Novartis Answers About Gleevec
GIST Support International sometimes poses questions about imatinib (Gleevec) to Novartis, the manufacturer of the drug. This page is a collection of the Novartis replies. Rebeca Porto, MD has kindly agreed to forward our questions to novartis, so replies may be addessed to her.
Is it OK to Split my Dose of Gleevec?
One Health Plaza East Hanover, NJ 087939-1080
March 11, 2008
Dear Dr. Porto:
This letter is in response to your request for information regarding Gleevec® (imatinib mesylate). As long as the full daily dose is consumed, there are no problems anticipated in taking Gleevec 2-4 times a day. Anecdotally, taking a 400 mg or 600 mg daily dose on a BID basis seems to decrease GI distress. It is important, however, that patients remember to take all doses, and with a full glass of water and after food.
Thank you for your interest in Novartis Oncology.
Juana Ramos Allen Pinsky, MS, RPh Medicus Support Staff Senior Medical Information Specialist
Medical Information, Communication & Medical Information, Communication & Education Education
What Pain Medicines are OK to Take with Imatinib (Gleevec)?
response from Kavita Bhagat/PH/Novartis 08/22/2008 01:11 PM
Our drug interaction letter shows drugs known to be metabolized by CYP450 isoenzyme 2D6 (beta blockers - substrates), CYP450 isoenzyme 2C9 (NSAIDS - substrates), and CYP450 isoenzyme 3A 4/5 (benzodiazepines - substrates).
Gleevec is primarily metabolized to its active metabolite, an N-demethylated piperazine derivative, as well as to various inactive metabolites by the human P450 cytochrome isoenzyme CYP3A4. Cytochrome P450 enzymes, including CYP1A2, CYP2D6, CYP2C9 and CYP2C19 also play a minor role in the metabolism of Gleevec. In addition, in vitro human liver microsome studies demonstrate that Gleevec is a potent competitive inhibitor of the cytochrome P450 isoenzymes CYP3A4/5 and CYP2D6, as well as CYP2C9. Therefore, interactions with Gleevec are possible and caution is recommended when Gleevec is administered with drugs whose metabolism is dependent on or which alter levels of these isoenzymes.
Acetaminophen (Tylenol) is a CYP3A4 substrate and, in vitro, Gleevec was found to inhibit acetaminophen O-glucoronidation (Ki value of 58.5 µM) at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased when co-administered with Gleevec.
A case of death due to acute liver failure occurred in a patient treated with Gleevec who was also taking acetaminophen regularly for fever. This patient was participating in a Phase II clinical trial examining Gleevec in patients with Philadelphia positive (Ph+) chronic myelogenous leukemia (CML) in accelerated phase. Death occurred within 11 days of initiating Gleevec therapy.
Based on the limited data available patients should be warned to limit their use of over-the-counter and prescription medications which contain acetaminophen (Tylenol) and to avoid chronic use of acetaminophen while receiving Gleevec.
How Do Grapefruit and Orange Juice and Other Foods Affect Gleevec?
October 1, 2008
REBECA PORTO MD
6041 SW 88TH ST
MIAMI, FL 33156
Dear Dr. Porto:
This letter is in follow up to your recent telephone request for information regarding Gleevec(r) (imatinib mesylate).
Gleevec is primarily metabolized to its active metabolite, an N-demethylated piperazine derivative, as well as to various inactive metabolites by the human P450 cytochrome isoenzyme CYP3A4. This active metabolite demonstrates in vitro potency similar to the parent drug and has a plasma area under the curve (AUC) that is about 15% of the AUC for the parent drug. The elimination half-lives of the parent drug and this active metabolite following oral administration in healthy volunteers were approximately 18 and 40 hours, respectively.
Inhibitory Effect of Cytochrome P450 Isoenzymes by Gleevec
Cytochrome P450 enzymes, including CYP1A2, CYP2D6, CYP2C9 and CYP2C19 also play a minor role in the metabolism of Gleevec. In addition, in vitro human liver microsome studies demonstrate that Gleevec is a potent competitive inhibitor of the cytochrome P450 isoenzymes CYP3A4/5 and CYP2D6, as well as CYP2C9. Therefore, interactions with Gleevec are possible and caution is recommended when Gleevec is administered with drugs whose metabolism is dependent on or which alter levels of these isoenzymes.
Based on pharmacokinetic results from a drug-food interaction study conducted in 10 patients with chronic myeloid leukemia (CML), Gleevec may be given with or without food. In fact, it is recommended in the Gleevec prescribing information that Gleevec be administered with food and a large glass of water to minimize gastrointestinal (GI) irritation that may occur during treatment. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice.
Potential interactions; however, should always be considered when administering Gleevec with other substances (whether drug, herbal, food or beverage) that are known to be metabolized by the CYP450 isoenzymes 2C9, 2D6 and 3A4/5. In addition, patients who experience GI irritation or other unwanted GI effects (i.e., diarrhea, abdominal pain, dyspepsia, etc.) during Gleevec use may want to avoid certain foods and beverages (i.e., spicy foods, chocolate, caffeine, citrus juice, dairy products, etc.) that may exacerbate these unwanted effects.
Grapefruit Juice and other Citrus Juice
Although no formal studies with Gleevec and grapefruit juice have been conducted, the fact that grapefruit juice is a known inhibitor of the CYP450 isoenzyme 3A4, suggests that co-administration may lead to increased Gleevec plasma concentrations.
Likewise, although no formal studies were conducted, co-administration of Gleevec with another specific type of citrus juice called Seville orange juice (SOJ) may lead to increased Gleevec plasma concentrations via inhibition of the CYP3A isoenzymes. Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. Seville orange juice has been reported to be a possible inhibitor of CYP3A enzymes without affecting P-glycoprotein when taken concomitantly with cyclosporine.
No formal studies have been conducted to specifically assess a pharmacokinetic interaction between Gleevec and caffeine. However, a potential interaction may exist in that 8-hydroxylation of caffeine is catalyzed predominantly by the CYP450 isoenzyme 3A4, which is an isoenzyme that can be inhibited by Gleevec. Co-administration may therefore lead to increased plasma concentrations of caffeine.
Although no formal studies have been conducted to specifically assess a potential interaction between milk and Gleevec, it would seem highly unlikely that any significant interaction would exist.
Although no formal studies have been conducted to specifically assess a potential interaction between calcium supplementation and Gleevec, a potential interaction may exist by alteration of the absorption of Gleevec via changes in gastric pH levels.
According to the Description section of the Gleevec package insert:
"Gleevec is soluble in aqueous buffers = 5.5 but is very slightly soluble in neutral/alkaline aqueous buffers."
Consequently, by increasing the gastric pH, calcium supplements may delay the dissolution of Gleevec, resulting in delayed or decreased absorption. Since maximum concentration of Gleevec is achieved within 2 to 4 hours post-dose, it may be possible to minimize a potential interaction with Gleevec by administering calcium supplementation at least 4 hours after administering Gleevec. Similarly, since the duration of action of calcium supplementation can range from 20-40 minutes when taken on an empty stomach to up to 3 hours when taken after a meal, it may be possible to minimize a potential interaction with calcium supplementation by administering Gleevec at least 40 minutes after administering calcium supplementation in the fasting state and at least 3 hours after administering calcium supplementation in the fed state.
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Please contact us if you have additional questions. Full prescribing information on Novartis marketed products is available at www.pharma.us.novartis.com/product/pi.jsp
Limca Jhaveri, MSN
Manager, Medical Information
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