Summary of Scientific Narrative
The summary of Scientific Narrative is based on published medical literature, public information and information sources from US and European regulatory authorities. All recommendations must be considered in the light of the patients? clinical condition. Before prescribing any medication always consult the complete prescribing information for your country or territory. All brand names are trademarks or registered trademarks of their respective owners.
Chemical designation (IUPAC)
4-methyl-N-[3-(4-methyl-1-H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
White to slightly yellowish to slightly greenish yellow powder
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).
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.
Europe (EMEA): EU/1/07/422/001-004
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.
Europe (EMEA): 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.
Nilotinib capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint ?NVR/TKI?. Nilotinib capsules are supplied in blister packs as cartons of 4 blister pack or blisters of 28 capsules. Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.
Pharmacology Disease Overview
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.
How is nilotinib expected to act?
Enzymes are proteins produced by the human body that speed up the transformation of certain substances into other substances. Nilotinib inhibits a certain class of enzymes called tyrosine kinases. These enzymes play a role in a cascade of molecular reactions that bring a certain signal from outside the cell into the cell thereby controlling the growth of cells. In chronic myeloid leukaemia, the function of these enzymes is disturbed causing uncontrolled growth and multiplication of the cancer cells. Nilotinib might, by inhibition of one or more of these enzymes activity, at certain levels in the cascade, help in slowing down or stopping the further growth of the cancer cells.
Nilotinib, and certain other medicines, including over the counter medications or herbal supplements (such as St. John?s Wort) can interact with each other. Nilotinib should not be taken within two hours before and one hour after eating.
Nilotinib is metabolised by CYP3A4 and strong inhibitors or inducers of this enzyme may significantly affect exposure to nilotinib. Patients taking nilotinib should avoid foods such as grapefruit juice which inhibit CYP3A4.
Pregnancy Category: D (USA)
The use of nilotinib during pregnancy may cause serious harm to the fetus. Unless strictly necessary, nilotinib should not be taken during pregnancy. Women of childbearing potential should use effective contraceptives if taking nilotinib. Sexually active female patients taking nilotinib should use adequate contraception.
Nilotinib is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy data.
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.
Europe (NICE): A National Institute for Health and Clinical Excellence (NICE) assessment for nilotinib is pending.
Efficacy data for nilotinib are limited to 3 case series in patients with CML with resistance or intolerance to imatinib. One of these trials included 13 patients with ALL, but they were excluded from efficacy analyses. The majority of data from these trials was from patients with chronic phase or accelerated phase CML. A major cytogenetic response was observed in 18% – 48% of patients, and a complete hematologic response in 26 – 92% of patients. There are no published trials comparing nilotinib to other agents. Patients diagnosed with advanced gastrointestinal stromal tumors (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. An evaluation tested the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use program in 12 European cancer centers were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilization. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib.
The most common drug related adverse effects include rash, pruritus, constipation, nausea, vomiting, diarrhea, thrombocytopenia, and neutropenia. Other serious adverse events with nilotinib include elevated lipase and liver function tests, and electrolyte abnormalities. Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, and CYP2D6. Nilotinib is also metabolized by the hepatic enzyme CYP3A4 and is transported through the P-glycoprotein efflux system. Drugs that are substrates, inducers, or inhibitors of these enzymes may have significantly interacted with nilotinib.
 Highlights of Prescription information Nilotinib (August 2007) Novartis Pharmaceuticals Corporation (USA)
 Summary of Product Characteristics Nilotinib (November 2007) Novartis AG ((Europe)
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Las updated: May 10, 2011