Before turning back to brain metastases, I wanted to cover a topic that has generated some recent questions, and that is the issue of potential interactions of tarceva with food and other drugs. Just as an introduction, the standard dose of single-agent tarceva in lung cancer is 150 mg by mouth daily, and this is meant to be taken on an empty stomach, at least one-hour before or two hours after eating. Taking tarceva with food can make the absorption of tarceva greater but is overall so variable that it’s very hard to know what kind of blood levels to expect, so the established target is 150 mg taken on an empty stomach. Tarceva is broken down by a collection of liver enzymes known as the CYP (pronounced “sip”) family, and particularly a liver enzyme known as CYP 3A4. These enzymes can also be found in the intestinal lining and can affect absorption of drugs like Tarceva. The CYP enzymes, and particularly CYP 3A4, can have their levels affected by other medicines and foods. Interestingly, tobacco smoking is another factor that can increase clearance of tarceva: in active smokers, tarceva clearance is about 25% faster, so the blood levels are lower. The potential that tarceva may need a different dose level for active (not likely former) smokers is a question that needs to be addressed further, and one I’ll have to cover in a separate post.
The medicines that inhibit CYP 3A4 can dramatically increase levels of tarceva. These are drugs like ketoconazole, an antifungal medicine, and other antifungal and antiviral drugs, including several used to treat HIV/AIDS. Grapefruit juice also inhibits CYP3A4. Any of these agents can decrease tarceva clearance by about 2/3, so reducing the dose of tarceva should be considered, particularly if a patient is experiencing significant tarceva-related side effects.
On the flipside, a bunch of other medicines can significantly increase CYP3A4 activity and reduce tarceva levels by about 2/3. These include an antibiotic called rifampin, multiple anti-epilepsy drugs (including dilantin, tegretol, and phenobarbital), and St. John’s Wort. One recommendation in the tarceva product information is to not take these other drugs if there is a possible alternative, but otherwise, it is recommended that a higher dose than 150 mg daily be considered. In fact, studies of patients with primary brain tumors, who often need to be on anti-convulsant drugs like dilantin, have demontrasted that higher doses of 300 mg or even up to 500 mg daily are safe (abstract here), and that the 500 mg daily dose in someone on a CYP 3A4 inducing-drug like dilantin is associated with tarceva blood levels similar to the 150 mg dose in someone who isn’t on one of these CYP 3A4 inducers (abstract here). While there isn’t an official recommendation to prescribe a higher dose, the FDA acknowledges that this is something that should be considered for patients on drugs that are known to increase tarceva clearance.
Another potentially important interaction can occur between tarceva and the oral blood-thinner coumadin, which many patients need to be on because of a history of blood clots or atrial fibrillation. There is a tendency for patients to run higher International Normalized Ratio (INR) results, in other words to have blood be too thinned, when tarceva is added, so it is recommended that patients on coumadin have their INR checked frequently, particularly in the first few weeks, when a new equilibrium is being established.
This certainly doesn’t cover every drug that can interact with tarceva, but those are the highlights. There’s more detail in the official document of tarceva product information.
posted by Dr. West @ 5:05 pm link to this post
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April 14th, 2007 at 7:01 pm
What is the minimum affective dosage of tarceva?
April 15th, 2007 at 7:07 am
I was very interested in reading that grapefruit and grapefruit juice should not been given when taking Tarceva. My husband has been on Tarceva 150mg., since the begining of March. He is now on his second month of it, and had a really bad rash on his face and neck. His doctor prescribed an antibiotic which really helped. He had Gemzar\Carboplatin for 3 cycles, which did not make things worse, but did not shrink. He then went on Atlima which did not help either. He has been having some really good days on the Tarceva, and will have another complete month before they do a CAT scan. He also has mets to the brain, and had radiation back in August. The radiation helped, but now the brain lesions have returned, and he underwent Cyberknife for the 2 biggest ones. We are hoping for some good results.
I was a bit concerned when I read about the grapefruit. He had been drinking so much sugar free grapefruit juice, since this is the only liquid besides soda, that didn’t taste bad. He is also on Decadron. I hope the drinking of the grapefruit juice will not harm the good effects from the Tarceva. He never took the pill with the juice, just drank it whenever he needed to. I am worried now, and have stopped the juice. What are the dangers of him drinking it? Will it make the Tarceva not work as well?
Thanks so much. I have been reading this website for awhile, just never posted before. It has helped me so much.
Best wishes Momi
April 15th, 2007 at 11:35 am
Grapefruit juice does not weaken drugs. It increases their potency by preventing them from being broken down by enzymes. This increases the half life of the drugs. With some statin drugs this can be very bad for one’s liver. I have no idea if Tarceva is bad for one’s liver in higher concentrations, which could be caused by grapefruit.
April 15th, 2007 at 3:19 pm
As Rodney clarifies, grapefruit juice can lead to a slowing of the metabolism of tarceva, so the risk is that it will lead to higher rather than lower blood levels than are targeted. Higher blood levels can certainly lead to greater toxicities, which can include liver test abnormalities. The official recommendation is to avoid grapefruit juice while on tarceva.
There is not a clear “minimum dosage” of tarceva. For people with an EGFR mutation, there is some lab-based evidence that these tumors can be sensitive to very loew doses of EGFR inhibitors, as low as 1/10 of the standard dose. But there still isn’t any recommendation to use a lower dose of Iressa or Tarceva in people with EGFR mutations. The standard dose is tarceva 150 mg by mouth daily, and iressa is off the US market now. It’s appropriate to lower the dose if needed to for side effect problems. It’s not really possible to declare a “minimum effective dosage” because it likely is different for different patients.
-Dr. West
April 16th, 2007 at 7:08 am
Thank you Rodney and Dr. West for your replies. When I had the prescription filled for the Tarceva, they never gave me any instructions on what interactions there were. Usually it is printed right on the label of the bottle, but there was none. I know for the Zocor he takes, it says not to drink grapefruit juice. I guess I should have read the inside, but I didn’t. We have a doctor appointment tomorrow, so I will mention it then. They do blood work on my husband, so I am sure if there was a problem with the liver, they would let us know. Thanks again for your quick replies. Momi
April 16th, 2007 at 7:47 am
Dr.West,
Thanks for being here! I just realized after reading the above, that I had forgotten entirely the advice to wait before and after eating when taking the Tarceva pill. So on some days I have mixed the food in with the pill. In the last three days I have an alarmingly trend to having to gasp for breath, even with my Oxygen supply at 4. Whenever I just take a drink of water, or urinate, or stand a bit, I seem to be unable to get enough air to breathe. Its become scary, because if it gets any worse, I don’t know how I’ll manage. (I live alone). I only have one lung. I am asking my Onc to refrain from the Tarceva for at least a few days, which we have already done three weeks ago. The Tarceva did show stabilizing in the short time (3 weeks) I’d been using it before the one week hiatus.
I also start WBR tomorrow, for two weeks.
Thanks for your care.
Bob
April 16th, 2007 at 10:21 am
Thank you for this very comprehensive article Dr West, I am going to discuss my Dads dosage with his Onc this week. As usual you have come up with the goods !!
Best wishes
Dawn