Caution: This page is intended as an aid to understanding drug interactions and is a quick reference to some of the major drug interactions with Gleevec.

For a more complete, interactive source of information, we recommend one of the online drug interaction checkers such as epocrates.com (registration required) or drugs.com. At epocrates.com you can download a free drug interaction app to your iPhone, Android, Blackberry or Palm device. In addition, patients should talk to their doctors and/or pharmacists about potential drug interactions.

Tylenol (acetaminophen): In the NCCN guidelines, GIST experts state, “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 co-administered with imatinib, because imatinib inhibits acetaminophen glucuronidation.”

Other drugs affect Gleevec drug concentrations

In addition to the intended affects, many drugs have an effect on how quickly other drugs are metabolized by the liver. This is one type of drug interaction, but not the only type.

Gleevec is metabolized (broken down) by the liver. The enzyme most responsible for this is called CYP3A4 (one part of the “cytochrome P450” family of liver enzymes). The next most important enzyme for metabolizing Gleevec is CYP2D6.

Drugs that inhibit the activity/production of these two enzymes (but especially CYP3A4) slow down the metabolism of Gleevec. This results in a higher concentration of Gleevec in the blood. This could result in more side effects from Gleevec; similar to taking a higher dose of Gleevec. This would be more of a concern for patients already taking a high dose of Gleevec especially if they were already having significant Gleevec side effects.

For patients on a lower dose of Gleevec, having few or no side effects, taking a drug that might “inhibit” CYP3A4 or CYP2D6 would probably have less effects and perhaps not even be noticed.

Drugs that may alter Gleevec, Sutent and Stivarga plasma concentrations

Note: Sutent, Stivarga and most other TKI’s are also metabolized by CYP3A4 and are affected by drugs that induce or inhibit CYP3A4. (This is a “short list”)

 

Drugs that may reduce Gleevec penetration into tumor cells

Major
Inducers of CYP3A4
Major
Inhibitors of CYP3A4
Major
Inhibitors of OCT-1
Reduce Gleevec levels

Note: Evidence suggests a minimum Gleevec blood level of 1100 ng/mL may be beneficial

Increase Gleevec levels Reduce Gleevec levels inside tumor cells

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  • May result in sub-therapeutic levels of Gleevec
  • May result in above normal levels of Gleevec
  • May result in less Gleevec inside tumor cells
  • May be more of a concern for lower doses of Gleevec
  • May be more of a concern for higher doses of Gleevec
  • Will not be detected as a problem with Gleevec blood level monitoring
  • OCT-1 inhibitors
  • St. John’s Wort
  • Antiepileptic drugs

Phenytoin (Marketed as Dilantin, Phenytek, Eptoin, Epanutin)

Carbamazepine (Marketed as Tegretol and other names)

Oxcarbazepine (Marketed as Trileptal and Trexapin)

  • Rifampin
    Phenobarbital
  • Ketoconazole
  • Itraconazole
  • Erythromycin
  • Clarithromycin
  • Grapefruit juice
  • Prazosin (Marketed as Minipress, Vasoflex, and Hypovase)
  • Procainamide (Marketed as Pronestyl, Procan, and Procanbid)
  • Progesterone
  • Ibuprofen

People also metabolize drugs at different rates. Given the vast amount of differences that can occur, it is critical to clinically monitor patients and adjust dosages of medicines as needed. This is a job for your doctor, but patients also need to keep their doctor informed of side effects. How you feel may be just as important as whether the drug you are taking appears on the CYP3A4 or CYP2D6 INHIBITOR lists.

A different situation exists when taking a drug that could INDUCE CYP3A4 or CYP2D6. In this case, the drug might cause Gleevec to be metabolized faster, possibility resulting in AN INEFFECTIVE AMOUNT OF GLEEVEC IN THE BLOOD. In the worst-case scenario, you could stop responding to Gleevec.

The danger of this type of interaction is probably higher for patients taking a lower dose of Gleevec since they are closer to the minimum therapeutic levels of Gleevec. In that case, taking a drug that increases Gleevec metabolism might result in Gleevec levels being below the minimum needed to keep GIST (or CML) under control. Patients on higher doses of Gleevec are not immune to this problem either, as at least one drug, phenytoin, reduced plasma levels of Gleevec by 75% in a CML patient.

Your body will be more likely to give you some indication of a problem with the drugs on the inhibitor list, due to an increase in side effects (which reinforces the need to keep your doctor informed of your side effects). Drugs that induce CYP3A4 or CYP2D6 may be less likely to produce side effects, since they tend to lower the concentration of Gleevec in the blood.

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. Another CML patient taking 400 mg of Gleevec and 500-1000 mg of acetaminophen per day also died of liver failure. Liver failure and death has also occurred in some patients taking Gleevec but not taking acetaminophen.

Thus, the contribution of acetaminophen to liver toxicity is not always absolutely clear. Many patients have taken these two drugs in combination safely. Nevertheless, caution is recommended and patients should be advised to use acetaminophen in moderation.

In July of 2007, GIST experts made a specific recommendation in the NCCN Task Force Report on GIST management.4  Their 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 co-administered with imatinib, because imatinib inhibits acetaminophen glucuronidation.”

The first 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.  <- I would put this piece of information at the very beginning of acetaminopjen. Not too many people are going to read through all the quotes/examples to get to this significant statement.

Carbamazepine – A CYP3A4 inducer – Blood samples were taken from 224 brain cancer patients receiving Gleevec (imatinib). Mean trough levels of imatinib were decreased up to 2.9 fold in patients taking imatinib and CYP3A4 enzyme-inducing anti-epileptic drugs (EIAEDs), like carbamzaepine, phenytoin and oxcarbazepine. Mean trough levels of imatinib were reduced from 1400 ng/ml in patients not taking EIAEDs to 477 ng/ml in patients taking EIAEDs (preliminary data (January 2008) suggest a minimum trough level of 1100 ng/ml should be maintained)5

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).

Oxcarbazepine – A CYP3A4 inducer – Blood samples were taken from 224 brain cancer patients receiving Gleevec (imatinib). Mean trough levels of imatinib were decreased up to 2.9 fold in patients taking imatinib and CYP3A4 enzyme-inducing anti-epileptic drugs (EIAEDs), like carbamzaepine, phenytoin and oxcarbazepine. Mean trough levels of imatinib were reduced from 1400 ng/ml in patients not taking EIAEDs to 477 ng/ml in patients taking EIAEDs (preliminary data (January 2008) suggest a minimum trough level of 1100 ng/ml should be maintained)5

Phenytoin – A CYP3A4 inducer – Blood samples were taken from 224 brain cancer patients receiving Gleevec (imatinib). Mean trough levels of imatinib were decreased up to 2.9 fold in patients taking imatinib and CYP3A4 enzyme-inducing anti-epileptic drugs (EIAEDs), like carbamzaepine, phenytoin and oxcarbazepine. Mean trough levels of imatinib were reduced from 1400 ng/ml in patients not taking EIAEDs to 477 ng/ml in patients taking EIAEDs (preliminary data (January 2008) suggest a minimum trough level of 1100 ng/ml should be maintained)5

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.
  1. Practical Management of Patients With Chronic Myeloid Leukemia Receiving Imatinib, 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.
  1. Medical review for Gleevec submitted to the FDA, 5/8/2001. NDA 21-335, 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.
  1. Influence of enzyme-inducing anti-epileptic drugs on trough level of imatinib in glioblastoma patients. Carl Gustav Carus University, Internal Medicine I, Division of Hematology and Oncology, Dresden, Germany.

Core Values