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Celebrex is a new medication for the treatment of the inflammation and pain of the two most common forms of arthritis, rheumatoid arthritis and osteoarthritis. Celebrex is classified as a nonsteroidal anti-inflammatory drug (NSAID), however, it is unique in its biologic action compared to previously available drugs of this class.
This article will describe the action of nonsteroidal anti-inflammatory drugs and some of the unique properties of Celebrex. It will then conclude with an in-depth interview of the chief scientist involved in the development and testing of Celebrex.
What are NSAIDs?
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed medications for the inflammation of arthritis and other body tissues, such as in tendonitis and bursitis. Examples of NSAIDs include Aspirin, indomethacin (Indocin), ibuprofen (Motrin), naproxen (Naprosyn), piroxicam (Feldene), and nabumetone (Relafen). The major side effects of NSAIDs are related to the gastrointestinal system. Some 10%-50% of patients are unable to tolerate NSAID treatment because of side effects, including abdominal pain, diarrhea, bloating, heartburn, and upset stomach (dyspepsia). Approximately 15% of patients on long- term NSAID treatment develop ulceration of the stomach and duodenum. Even though many of these patients with ulcers do not have symptoms and are unaware of their ulcers, they are at risk of developing serious ulcer complications such as bleeding or perforation of the stomach.
NSAIDs are taken regularly by approximately 33 million Americans!
The annual risk of serious complications is 1%-4% with chronic NSAID treatment. The risk of complications is higher in elderly patients, rheumatoid arthritis sufferers, patients taking blood thinning medications (anticoagulants such as Coumadin and heparin) or prednisone (cortisone medication), and patients with heart disease or a prior history of bleeding ulcers.
How do NSAIDs cause stomach ulcers and bleeding?
Prostaglandins are natural chemicals which are involved in body inflammation. By inhibiting the body's production of certain chemical messengers (prostaglandins), NSAIDs decrease inflammation. However, certain prostaglandins are also important in protecting the stomach lining from the corrosive effects of stomach acid as well as maintaining the natural, healthy condition of the stomach lining. By disrupting the production of prostaglandins in the stomach, NSAIDs can cause ulcers and bleeding.
What is the basic difference between traditional
NSAIDs and the newly designed COX-2 inhibitors?
Cyclooxygenase-1 (COX-1) is an enzyme which is normally present in a variety of areas of the body, including sites of inflammation and the stomach. The COX-1 enzyme of the stomach produces certain chemical messengers (called prostaglandins) that ensure the natural mucus lining which protects the inner stomach. Common anti-inflammatory drugs like Aspirin block the function of the COX-1 enzyme along with another enzyme, COX-2 (see below). When the COX-1 enzyme is blocked, inflammation is reduced, but the protective mucus lining of the stomach is also reduced, which can cause stomach upset, ulceration, and bleeding from the stomach and intestines.
Another enzyme, cyclooxygenase-2 (COX-2), also produces these chemical messenger molecules, but the COX-2 enzyme is located specifically in areas of the body that are responsible for inflammation and not in the stomach. When the COX-2 enzyme is blocked, inflammation is reduced. Since the COX-2 enzyme does not play a role in the normal function of the stomach or intestinal tract, medications which selectively block COX-2 do not present the risk of injuring the stomach or intestines.
Newly developed drugs that selectively block the COX-2 enzyme are called COX-2 inhibitors. Blocking this enzyme impedes the production of the prostaglandins that cause the pain and swelling of arthritis inflammation. The common anti-inflammatory drugs (like Aspirin, ibuprofen, and naproxen) all act by blocking the action of both the COX-1 and COX-2 enzymes.
The COX-2 inhibitors represent a new class of drugs that do not affect COX-1, but selectively block only COX-2. This selective action provides the benefits of reducing inflammation without irritating the stomach. These drugs pose a significant advantage in comparison to previous anti- inflammatory drugs in that they carry nowhere near the risk of stomach ulceration and bleeding. The COX-2 inhibitors are now on the market in the form of celecoxib (Celebrex). It is widely expected that COX-2 inhibitors will be of great value to people with arthritis.
