Paxil Linked To Deaths In Breast Cancer Patients
19 CommentsBy Ed Silverman // February 9th, 2010 // 8:37 am
Women taking Paxil at the same time as tamoxifen to stop breast cancer from recurring are more likely to die from the disease, according to a study in BMJ. The cancer med is prescribed for five years at a time to thousands of breast cancer survivors, many of whom also suffer from depression. But other antidepressants did not have the same effect.
The study looked at 2,430 women aged 66 and over who were being treated between 1993 and 2005. All were taking tamoxifen and one of five antidepressants, and over the next 2.4 years, 374 died from breast cancer. The data, as The Daily Mail notes, showed those taking Paxil were far more likely to die from breast cancer and slightly more likely to die from any other cause, compared with women not on the drug.
The results also found that if patients took GlaxoSmithKline’s Paxil for 25 per cent of the time they were on tamoxifen, they were 24 per cent more likely to die from breast cancer. When the antidepressant was taken for 50 per cent of the time, there was a 54 per cent increase in the chance of death, and when taken for 75 per cent of the time, patients were 91 per cent more likely to die.
The reason? Paxil interferes with an enzyme known as CYP2D6, which may reduce the clinical benefit of tamoxifen, particularly when the antidepressant is used for extended periods. “Our findings indicate that the choice of antidepressant can significantly affect survival in women receiving tamoxifen for breast cancer,” the researchers concluded.
Salmon
This is not surprising. There are many many cases where drug interactions either decrease a drug’s efficacy or increase toxicity or both, and it doesn’t even have to be an effect on the parent drug.
For example Schering-Plough now Merck misrepresented the effect of drug interactions on asenapine. Specifically in the advisory committee meeting they claimed there was no effect of cimetidine on asenapine levels which is correct however they failed to mention that figures and data in the review clearly show a more than doubling of the N-desmethyl-asenapine metabolite and a much smaller increase in the 11-hydroxy sulfates and increases in the N-oxide. Thus there are clear effects of cimetidine on drug metabolites and evidence for a greater risk of agranulocytosis due to interactions with cimetidien (an OTC drug) in fact there is clinical evidence for increased agranulocystosis with clozapine (whose use in restricted due to this) with cimetidine (presumably due to the same drug interaction).
Even worse the FDA simply went along with Schering and did not even present their own reviewer’s analysis (see page 664 of the FDA backgoround package) which clearly refuted SP’s position.
Technically almost every drug is marketed in violation of the law as the drug metabolism sections are clearly misleading and thus the drugs are misbranded. (There’s a lot of potential Qui Tams if any lawyer would be interested.) Even when the labeling is adequate they only discuss metabolism in general as not every individual interaction can be mentioned no physician understands this and so lethal drug interactions occur all the time.
There are of course other examples that I know of where companies and the FDA have hid that certain cancer drugs are metabolized differently by african americans so that not only are the drugs ineffective cancers but they are apparently much more likely to die from simply horrific drug reactions. The FDA has failed to mention anything in labeling even though there are other drugs that don’t have these problems because doing so would decrease sales for the companies by billions of dollars.
Salmon
gpawelski
The recent AHRQ report found there was “no consistent associations” between breast cancer patients with the relevant CYP2D6 polymorphism and the outcome of tamoxifen therapy, whether as primary treatment or in as post-operative adjuvant therapy.
Estimates vary, but anywhere from 10 to 40 percent of women have the gene variant of CYP2D6 that is believed to slow the metabolism of tamoxifen and make it less effective.
A number of companies sell a $300 test that can show if women have the allegedly telltale CYP2D6 polymorphism.
There are some challenges in the development and practical use of pharmacogenomics. Many doctors now do not widely practice pharmacogenomics when treating patients since the field is still new.
Paul
Ed,
I liked this site a lot more when there was balanced discussion. It was much more interesting to hear all sides as opposed to right now when it is only one side bashing and piling up on the other - mostly silent - side
As they say, there are three sides to every story and unless the second side gets heard without getting personally and brutally attacked, then the third side will never see the light of day.
