The Food and Drug Administration (FDA) approved esomeprazole (NEXIUM) on February 20, 2001 as the fifth member of the “proton pump inhibitor,” or PPI, family of drugs. These drugs work by blocking the final step in the secretion of stomach acid for the treatment of various forms of ulcer and gastroesophageal reflux disease (GERD) often manifested as nighttime heartburn. The four other PPIs currently on the market are lansoprazole (PREVACID), omeprazole (PRILOSEC), pantoprazole (PROTONIX), and...
The Food and Drug Administration (FDA) approved esomeprazole (NEXIUM) on February 20, 2001 as the fifth member of the “proton pump inhibitor,” or PPI, family of drugs. These drugs work by blocking the final step in the secretion of stomach acid for the treatment of various forms of ulcer and gastroesophageal reflux disease (GERD) often manifested as nighttime heartburn. The four other PPIs currently on the market are lansoprazole (PREVACID), omeprazole (PRILOSEC), pantoprazole (PROTONIX), and rabeprazole (ACIPHEX).
Both esomeprazole and omeprazole are produced by the same company, AstraZeneca Pharmaceuticals based in Wilmington, Delaware.
Esomeprazole is not a new drug. Patients who have been taking omeprazole since it was approved in 1989 have also been getting esomeprazole with each dose. Like many drugs, omeprazole is a mixture of two forms that are identical, chemical “mirror images” of each other, known scientifically as optical isomers. Esomeprazole is one of the two isomers that make up omeprazole.
With some drugs, all of the therapeutic activity is associated with one optical isomer, but this is not the case with omeprazole. In the publicly available FDA review of esomeprazole it was found in a rodent study that: “… no significant differences in the antisecretory potency of [the] three drugs were noted.” The three drugs the reviewer was referring to were omeprazole, esomeprazole, and omeprazole’s other optical isomer.
Developing and patenting a single optical isomer from an old drug as a new drug is an abuse of the patent system that primarily benefits the company’s stockholders, without regard to the welfare of consumers—certainly not their economic welfare. More on this later.
Like omeprazole and the other approved PPIs, esomeprazole is approved for the treatment of three GERD-related diseases. These are:
1) symptomatic GERD or heartburn; 2) erosive esophagitis which damages the tube connecting the mouth and stomach due to acid reflux; and 3) the healing of erosive esophagitis.
See the box below for the non-drug and drug treatments for nighttime heartburn that should be tried before using any PPI, including esomeprazole.
Esomeprazole was reviewed by the editors of the highly respected Medical Letter on Drugs and Therapeutics, a source we frequently cite because of its well deserved reputation for independence. They concluded their April 30, 2001 evaluation of this drug by saying:
Esomeprazole may be somewhat more effective than 20 mg of omeprazole and no more expensive, but omeprazole is going off patent and will soon be available generically. Whether 40 milligrams of omeprazole would be as effective as esomeprazole for treatment of GERD or erosive esophagitis remains to be determined.”
The above conclusion was based on published studies in medical journals and unpublished clinical trials described in esomeprazole’s professional product labeling, the drug’s so-called “package insert.” The majority of these trials compared 40 milligrams of esomeprazole to 20 milligrams of omeprazole or to a dummy drug called a placebo.
Contrast The Medical Letter’s conclusion with that of an FDA medical officer’s evaluation of esomeprazole:
The sponsor’s [AstraZeneca] comparisons of H 40 [esomeprazole 40 milligrams] vs O 20 [omeprazole 20 milligrams] do not yield valid conclusions about the superiority of H [esomeprazole] over O [omeprazole], although these comparisons are adequate to demonstrate that H is active in the assessed indications. Therefore, the sponsor’s conclusion that H 199/18 [esomeprazole] has been shown to provide a significant clinical advance over omeprazole in the first-line treatment of patients with acid-related disorders is not supported by data [emphasis supplied in the original].
The Medical Officer goes on to say:
Specifically, there are no scientific bases [sic] for the sponsor’s statement that compared to omeprazole, H 199/18 offers a faster and improved resolution of heartburn symptoms and higher rates of healing in the treatment of erosive esophagitis. The two compounds are comparable in their efficacy for this indication. Like omeprazole, H 199/18 is highly effective in the maintenance of healing of erosive esophagitis but there are no side-by-side studies to assess comparative efficacy of these two drugs in this indication. Although H 199/18 provides predictably and reproducibly higher rates of symptom resolution than placebo within four weeks in patients with s-GERD [heartburn], these effects are very similar if not identical to those seen with omeprazole.
The Medical Officer noted in his summary “… that in order to determine whether one compound is superior to another these need to be tested at comparable amounts …”, meaning esomeprazole 20 milligrams vs omeprazole 20 milligrams and esomeprazole 40 milligrams vs omeprazole 40 milligrams.
