Tasigna carries the FDA's "Black Box Warning" because approximately 0.5% of patients in their Phase I/II clinical trials displayed a significant lengthening of QTc. The consequences of an extremely lengthened QT interval are such that it can produce sudden death without any warning symptoms noticeable to the patient. Low potassium or magnesium levels in the blood increase this risk.
When the QT interval gets long enough (around 500+ msec) for one phase of the heart beat to "step on the toes" of the next phase, the heart rhythm goes into an uncoordinated fibrillation. This loss of normal pumping rhythm means that there is no blood being pumped - and the patient loses consciousness immediately. Death from brain anoxia follows if normal breathing and heart rhythm are not restored within a few minutes. Normal CPR is not effective in restoring function to a patient in fibrillation. An Automatic External Defibrillator (AED) may be effective, but even that is far from any guarantee of successful conversion.
The clinical evidence is -
(Test group of 200 patients) Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec. Earlier testing had somewhat worse statistics -
There were five sudden deaths reported in patients receiving nilotinib in an on-going study (n=867; 0.6%). A similar incidence was also reported in the expanded access program. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
In a placebo-controlled study in healthy volunteers designed to assess the effects of Tasigna on the QT interval, administration of Tasigna was associated with concentration-dependent QT prolongation; the maximum mean placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec). A positive control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study were 26% lower than those observed in patients enrolled in the singlearm study.
Taking Tasigna on an empty stomach is therefore important in that there is evidence that QTc is dependent to some degree on plasma concentration of the drug.
The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal. Bioavailability of Tasigna is affected by many things. The variability between individual patients in tests showed systemic exposure variance from 32-64%. Tasigna absorption is favored by low pH in the stomach. Taking proton-pump inhibitors for "reflux" control raises the stomach's pH and may reduce Tasigna absorption as much as 34%. Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. The converse also applies - Tasigna can greatly affect the plasma concentrations of other drugs. (see interactions list by link below). Best thing to do with Tasigna or any other drug is to follow the dosage recommendations and discuss any desire to deviate from them with your doctor. CML Society of Canada's website has a really good summary of drug and food interactions that concern those of us taking TKI drugs.
http://www.cmlsociet...August 2010.pdf
Doug