As a master Editor that you are, perhaps you can find ways of fostering a balanced debate.
p.s. I am not on either extreme or married to either side, just want informed and intelligent discussion
Salmon
I was not familiar with any specific tamoxifen data and was commenting on the principle in general. Having worked with these tests I can say that genotype does not necessarily correlate with phenotype and that drug inhibition by other drugs are much more reliable. On the other hand many more people will have poor metabolism due to genetics than due to drug interactions. However I question figure of 40% with a specific mutation. As I recall 3% - 7% of caucasians are CYP2D6 poor metabolizers. So if it is 40% then it may be a silent mutation with no effect. Also any drug-drug interaction may not be due to CYP2D6 inhibition but other pathways or mechanisms.
Even so the information I quote on other drugs, and the situation with the cancer drug, I have gone over and am as certain as the available information allows and I stand by my opinions on them. So if anyone has any concerns about what I say about a specific drug let them argue with data as gpawleski did.
harpy
how are drug interactions determined? Obviously they don’t test a new drug with every other known drug, so how do they figure out which ones aren’t going to work well together?
anyone? I don’t need a book, just curious as to the process of determining safety before a drug is released.
Salmon
Good question Harpy. I will tell you how it should be done. First some drug interactions are predictable due to synergistic or antagonistic pharmacologic effects, such as stimulants and other drugs that raise or lower blood pressure. However the majority of drug interactions are due interference with how the drugs or metabolites are eliminated or transported in the body. For the parent drug you can test what enzymes and transporters they effect in vitro (i.e. in the test tube) and how potent they are. By looking at potency and the concentrations in the body you can make predictions and then do human studies with selected drugs. However it’s not only the parent drug that’s causing the interaction they’re also due to metabolites. So the first thing you need to know is how is the drug eliminated (metabolized and excreted) as well as how it’s transported within the body. To do this a mass balance study is done.
First the drug is radiolabeled and a single dose is given to several people (typically 3 - 4 young men which is clearly not enough to even minimally get an ideal of the variability but that’s another issue). Blood samples as well as urine and feces are then collected until all the radioactivity is recovered. You need at least 85-90% recovery. Pfizer has published a review of several hundred drugs that shows that 95% recovery typically obtainable. Nasty metabolites will bind to or otherwise be retained in tissues and this was one of the issues that caused the hold up in the approval of thalidomide. Sometimes you can predict these nasty metabolites from the chemical structure and what we know about how certain structures are metabolized. In these cases companies will sometimes only collect urine and feces for a couple of days so they don’t see very much of the toxic metabolites which may trickle out of the body for a week or two. Low recoveries and short sampling periods are tip offs to companies trying to hide things. (There are other ways to rig the studies but I won’t go into them here.) Once you know the metabolites, the enzymes and transporters that transport them, the potency of the metabolites against these enzymes and transporters, the pharmacologic activity of these metabolites, and the concentrations of the metabolites in the body you can then design human studies with other drugs to look at the likely interactions. Even so a company can then selectively look or not look at effects on metabolites and can selectively study the pharmacologic receptor binding of the metabolites. This is how they avoid really finding basic pharmacologic data that would point to the clinically important stuff.
For example take a look at http://pharmaheretic.wordpress.com/2010/01/07/finicky-sar-01/ which was just recently highlighted in a recent post. If you look at three ring structure there is one side ring with a cloride attached (or methyl i.e. CH3 in the case of olanzapine). These are place there to prevent metabolism of the that ring that means that the benzene (6 sided ring on the other side of molecule) will be metabolized and an OH group will be added. From experience we also know that since these compounds effect serotonin receptors that they likely enzymes that will cause this reaction will be CYPs 3A4/5 and 1A2. We also know from phen-fen that hydroxylated serotoninergic compound have the risk of causing pulmonary arterial hypertension especially when combined with SSRIs. If you look at the Summary Basis of Approval for Zyprexa (avialable at Drugs@FDA.gov) you find that Lilly only mentions the 7-OH metabolite (which you expect to be quantitatively the most important metabolite of all ) in passing and doesn’t even include it in their diagram of how olanzapine is metabolized. Also they only report the olanzapine and the metabolites that make up 35% of the radioactivity circulating in the blood. So it’s pretty clear that they’re hiding what’s going on with the other 65% of that’s in the blood and also hiding the 7-OH and what it might do pharmacologically. (remember as I said
Looking at http://pharmaheretic.wordpress.com/2010/01/07/finicky-sar-01/ again you see a piperazine group (a 6 sided ring with 2 nitrogens (N) opposite each other and side groups attached to one of the N’s. This side group is likely to be metabolized and also inhibit CYP2D6 which is genetically polymorphic. Also piperazines tend to cause agranulocytosis. So for a low potency compound like clozapine where you have lots more piperazine around you’re more likely to get agranulocytosis even though it’s been reported with many of these psych drugs.
