Nilotinib (Tasigna)

Highly active agent for imatinib resistant/intolerant for CML.

A tyrosine kinase inhibitor able to inhibit the activity of five kinases: ABL1, ABL2, KIT, PDGFRalpha, and PDGFRbeta.

Its use may be superior to imatinib as a first-line therapy for CML, based on the rates of major molecular response and complete cytogenetic response.

Approximately 20 times more potent than imatinib in inhibiting ABL kinase activity, and is even more potent at killing cells dependent on ABL signaling.

In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENESTnd) 846 patients with newly diagnosed Philadelphia chromosome positive CML were enrolled and randomized to 300 mg of nilotinib twice daily , 400 milligrams twice daily or 400 mg of imatinib once daily: at one year the nilotinib arms were significantly better than the imatinib arm achieving major molecular response (44% vs 22%), and for complete cytogenetic response approximately 79% of patients receiving nilotinib compared with 65% of patients treated with imatinib (Saglio G).

In the above studyanalysis at 12 months revealed that nilotinib had a significantly lower rate of progression to accelerated or blast phase disease than patients treated with imatinib.

In the above study at 4 year follow-up continued superiorityin the efficacy ofnilotinib with a MMR of 74.5% compared to imatinib 56%, and a significant reduction in risk progression to accelerated or blast phase disease.

Most frequent side effects include rash, nausea, fatigue, headache, diarrhea and arthralgias.

Compared with imatinib, nilotinib more frequently causes rash, headache, liver function abnormalities, high cholesterol, hyperglycemia, lipase and electrolyte abnormalities.

Can elevate bilirubin and lipase.

Drug disposition and tolerability similar in pediatric patients as adults (Aplenic R et al).

Prolongs QT interval, and may be associated with sudden death.

Ischemic heart disease peripheral arterial occlusive disease and cerebral vascular events have reported in patients with newly diagnosed disease treated with Nilotinib,, as has pancreatitis hepatotoxicity, electrolyte abnormalities and tumor lysis syndrome along with fluid retention and pericardial and pleural effusions.

Should not be used in patients with hypokalemia or hypomanesemia or long QT syndrome.

Drugs that prolong the QT interval and strong CYP3A4 should be avoided.

Patients should avoid food two hours before a one hour after taking this medication.

Dose reductions should be recommended for patients with hepatic impairment.

Electrocardiograms should be obtained to monitor to QTc at baseline, seven days after initiation and periodically thereafter.

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