MedicineNet is delighted to provide our viewers
with the following exclusive interview with the Director of
COX-2 Technology for the Searle Pharmaceutical Company,
which was responsible for developing and testing Celebrex.
William C. Shiel, Jr., MD, FACP, FACR
Chief Medical Editor, MedicineNet
January 29, 1999
MedicineNet (by Dr. Shiel): As a practicing
(arthritis specialist), I am well acquainted with celecoxib (Celebrex) and the COX-2 story. Applications of the drug
and its advantages were major topics at a recent national
meeting (of rheumatologists) in San Diego.
Dr. Isakson, why should patients be excited about Celebrex?
Dr. Isakson: I think Celebrex provides a form of arthritis therapy that is different from what's available now. Current arthritis anti-inflammatory therapy with the Aspirin-like drugs (NSAIDs) has a high degree of effectiveness. That is, each of the NSAIDs can treat arthritis, including the pain, but they also carry along potential side effects in the gastrointestinal (GI) tract that can be serious. Approximately 100,000 hospitalizations and 16,000 deaths occur annually in the United States simply due to the ingestion of the Aspirin-like drugs, and that's a serious problem. Celebrex is targeted to the COX-2 in a way that leaves alone the other enzyme, COX-1, and has been shown not to cause the GI ulcers to anywhere near the extent that the nonsteroidals such as naproxen (ALEVE and others) or ibuprofen do. So, for the patient, we think Celebrex will provide the effectiveness of the currently available therapy without some of the serious side effects that can occur with the nonsteroidals.
MedicineNet: More specifically, in regard to the labeling of Celebrex in the Physicians' Desk Reference, the risks of gastrointestinal bleeding have been reported in the lay press as an issue. Can you address that concern?
Dr. Isakson: The part of the label you're referring to, which is the standard gastrointestinal warning carried by all NSAIDs, refers to a rate of 2-4% serious gastrointestinal events per year for people taking NSAIDs. In fact, the data we collected during a very careful analysis during a large clinical trial experience, suggested that the rate of occurrence of these events was very low in patients taking Celebrex, on the order of 2 in 5000 patients, for a rate of 0.04%. The strength of our data allowed us to get the F.D.A. to agree to put this information in as a qualifier to the standard gastrointestinal warning. We think this qualifier is an important distinction from all of the other NSAIDs that are currently available. So I wouldn't look at it as a concern. In fact, it is quite a distinction to have any change in the label, especially with regard to that warning.
MedicineNet: A common question asked by patients is "how long will it be before I can expect my inflammation to decrease?" Realizing that various conditions respond differently, can you comment in a general sense?
Dr. Isakson: Sure. I think we should talk about rheumatoid arthritis and osteoarthritis separately. In the clinical trials with rheumatoid arthritis, a classic inflammatory disease, the earliest time point for evaluation, which is typical in a clinical trial setting, is at 2 weeks. And at 2 weeks, the level of improvement with Celebrex is essentially achieved and sustained with further treatment over the 3 month to 6 month periods that we've reviewed.
Osteoarthritis is not a classic inflammatory disease, but pain is a characteristic feature of the disease. Therefore, we initiated, as part of some of our clinical trials, a program where we evaluated patients using the American Pain Society questionnaire. This questionnaire is a new way to monitor pain in a more chronic setting. In those trials, we observed a significant improvement of the pain in 1 to 2 days, which continued to improve over the first week of therapy. From week 1 on, the treatment effect was sustained at about the same level. I should qualify that by saying that we were looking at a whole population of people being treated. It is important to note that the effects of treatment may vary from patient to patient.
MedicineNet: If a patient needs to discontinue the medication for a complication, a common question might be "how long is it still in my system"? Dr. Isakson, what is the half-life of Celebrex? (The half-life is the time that it takes the body to naturally eliminate a drug so that the blood level is reduced by one half.)
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Dr. Isakson: The half-life of Celebrex is about 11 to 12 hours which means that it is expelled from the body within about 2 1/2 to 3 days after discontinuing the medicine.
MedicineNet: My understanding is that Celebrex is an indicated drug for osteoarthritis and adult rheumatoid arthritis. Is it true that the drug has not yet been studied in children (juveniles)?
