A) for progressive disease when patient is no longer receiving benefit from imatinib or sunitinib.
UK (NICE): NICE guidance on dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance (January 2012): Nilotinib is recommended for the treatment of chronic or accelerated phase Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) in adults:
whose CML is resistant to treatment with standard-dose imatinib, or
who have imatinib intolerance, and if the manufacturer makes nilotinib available with the discount agreed as part of the patient access scheme.
High-dose imatinib is not recommended for the treatment of chronic, accelerated or blast-crisis phase Philadelphia-chromosome-positive CML that is resistant to standard-dose imatinib.
- Official Manufacturer Website http://www.tasigna.com
- "Cancer Drug Information: Nilotinib".
- Novartis 29/10/2007 Press Release.
- Kantarjian H et al. (2006). "Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL". N Engl J Med 354 (24): 2542–51. doi:10.1056/NEJMoa055104. PMID 16775235.
- "Patients with treatment-resistant leukemia achieve high responses to Tasigna (nilotinib) in first published clinical trial results". MediaReleases (Novartis). 2006-06-14. Retrieved 2009-08-04.
- "FDA Approves Tasigna for Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia". U.S. Food and Drug Administration. 2007-10-30. Retrieved 2009-08-04.
- "Prescribing information for Tasigna (nilotinib) Capsules" (PDF). NDA 022068. U.S. FDA. 2007-10-29. Retrieved 2009-08-04.
- Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD (June 2006). "AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL". Br. J. Cancer 94 (12): 1765–9. doi:10.1038/sj.bjc.6603170. PMC 2361347. PMID 16721371.
- Manley, PW; Drueckes, P; Fendrich, G; Furet, P; Liebetanz, J; Martiny-Baron, G; Mestan, J; Trappe, J et al. (2010). "Extended kinase profile and properties of the protein kinase inhibitor nilotinib". Biochimica et Biophysica Acta 1804 (3): 445–53. doi:10.1016/j.bbapap.2009.11.008. PMID 19922818.
- Discovery and development of Bcr-Abl tyrosine kinase inhibitors
- New drug information/Abbreviated Scientific Narrative
- Highlights of Prescription information Nilotinib (August 2007) Novartis Pharmaceuticals Corporation (USA)
- Summary of Product Characteristics Nilotinib (November 2007) Novartis AG (Europe)