Drug Detail

Information about Tasigna

Generic Name
Nilotinib
IND
AMN107
Brand Name (US)
Tasigna
Manufacturer
Novartis
Drug Type
Tyrosine Kinase Inhibitor
Delivery
Oral
Approval Status
Approved for a non-GIST cancer
Indications
CML
Overall Strategy
KIT Protein Based
Strategy
Block KIT
Drug Category
KIT/PDGFRA inhibitor

Approved Uses: Chronic Mylogenous Leukemia on 10/29/07

Nilotinib has been tested in a phase III trial for Gleevec and Sutent-resistant GIST. Another phase III trial opened in January, 2009 to test whether nilotinib is better than imatinib when given as initial (front-line) therapy in metastatic/unresectable GIST. Both of these trials failed to produce superior results to imatinib.

Targets: Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM) and c-Kit (210 nM)(Nilotinib prescribing information). Nilotinib is one of the more potent inhibitors of "wild-type KIT".

Dosage: 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.

Side Effects (also see prescribing information): In the phase I trial in GIST rash and puritis where more common with the combination (Gleevec & Tasigna) cohort while fatigue and abdominal pain were more common with Tasigna monotherapy cohort.

Patients with low blood potassium or magnesium should not use Tasigna.These conditions must be corrected prior to Tasigna administration and should be periodically monitored.

WARNING: QT PROLONGATION AND SUDDEN DEATHS
Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to Tasigna 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. Use with caution 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.
Drugs known to prolong the QT interval should be avoided. These include:amiodarone, arsenic trioxide, chloroquine, chlorpromazine, clarithromycin, disopyramide, dofetilide, droperidol, erythromycin, haloperidol, ibutilide, methadone, moxifloxacin, pentamidene, pimozide, procainamide, quinidine and sotalol. For lists of other "possible" or "conditional" risk drugs, please see the Arizona CERT at www.azcert.org.
CAUTION: Patients that have had a major gastrectomy may have decreased absorption of nilotinib. See the link below.
See the prescribing information (link below) for complete details.

Drug interactions (see nilotinib prescribing information for complete information about possible drug interactions)

Nilotinib can interact with other drugs in a number of different ways.

Drugs that inhibit or induce CYP-3A4 can decrease or increase the concentrations of nilotinib, leading to inadequate drug levels or excessive toxicity.

Nilotinib also inhibits some liver enzymes, including CPY314, CYP2C8, CPY2C9, CYP2D6 and UGT1A1, potentially increasing the concentrations of drugs that are eliminated by these enzymes.

Drugs that affect gastric pH such as proton pump inhibitors (which may increase gastric pH), may reduce the amount of nilotinib absorbed. For gastric upset, calcuim carbonate (e.g., Tums), does not appear to affect absorption (in healthy volunteers, see link below).

Drugs that may prolong the QT interval such as anti-arrhythmic medicines, should be avoided (see black box warning on prescribing information). Since nilotinib also can increase the QT interval, any drug interaction that increases concentrations of nilotinib also increases the risk of further prolonging the QT interval (drugs such as CPY3A4 inhibitors and drugs that inhibit P-gp).
Nilotinib may increase cholesterol (see link below), and may increase the risk of occlusive arterial events (see links). Also, the SCORE chart is a set of criteria used to predict cardiovascular risk. There appears to be a correlation between SCORE risk groups and development of cardiovascular events on nilotinib (see link below). Other possible risk factors have been suggested including high dose, time on treatment and elevated homocystein (see links).


Links

 

Nilotinib prescribing information
   

 

Tasigna.com
   

 

Tasigna International Patient Assistance Program (TIPAP)
   

 

Tasigna medication guide
   

 

Nilotinib scientific discussion (pdf)
   

 

Novartis discontinues clinical trial of Tasigna® for investigational use in newly diagnosed patients with unresectable and/or metastatic GIST
   

 

FDA approves Tasigna for CML
   

 

Nilotinib for patients with advanced GIST who failed imatinib and sunitinib: Negative effect of prior major gastrectomy on exposure to nilotinib -ASCO 2010
   

 

Pharmacokinetics and pharmacodynamics of nilotinib in gastrointestinal stromal tumors (Pubmed)
   

 

Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML
   

 

Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site
   

 

Severe adverse events associated with the use of second-line BCR/ABL tyrosine kinase inhibitors: preferential occurrence in patients with comorbidities
   

 

Calcium carbonate does not affect nilotinib pharmacokinetics in healthy volunteers.
   