Dr. Isakson: That's correct. Our clinical program was designed for adults, meaning 18 years and older, so no one under the age of 18 has been in our trials. We currently have a program ongoing, though, to assess Celebrex in younger patients, with the idea that it could potentially be beneficial in juvenile rheumatoid arthritis. That's where we would like to go next with Celebrex in terms of arthritis therapy.
MedicineNet: Nonsteroidal anti-inflammatory drugs are oftentimes used in clinical practice for a variety of purposes beyond the stated indications as listed in the Physicians' Desk Reference recommendations and by the F.D.A. A classic example involves inflammatory conditions which may be temporary, such as sprains and strains. At this time can you speak to other uses of Celebrex?
Dr. Isakson: Celebrex is specifically indicated for the treatment of osteoarthritis and rheumatoid arthritis. There currently is no data to support the use of Celebrex for other conditions. Nevertheless, we do have trials, either ongoing or soon to begin, in other potential uses, for example in back pain and sprains and strains.
Dr. Isakson: Sure. One of the most exciting aspects of working on this whole COX-2 inhibitor program has been seeing it evolve from treating the signs and symptoms of arthritis and then seeing it broaden out into other areas as we have gained a better understanding of actually what the nonsteroidals do. There is a very compelling case for COX-2 being involved in treating colon polyps and eventually colon cancer, and this, of course, is a very serious disease and a major medical issue. There is very good epidemiological evidence that the nonsteroidals can reduce the occurrence of colon cancer by 40 or 50%. We have had a very active program in the research area, the preclinical animal model area, the results of which supported the notion that a drug such as Celebrex, a selective COX-2 inhibitor, might have some utility there. And we're just in the process of completing our first clinical trial in a patient population that is highly susceptible to developing colon polyps. We will know the results of that study fairly soon. Assuming the outcome will be positive, we'll be potentially moving into other areas of colon polyp prevention.
We also have a program for Alzheimer's where there is somewhat less compelling but nevertheless extremely interesting epidemiological data that suggests that nonsteroidals, the Aspirin-like drugs, might have a role in retarding the progression of Alzheimer's. The animal model data is harder to get, there are no good animal models, so we went directly into a clinical trial, which is moving along very well. We should know, probably by the end of the year, whether or not the concept of using Celebrex in the treatment of Alzheimer's has some merit. And if it does, that would clearly be another important advance and potential use of this class of drugs.
MedicineNet: In terms of effectiveness rate (efficacy), does Celebrex have advantages over other nonsteroidal anti-inflammatory drugs currently on the market?
Dr. Isakson: The data that we have obtained in our extensive arthritis trials, both for rheumatoid arthritis and osteoarthritis, suggests that the basic efficacy of a selective compound like Celebrex is roughly the same as the best NSAIDs, for example, naproxen. Our original hypothesis was that NSAIDs, in fact, are COX-2 inhibitors, and a specific COX-2 inhibitor, then, should have the same spectrum of antiarthritic activity as the NSAIDs, just without the side effects. In terms of the overall effectiveness for a patient, that may turn out to be different, because the side effect profile clearly affects the overall use of the drug and its effectiveness. Therefore, if you look more at how the patient overall is able to tolerate the drug and function in their daily life, there is certainly the potential for Celebrex to have an advantage over other NSAIDs.
MedicineNet: What are the most common side effects reported with Celebrex? Among the most commonly reported side effects according to the current F.D.A. information were gastrointestinal symptoms. Given that Celebrex is a COX-2 inhibitor drug, what do you propose is the mechanism for the development of these side effects?
Dr. Isakson: The top three gastrointestinal side effects noted in the studies of Celebrex were dyspepsia (upset stomach), diarrhea, and abdominal pain. Other reported significant side effects were headache, upper respiratory tract (breathing passages) infection, and sinusitis. To help explain these findings, I think that it is important to understand how trial study information is collected. A clinical trial setting is not equivalent to what happens out in the community with a physician and a patient. In a trial setting, patients are asked to take a new drug. However, the patients are unaware if they are receiving the study drug, a placebo, or a standard NSAID. They are then asked to register any complaints they might have. And they do. Even in the group given a sugar pill or placebo, the top three complaints are typically headache, dyspepsia, and abdominal pain, depending on the exact wording. And those complaints are identical to what we saw in the clinical trial with Celebrex--headache, dyspepsia, and abdominal pain. The only distinction was that we saw somewhat of a lower incidence of headache with Celebrex. In terms of these complaints, there was not much of a difference between the placebo and Celebrex.