Because of what we know we can select other drugs for drug interaction studies to then rev up or block the important enzymes/pathways and see if it’s important or not. Then by knowing what other drugs effect these pathways in general you can decide what to do clinically. Even so I know obstetricians who don’t even know what CYP3A4 is even though it metabolizes 70% of all drugs, and this isn’t uncommon. So many physicians in essence would have no idea how to interpret labeling although pharmacists tend to have a much better idea. So even if the data were included in the labeling which it often isn’t many physicians would have no idea how to interpret it and I would bet that these topics are not high on drug company paid for CE.
MOST DRUGS WITHDRAWN FROM THE MARKET are due to toxicities due to metabolites and drug interactions so this information is critical. If you see good information provided in submissions you know the drug is likely clean. If information is missing, the drug metabolism studies are designed so as not to collect standard data, and the writing in the reports is so convoluted that it takes weeks or months to decipher it’s a red flag that there’s major problems with a drug. Things also don’t show up in development because clinical studies are intentionally designed to avoid drug interactions or picking up expected problems.
gpawelski
Drug interactions are a major concern for the patient population in general but are often overlooked in cancer patients. The disease is so serious that most doctors overlook the interactions in order to aggressively treat the disease. This attitude makes any cancer patient an unwitting guinea pig to their oncologist and often results in treatment that is worse than the disease.
Scientists are aware of polymorphisms in the pharmacokinetics of drugs due to variations in the expression of the enzymes responsible for the absorption, distribution, metabolism, and excretion of drugs and their metabolites.
It’s great that they’ve identified some genes that seem to be associated with drug resistance, or even sensitivity to cancers. The problems though, include (but are not necessarily limited to):
1. If you find one or more implicated genes in a patien’t tumor cells, how do you know if they are functional - i.e. is the encoded protein actually produced?
2.) If the protien is produced, is it functional?
3. If the protein is functional, how is it interacting with other functional proteins in the cell. All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions.
4.) Are you sure that you’ve identified every single gene that might influence sensitivity or resistance to a certain class of drug?
5.) Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between suscepitbiliy of the cell to different drugs in the same class.
6.) Nor can you tell anything about susceptibility to drug combinations.
7.) And what about external facts such as drug uptake into the cell?
8.) Gene profiling tests for individual patients are performed on dead, preserved cells that are never actually exposed to the chemotherapy drugs whose activity you’re trying assess.
Assessing gene expression is important in order to identify new therapeutic targets and thereby to develop useful new drugs.
However, it is still years away from working successfully in predicting treatment response for individual patients and it will never, for very practical reasons be as effective as functional cell-based profiling, which exists and is not hampered by the problems associated with gene expression tests.
Functonal profiling measures the net effect of all processes within the cancer acting with and against each other in real time - and it tests living cells actually exposed to drugs and drug combinations of interest.
blackhat seo tactics
well side effects of mixzing any drugs cant be fully disclosed. paxil surely helped many people, but it may interact with others in unknown ways
ex-FDA
I agree with everything in the last two posts however there are things we can predict or at least consider are possibilities with high or low risk probability.
“Drug interactions are a major concern for the patient population in general but are often overlooked in cancer patients. The disease is so serious that most doctors overlook the interactions in order to aggressively treat the disease. This attitude makes any cancer patient an unwitting guinea pig to their oncologist and often results in treatment that is worse than the disease.” - gpawelski
True but it doesn’t give the true flavor of what this means. I’ve seen this in real life where the drugs and treatment were worse than dying from the cancer. Young children begging, pleading, and screaming for their physicans to stop. Being so traumatized that they stop eating and become skeletal, curl up into a fetal position, become mute, and simply suck their thumbs until they die. Others their skin falling off, , grade IV mucositis sloughing the mucus membranes from their mouth to their anus, throwing clots to the brain and liver, lungs filling up with fluid and drowning, and taking weeks to die while shunted to a backroom so it won’t be seen and show other parents the true risks. All the while refusing to give true informed consent to parents even to the point of intentionally misleading them.
In drug development there’s a difference between looking into things and still not knowing for sure but moving ahead prudently, and simply plowing ahead disregarding all science and thought.
