All About Gleevec (Glivec)
General Information |
Response Rate & Related Exon Mutations
Dosage |
Side Effects |
Drug Interactions
Drug Interactions
Other drugs affect Gleevec |
Gleevec affects other drugs
Long list of inhibitors and inducers |
Drug Interaction Glossary | Article about Gleevec Drug Interactions
Drug Interaction Glossary
NOTE: We have some specific information about some drugs on the "Drug Interactions" lists. When we have specific or detailed information about a drug interaction, it will appear on this page. Note that for the great majority of drugs we do not have any specific information beyond what is in the lists.
Acetaminophen
(Tylenol)-
There has been some controversy
regarding the safety of acetaminophen in
patients treated with Gleevec. A CML
patient in accelerated phase taking
Gleevec together with high-doses of
acetaminophen to treat fever died of
hepatic (liver) failure. Whether this
death was causally related to the
combination of Gleevec and acetaminophen
is not known. However, many other
patients have taken these two drugs in
combination safety. Nevertheless,
caution is recommended, and patients
should be advised to use acetaminophen
in moderation.2
In July of 2007, GIST experts made a specific recommendation in the NCCN Task FOrce Report on GIST manangement.4 There comments were:
"Imatinib can cause LFT abnormalities. Liver failure and death occurred
in one patient taking large doses of both acetaminophen
and imatinib. The use of acetaminophen should be limited in patients
taking imatinib. For most patients, this means taking 1300
mg acetaminophen per day or less. Acetaminophen levels increase
when it is coadministered with imatinib, because imatinib
inhibits acetaminophen glucuronidation."
The CML patient that died from liver
failure was taking 3-3.5 grams/day of
acetaminophen for one month prior to
entry into the (Gleevec) trial. This was
for fever and the patient also took
fluconazole. The patient took Gleevec
for 7 days at a dose of 600 mg/day. At
study entry, liver transaminases and
alkaline phosphatase were mildly
elevated. Right upper quadrant pain led
to detection of severely elevated liver
function tests on day 7. Gleevec was
discontinued, but the patient died of
hepatic (liver) failure on day 12.3
Patients should be aware that over 300
medications contain acetaminophen.
Caution should be used so that these
medications are not accidentally
combined as this could result in an
overdose.
American Liver Foundation-Position
Statement on Acetaminophen Use and Liver
Injury
Ketoconazole-
A CYP3A4 inhibitor
There was a significant increase in
exposure to Gleevec (mean Cmax and AUC
increased by 26% and 40%, respectively)
in healthy subjects when Gleevec was
co-administered with a single dose of
ketoconazole (a CYP3A4 inhibitor).1
Rifampin- A
CYP3A4 inducer
Pretreatment of 14 healthy volunteers
with multiple doses of rifampin, 600 mg
daily for 8 days, followed by a single
400 mg dose of Gleevec, increased
Gleevec oral-dose clearance by 3.8 fold
(90% confidence interval + 3.5- to
4.3-fold), which represents mean
decreases in Cmax,
AUC(0-24) and AUC(0-¥) by 54%, 68% and 74%, of the
respective values without rifampin
treatment.1
Simvastatin
Gleevec increased the mean Cmax
and AUC of simvastatin (CYP3A4
substrate) by 2- and 3.5-fold,
respectively, indicating an inhibition
of CYP3A4 by Gleevec.1
Warfarin-
A substrate of CYP2D6 and CYP2C9
One patient receiving warfarin and
imatinib suffered a major CNS
hemorrhage. Because the warfarin dose
was increased before the event, the
causality remains uncertain. In other
patients, a reduction, rather than
prolongation, or prothrombin time was
observed. The best approach is to
substitute low-molecular weight or
standard heparin for warfarin.
Alternatively, patients treated with
imatinib and warfarin need close
monitoring of the IN with adjustment of
the warfarin dose as necessary.2
Inducer (for example, of cytochrome P450): a drug (or other chemical) which causes an increase in the expression of an enzyme (P450) which metabolizes another drug.
Inhibitor: a compound (e.g. drug) which blocks the activity of an enzyme; e.g., Gleevec works by inhibiting KIT. Inhibitors of P450 enzymes can cause a decrease in expression of the affected enzyme, which can cause an increased concentration of other drugs that are metabolized by the affected enzyme.
References
1.
Gleevec prescribing information,
USA, T2005-18
2.
Practical Management of Patients
With Chronic Myeloid Leukemia Receiving
Imatinib
By Michael W. N. Deininger, Stephen G.
O’Brien, John M. Ford, and Brian J.
Druker
J Clin Oncol 21. © 2003 by American
Society of Clinical Oncology.
3.
Medical review for Gleevec submitted to
the FDA, 5/8/2001. NDA 21-335
4 .NCCN Task Force Report: Optimal Management of Patients with Gastrointestinal Stromal Tumor (GIST)—Update of the NCCN Clinical Practice Guidelines (July, 2007)
George D. Demetri, MD; Robert S. Benjamin, MD; Charles D. Blanke, MD; Jean-Yves Blay, MD, PhD; Paolo Casali, MD; Haesun Choi, MD; Christopher L. Corless, MD, PhD; Maria Debiec-Rychter, MD, PhD; Ronald P. DeMatteo, MD; David S. Ettinger, MD; George A. Fisher, MD, PhD; Christopher D.M. Fletcher, MD, FRCPath; Alessandro Gronchi, MD; Peter Hohenberger, MD, PhD; Miranda Hughes, PhD; Heikki Joensuu, MD; Ian Judson, MD, FRCP; Axel Le Cesne, MD; Robert G. Maki, MD, PhD; Michael Morse, MD; Alberto S. Pappo, MD; Peter W.T. Pisters, MD; Chandrajit P. Raut, MD, MSc; Peter Reichardt, MD, PhD; Douglas S. Tyler, MD; Annick D. Van den Abbeele, MD; Margaret von Mehren, MD; Jeffrey D. Wayne, MD; and John Zalcberg, MBBS, PhD