Additionally, the study results don't indicate how serious the complaints are. Another way to evaluate the severity of complaints is to gauge the number of people who withdraw from the study because they are having more troublesome side effects. The rate of patient withdrawal due to these adverse effects was very low in the trial and difficult to distinguish from the withdrawal rate seen with placebo, and was, in fact, lower than what was seen with the other nonsteroidals. In summary, it appears that any time you add something to the digestive tract of that patient population you will get some complaints, and it is not clear to us yet whether the complaints really reflect the drug or simply the clinical trial setting.
MedicineNet: The data published by the F.D.A. strongly supports what you've just said about the placebo having the potential for side effects. I noticed that 1 out of 5, or 20% of patients on the placebo, developed a headache! That was very impressive but is probably consistent with your experience in conducting placebo studies.
Dr. Isakson: Yes, it is. The other very common side effect reported was upper respiratory tract infections, which can develop whether or not the patient is taking one of these drugs.
MedicineNet: (Aside information for the next question: Platelets are irregular disc-shaped elements of the blood which assist in natural blood clotting. During normal blood clotting, the platelets group together or aggregate. This aggregation is blocked by traditional NSAIDs.)
Dr. Isakson, in the published reports, I noticed that there were five "platelet studies." As a clinical rheumatologist (arthritis specialist), I can see a potential for an extremely powerful advantage that a drug that was strictly a COX-2 inhibitor would have because of its lack of an effect on blood clotting elements, the platelets. Can you address that point?
Dr. Isakson: The whole platelet part of the Celebrex story was very important to us for two reasons. First, as you allude, there is a potential medical benefit if a drug doesn't have an effect on the blood platelets. Second, in terms of establishing a true distinction for Celebrex, the platelet provided us with the one tissue source that was easily accessible, easily monitored, and that we knew was only driven by COX-1. So we had a double reason for wanting to evaluate the platelet effects very carefully, which we did in five studies.
We found that even with increasing the dose of Celebrex to 600 mg twice a day, or 1200 mg per day, we saw absolutely no effect on platelet aggregation. This dose is three to six times higher than the full therapeutic dose in osteoarthritis and rheumatoid arthritis, at what we call a supertherapeutic, or above therapeutic dose range. By contrast, the NSAIDs caused a very dramatic effect on platelet aggregation in those same studies. These findings were confirmed by bleeding time studies, which are much more difficult to conduct and have a much higher degree of variability, but nevertheless were consistent in demonstrating that Celebrex had no effect on bleeding time. The results of these studies were very important for us, again from the medical standpoint, but also in distinguishing Celebrex as a separate and distinct type of therapy.
MedicineNet: In a clinical context, patients are often treated with anticoagulants (blood thinning medications) either chronically or acutely, for example, after an operation. What about the use of Celebrex in a patient who is being treated with the blood thinners, heparin, Coumadin, or warfarin?
Dr. Isakson: One of the advantages of Celebrex is its lack of the platelet effect. There wouldn't necessarily be a concern with taking Celebrex and any of those agents. With Coumadin, there are additional potential reactions, both by displacement of protein binding as well as interference with metabolism. Therefore, we conducted a drug interaction study between Celebrex and Coumadin, or warfarin, and found no adverse effects whatsoever. We have not conducted any studies directly related to heparin.
MedicineNet: Does Celebrex adversely affect the liver and/or the kidney?
Dr. Isakson: We've examined possible negative effects of Celebrex on both the liver and kidney through our clinical data base and to some extent done some studies to specifically address the kidney. In terms of the liver, neither in preclinical or in clinical settings have we seen anything that would suggest that Celebrex has a deleterious effect on the liver. In the patient populations we reviewed, we looked very carefully at liver function tests, the classical sort of serum evaluations, and didn't find anything that was distinct from what was observed with a placebo.