We attribute the difference in conclusions reached by The Medical Letter editors and the FDA reviewer to the fact that unlike The Medical Letter, the FDA had access to the details of every study submitted by AstraZeneca to the agency in support of esomeprazole’s approval. We have been pointing out to our professional colleagues for several years that it is impossible to conduct a valid independent assessment of the therapeutic value of a new drug without including the FDA reviews of the drug. The FDA reviews all studies submitted by a manufacturer, some of which may never be published because they do not shine the most favorable light on the product. Drug manufacturers are very adept at managing the information published about their products.
The FDA reviews of esomeprazole can be accessed on the Internet at http://www.fda.gov/cder/approval/index.htm.
We have been concerned about all the PPIs including esomeprazole because they consistently cause a type of gastrointestinal growth in rats known as carcinoid tumor. In a safety study submitted by AstraZeneca to the FDA, more than 98 percent of patients had normal biopsies before starting treatment with esomeprazole. At the end of this study, 6.5 percent of the patients had non-normal biopsy results. However, no actual cases of cancer were reported.
The FDA Medical Officer commented that the data on esomeprazole’s safety seem reassuring, but added, “However, little is known about long term (many years of continuous administration) safety of PPIs.” The medical officer also noted that “Some patients have received continuous treatment with omeprazole in monitored clinical trials for longer than 13 years ….”
A single case report of a carcinoid tumor in a human using a PPI was published in the medical journal The Lancet on November 18, 2000. The patient was a 56-year-old woman who had been taking 40 milligrams of omeprazole daily for four years. Her tumor was surgically removed. The bottom line is that the long term safety of esomeprazole and the other PPIs is unclear. It may take 20 years or even longer for drug-induced cancer to appear if one is indeed going to develop.
What was AstraZeneca’s motive in developing esomeprazole, a drug that has not been shown to be any better than the company’s other PPI, omeprazole? Omeprazole was the largest selling prescription drug in the U.S. in 2000 with more than $4 billion in retail sales, but as mentioned above it is due to lose patent protection in the near future. When patent protection is lost, a manufacturer can expect a 40 to 60 percent drop in sales very soon—in the case of omeprazole, a loss in the neighborhood of $2.0 billion for AstraZeneca, not a pleasant prospect for the company’s stockholders.
So clearly AstraZeneca’s motive in looking for another PPI was to find something to replace its old financial standby, and the most expedient and economical strategy was to develop esomeprazole, a drug that clearly is not an innovation that required much scientific ingenuity, and then get physicians to switch their omeprazole patients to the “new, improved” product.
This ploy to move patients from a drug that is going off patent protection to one that will be protected for a long time to come (and will cost about the same as the old drug used to cost) may be questionable from the point of view of medical ethics, but not from one of business. After all, making money for stockholders is what a company is really all about.
Medical Marketing & Media, an advertising trade publication, reported in its September 2001 issue that AstraZeneca is having success with its strategy to switch patients from omeprazole to esomeprazole. In the first several months since February 2001, when esomeprazole first became publicly available, 100,000 patients switched to esomeprazole, of which 40 percent were omeprazole users. Total promotional spending by Astra-Zeneca on esomeprazole alone in March 2001 alone was $16 million.
As mentioned above, Astra-Zeneca’s scheme is an abuse of the patent laws, which were enacted to reward ingenuity and innovation, not to protect products from competition after their patents expire. A solution to this abuse was suggested more than 40 years ago: a patent would not be granted for a minor modification of an existing drug unless the new drug was shown to be therapeutically superior to similar drugs already on the market. Unfortunately, this suggestion never made it to Congress for debate.
Omeprazole was due to lose its monopoly protection on October 5, 2001. However, by using the courts, in further exploitation of the law at the expense of those patients that must pay out-of-pocket for their prescription drugs, it is unlikely that generic omeprazole will be available before 2002. AstraZeneca has gained more time for the omeprazole-to-esomeprazole switch.
What You Can Do
If you are experiencing nighttime heartburn, the non-drug and drug treatments mentioned below should be tried before using any PPI, including esomeprazole.
If you are currently taking omeprazole and your symptoms are being adequately controlled, there is no medical reason for you to switch to esomeprazole.
Keep an eye out for the release of generic omeprazole, it may save you from 40 to 60 percent at the pharmacy.
Try These Nighttime Heartburn Treatments First
There are non-drug treatments, with no safety concerns, and less expensive drugs that may be effective for you that should be tried before turning to the proton pump inhibitors mentioned in the main story.
On the non-drug front: avoid food, and particularly alcohol, within two or three hours of bedtime and elevate the head of the bed about six inches or sleep with extra pillows. As to cheaper drug remedies, try simple over-the-counter (OTC) antacids such as an aluminum hydroxide and magnesium hydroxide product (examples are MAALOX and MYLANTA). If this does not relieve the symptoms, one of the family of stomach acid blocking drugs known as histamine-blockers such as cimetidine (TAGAMET), famotidine (PEPCID), nizatidine (AXID) or ranitidine (ZANTAC) can be tried. Histamine-blockers are available both in OTC and prescription strengths.
If, after 14 days, OTC histamine blockers have not given adequate relief, it is time to consult your physician.