Lisa Van Syckel
exFDA, I have a question, is Dilaudid a morphine derivative, and can this drug cause psychosis, suicidal ideation in cancer patients?
ex-FDA
causing suicidal ideation - I have no idea.
john
The Paxil prescribing information (package insert) clearly states that it is a CYP2D6 inhibitor, and can be expected to interact with drugs metabolized by that pathway.
Evidence that Tamoxifen is a prodrug that requires activation by CYP2D6 did not begin to really solidify until the last 12 months or so.
There is an old adage about not attributing to evil anything that can be explained by stupidity. To which I would add that one should be careful about attributing decisions to stupidity unless you have all information that was used to make the decision.
Salmon
John,
I believe this is consistent with my original statement that an interaction would not suprise me. Considering when tamoxifen was developed with it being first marketed in the early 1980’s the sort of studies I indicate should normally be done in drug development would not have been applicable at that time. ~10 years or so later yes.
As for all information that was used to make the decision for the example I gave, I have to rely on the FDA reviews which indicates that the company apparently designed their studies to hide the relevant information.
John
Salmon, I’d appreciate the link, as I appreciate those already provided in your comments. I was not able to find the original file for olanzapine at the link you provided, only those for the generic applications. If you could post the original I will appreciate it. If not, could you let me know whether “Indicates that the company apparently designed their studies to hide the relevant information” was your conclusion or the FDAs?
My comments were directed to the board as a whole, but also to:
“Technically almost every drug is marketed in violation of the law as the drug metabolism sections are clearly misleading and thus the drugs are misbranded.”
“There are of course other examples that I know of where companies and the FDA have hid that certain cancer drugs are metabolized differently by african americans so that not only are the drugs ineffective cancers but they are apparently much more likely to die from simply horrific drug reactions. The FDA has failed to mention anything in labeling even though there are other drugs that don’t have these problems because doing so would decrease sales for the companies by billions of dollars”
As a scientist I am sure you will appreciate the old adage that “extraordinary claims require extraordinary proof”.
As a practicing medicinal chemist for 17 years, I disagree with your conclusion that theoretically expected but not reported metablites are evidence of a conspiracy. In preclinical research, I spent many years looking at this type of data, and metabolite prediction is much less of a science than I felt was implied in your post.
Condor
John — take a look at these documents.
That, I think, is what Salmon is referring to.
Pages 916 - 918 especially at bottom of 918
Summary of Patients who died. Causes and preponderance with asenapine compared to olanzapine. . . .
It appears in the middle of about 1,000 pages of background material submitted by FDA at the time of the Advisory Committe’s approval vote on asenapine, last year.
Nmaste
harpy
Salmon - many thanks for taking the time to answer my question! Although my chemistry was long, long ago, I was able to follow most of it, or at least get an idea of what’s involved. Cheers!
harpy
oh, and Paul? We like this site a lot more when people throw their opinions and contributions into the ring in as civil a manner as possible and not try to drag Ed into it. We’re all adults here and if you don’t like what someone is saying then speak up! I don’t think any one of us is too keen on censorship.
Salmon
The SBA for olanzapine can be found at drugs@FDA.gov. Here is a more specific link. You still need to look at the reviews for the original approval.
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist
“Indicates that the company apparently designed their studies to hide the relevant information” was your conclusion or the FDAs?
This is the FDA’s conclusion and comes directly from the asenapine review. Take a look at pages 897 and 986 from the PDAC briefing document that Condor sites.
“As a scientist I am sure you will appreciate the old adage that “extraordinary claims require extraordinary proof”.”
Agreed. However I am not prepared to go into the basis for my beliefs at this time or in this forum.
A”s a practicing medicinal chemist for 17 years, I disagree with your conclusion that theoretically expected but not reported metablites are evidence of a conspiracy. In preclinical research, I spent many years looking at this type of data, and metabolite prediction is much less of a science than I felt was implied in your post.”
I never claimed conspiracy and I agree that drug metabolite prediction is an inexact art and if I gave the impression that in general it was easy then forgive me. As you know I was talking about a specific group of compounds. When we have many years of experience with similar type molecules with similar pathways and the enzymes involved such as with the azepine antipsychotics then I believe we can have a fairly high confidence in being able to predict a couple of the primary pathways and the likely enzymes involved.
Salmon
Amy Philo
This is no surprise, I remember when a study showed that there was a 7-fold increased risk of breast cancer in people taking antidepressants. Also remember that study about how SSRIs interfere with tamoxifen. Psych drugs are generally cancer-causing.