The potential effect of Celebrex on the kidney was of particular interest, because the NSAIDs are thought to have negative effects on the kidney, at least in certain individuals, and in rare instances can precipitate kidney failure. In examining the overall clinical data base specifically for effects on the kidney, we found an incidence of effects that is slightly higher than the placebo and the same as other NSAIDs. Although this is nothing to be alarmed about, the effects on the kidney do not clearly distinguish Celebrex from the NSAIDs, as is the case with its effects on the liver and blood platelets.
MedicineNet: NSAIDs can have negative inotropic effects on the heart; that is, they can affect the power of cardiac muscle and pose some risk in a patient with congestive heart failure. Have you noticed any effects with Celebrex related to the heart?
Dr. Isakson: No specific studies have been done in that particular patient population. We have scoured the extensive data base for cardiovascular events, and again we were unable to find anything which differentiated Celebrex from the placebo. Patients with congestive heart failure were excluded from these trials, although a few participated who have the condition, but in general that was an exclusion. We haven't directly looked at patients with congestive heart failure, but we are considering at least conducting a safety study for this group.
MedicineNet: Dr. Isakson, aside from the obvious advantage that Celebrex has in terms of its decreased side effect profile generally, are there other specific advantages for elderly patients?
Dr. Isakson: What we have found in looking at our data base (we do have a fairly large number of elderly within that data base), that the number and severity of complaints, particularly in the gastrointestinal area with the NSAIDs, increases in the elderly population. I think that is probably consistent with your clinical practice and the general thinking. The data for gastrointestinal side effects with Celebrex in the elderly population do not appear to be distinctly different from those in younger patients. So we think that Celebrex will offer an advantage for the elderly. I also believe that the markedly reduced rate of ulcer formation noted with Celebrex could well translate into a sense of less fear in the elderly taking this drug. The elderly is a group that is already taking a lot of drugs and they can be uncertain about medications. So, the peace of mind factor, I think, could be a major benefit for them.
MedicineNet: In patients taking Celebrex, whether they are young or old, are there recommended lab tests that should be monitored clinically?
Dr. Isakson: Nothing that pertains specifically to Celebrex. Certainly, if the patient has rheumatoid arthritis and is taking other medications, such as methotrexate, periodic lab tests would be done anyway, but nothing beyond what you would use in your ordinary practice with those patients.
There are some NSAIDs for which periodic lab testing is recommended, and the fact that lab testing is unnecessary for Celebrex may indeed be an additional advantage for Celebrex in clinical practice.
MedicineNet: Are there problems with taking antacids with Celebrex?
Dr. Isakson: No.
MedicineNet: So if a patient is taking an antacid, are there difficulties with the absorption of Celebrex or its beneficial effects?
Dr. Isakson: We saw a slight decrease in the absorption of Celebrex with antacids, but not enough to be clinically meaningful. It would not be sufficient to cause any change in the dose regimen.
MedicineNet: How frequently is Celebrex taken and is it necessary to either eat or abstain from eating prior to taking Celebrex?
Dr. Isakson: We think one of the advantages of Celebrex is the flexibility it offers the patient in terms of when to take the drug and in what context. For osteoarthritis, the recommended dose is 200 mg per day, which can be taken either singly or in divided doses. And, although we found that the absorption is slightly increased when Celebrex is taken with a meal (and that's a good thing), the difference is not enough to alter the dosing regimen. Therefore, Celebrex can be taken either with or without meals, whichever the patient would prefer. Additionally, the 200 mg can be taken either in the morning or at night. So there's a great deal of versatility in the dosing.
For rheumatoid arthritis, the recommended dose is 100 mg twice daily or 200 mg twice daily, with flexibility for the physician to increase the amount, if necessary for a particular patient.
MedicineNet: Dr. Isakson, thank you for such a fine review of the COX-2 story and issues related to Celebrex.
On behalf of all of our viewers and staff at MedicineNet we sincerely thank Dr. Isakson for his expertise and frank clarity in addressing such an important medical topic that will affect so many people.