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).