The multiple drug interactions of the new oncologic drug avapritinib/Ayvakit® are described rather briefly in a few lines in the prescriber information (1). Practically that means, however, that the prescribing doctor in the U.S. has roughly to take care of some 40 drug drug interactions due to the fact that avapritinib is substrate of cytochrome P450 CYP3A4 and any simultaneous use of CYP3A4 inhibitors or inducers should be avoided.
The prescribing doctor in Europe learns from the European prescriber information (2) that she or he has to take care also of the risk that the QT interval may be prolonged through avapritinib and therefore caution is indicated with patients having Long-QT-Syndrome or are on concomitant therapy with QT interval prolonging drugs; prolonged QT intervals may increase the danger of ventricular arrhythmia including Torsade de pointes with fatal outcome. Clinical data of 585 patients has shown that QT prolongation may occur in 2% of the cases with 0,2% of severe grade >= 3. This adverse QT effect of avapritinib is the reason that the number of drug interactions to have in mind substantially increases now to more than 350! The drug interaction risk is in particular high if a drug has both properties such as clarithromycin which is a strong CYP3A4 inhibitor and known for causing QT prolongation and TdP.
The prescribing doctor in Europe learns from the European prescriber information (2) that she or he has to take care also of the risk that the QT interval may be prolonged through avapritinib and therefore caution is indicated with patients having Long-QT-Syndrome or are on concomitant therapy with QT interval prolonging drugs; prolonged QT intervals may increase the danger of ventricular arrhythmia including Torsade de pointes with fatal outcome. Clinical data of 585 patients has shown that QT prolongation may occur in 2% of the cases with 0,2% of severe grade >= 3. This adverse QT effect of avapritinib is the reason that the number of drug interactions to have in mind substantially increases now to more than 350! The drug interaction risk is in particular high if a drug has both properties such as clarithromycin which is a strong CYP3A4 inhibitor and known for causing QT prolongation and TdP.
SCHOLZ DataBank is an international database and therefore permanently screening what major international health authorities believe to be important and what doctors should know when prescribing drugs. Our experience is that in general the U.S. Prescriber information provides more details and background information to the reader than the european equivalents; however, sometimes important aspects seem to be omitted for whatever the reason is. Relying on both, the FDA in the U.S. and the EMA in Europe, may diminish the risk of being surprised by unpublished side effects or drug interactions and increase drug safety when prescribing. SCHOLZ DataBank user benefit from this permanent international research effort; with more than 350 avapritinib drug interactions in their database they are alerted no matter if a comedication of avapritinib is involved in the CYP3A4 or the QT problem.
November 5, 2020
Wolfgang Scholz, Founder
Literature:
1) Ayvakit Prescriber Information 2020, Reference ID: 4544122
2) https://www.ema.europa.eu/en/documents/product-information/ayvakyt-epar-product-information_de.pdf
1) Ayvakit Prescriber Information 2020, Reference ID: 4544122
2) https://www.ema.europa.eu/en/documents/product-information/ayvakyt-epar-product-information_de.pdf