 

Nilotinib exacerbates diabetes mellitus by decreasing secretion of endogenous insulin
   

 

Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia.
   

 

Extended kinase profile and properties of the protein kinase inhibitor nilotinib
   

 

Clinical experience to date with nilotinib in gastrointestinal stromal tumors (Pubmed)
   

 

Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants
   

 

Early onset hypercholesterolemia induced by the second generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia
   

 

Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment.
   

 

Hyperhomocysteinemia and high doses of nilotinib favor cardiovascular events in chronic phase Chronic Myelogenous Leukemia patients
   

 

Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients
   

 

Nilotinib (Tasigna) in Wikipedia
   

 

Nilotinib Compassionate Use In Advanced GIST- A Retrospective Analysis (Poster PDF)
   

Trials of this drug

  

Study of AMN107 With Imatinib in Gastrointestinal Stromal Tumors (GIST)
   

  

Patients Completing Core Protocol (CAMN107A2103), Exhibiting Stable Disease (SD), Partial Response (PR) or Complete Response (CR) to Nilotinib in Combination With Imatinib
   

  

Efficacy and Safety of AMN107 Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib (ENEST)
   

  

Efficacy and Safety of AMN107 Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib - Extension
   

  

Nilotinib in Advanced Gastrointestinal Stromal Tumors (GIST) (07060)
   

  

Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib. (OPEN)
   

  

Efficacy and Safety of AMN107 in Patients With GastroIntestinal Stromal Tumors (GIST) Who Have Failed Both Imatinib and Sunitinib
   

  

Phase II Study Aiming to Evaluate the Efficacy and Safety of Nilotinib Patients With Gastrointestinal Stromal Tumors (GIST) Resistant or Intolerant to Imatinib and or to 2nd Line Tyrosine Kinas (TK) Inhibitor
   

  

Nilotinib Pharmacokinetics (PK) in Gastrointestinal Stromal Tumor (GIST)
   

  

Evaluation of Nilotinib In Patients With Advanced Gastrointestinal Stromal Tumor (GIST)
   

  

Efficacy of Nilotinib in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Imatinib and Sunitinib
   

  

Tasigna Neoadjuvant Gastrointestinal Stromal Tumor (GIST)
   

Trial results

  ASCO 2013 - Phase III trial of nilotinib versus imatinib as first-line targeted therapy of advanced gastrointestinal stromal tumors (GIST).
   
  Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib
   
  ClinicalTrials.gov (trial results)
   
  Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib.
   
  Nilotinib in Advanced Gastrointestinal Stromal Tumors after Imatinib and Sunitinib Therapy.
   
  Efficacy and Safety of AMN107 Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib (ENEST)
   
  Nilotinib in Advanced Gastrointestinal Stromal Tumors (GIST) (07060)
   
  A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST).
   
  Nilotinib in advanced GIST: A retrospective analysis of nilotinib in compassionate use (ASCO 2008)
   
  Assessment of response using FDG-PET and CT in a phase I study of AMN107 alone or in combination with imatinib (IM) in patients with imatinib-resistant (IM-R) gastrointestinal stromal tumors (GIST).
   
  Results with AMN107, a novel kinase inhibitor, in gastrointestinal stromal tumor (GIST): Preclinical rationale and early results in a patient (Pt) with imatinib (IM)-resistant GIST
   
  A phase I study of nilotinib alone and in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors (GIST): Study update.
   
  A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update.
   
  A Phase I Study of Single-Agent Nilotinib or in Combination with Imatinib in Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors.
   
  ASCO 2010 - Preliminary data of nilotinib in the first-line treatment of patients with metastatic or unresectable gastrointestinal stromal tumors (GIST).
   
  ASCO 2010 - Nilotinib for patients with advanced GIST who failed imatinib and sunitinib: Negative effect of prior major gastrectomy on exposure to nilotinib.
   
  ASCO 2010 - Evaluation of nilotinib (N) in advanced GIST previously treated with imatinib mesylate (IM) and sunitinib (S).
   
  ASCO 2010 - Phase III trial of nilotinib in patients with advanced gastrointestinal stromal tumor (GIST): First results from ENEST g3.
   
  Novartis discontinues clinical trial of Tasigna┬« for investigational use in newly diagnosed patients with unresectable and/or metastatic GIST
   

Search for this drug/combination in:

ClinicalTrials.gov

ASCO

Pubmed