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Reglan Settlements: Why Reglan Lawsuit May Eventually Settle*
Reglan is an antiemetic drug frequently prescribed by doctors for the treatment of Gastroesophageal Reflux Disease (GERD). GERD is the process by which stomach contents regurgitate back into the esophagus causing heartburn. Reglan helps controls GERD by blocking dopamine receptors in the brain and throughout the body. Dopamine is a chemical produced naturally by the human body that sends signals from one nerve to the next. Simple movements of muscles such as moving a finger are controlled by what is known as the pyramidal system. However, more coordinated muscle movements such as throwing a baseball, dancing or talking require fine motor control from the extrapyramidal system. By blocking dopamine receptors, Reglan can affect the extrapyramidal system causing extrapyramidal movement disorders such as drug-induced Parkinsonism, dystonia, akathisia and tardive dyskinesia.
Tardive dyskinesia refers to a specific type of extrapyramidal movement disorder typically involving involuntary movements of the mouth, tongue, lips or face, and often involving involuntary movements of the arms, legs or trunk. In addition to being a serious neurological condition, tardive dyskinesia can also affect breathing and eating, and can be socially disabling. Patients with tardive dyskinesia exhibit bizarre neuromuscular movements that they are unable to control. . Tardive dyskinesia can be a permanent neurological condition. . Medications used to treat tardive dyskinesia only treat its symptoms and do not cure the disease.
Although the published medical literature contained case reports of tardive dyskinesia in association with use of Reglan dating back to 1978, the Reglan label did not contain a warning for tardive dyskinesia until 1985. Until that time, the label contained only the following warning concerning extrapyramidal symptoms (EPS) generally:
Extrapyramidal symptoms, manifested primarily as acute dystonic reactions, occur in approximately 1 in 500 patients treated with the usual adult dosages of 30-40 mg/day of metoclopramide. These usually are seen during the first 24-48 hours of treatment with metoclopramide, occur more frequently in pediatric patients and young adults, and are even more frequent at the higher doses used in prophylaxis of vomiting due to cancer chemotherapy... If these symptoms should occur, inject 50 mg Benadryl (diphenhydramine hydrochloride) intramuscularly, and they will usually subside.
In 1985, a warning for tardive dyskinesia was added, although it did not separately quantify the risk of tardive dyskinesia other than the 1 in 500 risk of EPS generally:
Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the total cumulative dose.
Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.
There is no known treatment for established cases of tardive dyskinesias although the syndrome may remit, partially or completely, within several weeks-to-months after metoclopramide is withdrawn. Metoclopramide itself, however, may suppress (or partially suppress) the signs of tardive dyskinesia, thereby masking the underlying disease process. The effect of symptomatic suppression upon the long-term course of the syndrome is unknown. Therefore, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.
The portion of the Reglan label discussing EPS and tardive dyskinesia has remained unchanged since 1985. Because the Reglan label does not separately quantify the risk of tardive dyskinesia, physicians can only conclude that the risk is low, occurring with less frequency than the 1 in 500 risk for EPS generally, which the label indicated applied primarily to acute dystonic reactions and were usually reversible. While the risk of tardive dyskinesia is in fact low with use of Reglan for less than three months, there is nothing in the Warning or Adverse Events section of the label cautioning physicians that the risk of tardive dyskinesia significantly increases with use of Reglan greater than three months.
However, as early as 1989, movement disorder specialists began to comment in the published medical literature that the Reglan label underestimated the risk of EPS and tardive dyskinesia. In 1989, Dr. Lucinda G. Miller and Dr. Joseph Jankovic identified at least 1,031 patients with metoclopramide-induced movement disorders from the published medical literature, and concluded that despite the manufacturer's estimate of only 1 in 500 or 0.2% frequency of metoclopramide-induced movement disorders, "the actual prevalence is probably greater." In 1993, Dr. Linda Ganzini and others published the results of a case-control study in which 29% (almost 1 in 3) of the patients exposed to metoclopramide met the case definition of tardive dyskinesia, with an average duration of exposure to the drug of 2.6 years. In the Comment section, Dr. Ganzini concluded:
These data clearly suggest that both the prevalence and the severity of metoclopramide-induced acute EPSs and tardive dyskinesia have been underestimated and underrecognized and are approximately 100 times more prevalent than previously reported [citing to the Reglan label].
The following year, Dr. Daniel D. Sewell and others published a similar case-control study in which 27% (more than 1 in 4) of the patients exposed to metoclopramide met the case definition of tardive dyskinesia..
Prior to the publication of the Ganzini and Sewell studies, another article was published drawing attention to the common practice of long-term treatment with metoclopramide. In "Metoclopramide: An Analysis of Inappropriate Long-Term Use In the Elderly," published in the Annals of Pharmacology in 1992, Dr. Ron B. Stewart and others studied a population of 4,515 elderly patients at the Florida Geriatric Research Program. Of the patients who reported use of metoclopramide, 32% had used the drug for more than 1 year, leading the authors to conclude that "long-term treatment with metoclopramide is quite common," and that other prescription drugs were effective and safer to treat GERD:
The routine use of metoclopramide for gastroesophageal reflux should be questioned in light of the availability of safer, more effective drugs such as histamine[2]-receptor blocking agents cimetidine and ranitidine, and omeprazole. The long-term efficacy and symptomatic benefit of metoclopramide have not been documented.
Despite these reports of significantly increased risk of tardive dyskinesia with long-term use of Reglan, the Reglan warning label for EPS and tardive dyskinesia remained unchanged. Wyeth took no action to change its warning label for Reglan or even follow up on the reported studies demonstrating an increased risk of tardive dyskinesia with long-term Reglanuse. Dr. Frederick Wilson was Wyeth's Medical Monitor in charge of Reglan from 1989 until 1995. As Medical Monitor for Reglan, Dr. Wilson's duties included monitoring the medical literature for any reported side effects of Reglan and determining whether the Reglan labeling should be updated. (App. at 81-82). Although Dr. Wilson did not know the source of the 1 in 500 number on the Reglan warning label. Dr. Wilson testified that he determined "no action necessary" after reviewing the Ganzini and Sewell studies in the early 1990's, Despite the signals in the medical literature that its warning label was not accurate or adequate, Wyeth never conducted any safety studies or clinical trials to investigate the safety or efficacy of Reglan in long-term use.
In fact, the long-term efficacy of Reglan has never been scientifically documented by Wyeth or any other investigator. Thus, for the Reglan risk/benefit analysis, Dr. Wilson admitted that there are no studies documenting any benefits from long-term use of Reglan and that the medical literature indicates that there are serious side effects associated with long-term use of Reglan, specifically tardive dyskinesia and other types of EPS. Because of other effective and safer drugs on the market to treat GERD , Dr. Wilson admitted that the risk/benefit analysis for Reglan did not justify long-term therapy to treat GERD:
Q. Just so I'm absolutely clear on your answer, are you telling me that it is your opinion as Wyeth's medical monitor for Reglan, that Reglan should not be prescribed in long-term therapy for GERD because the side effects are too dangerous and because its efficacy in longer term use has not been established?
A. Today, as we are sitting here and with the other drugs that are currently on the market, I would agree.
Despite these opinions held by Wyeth's Medical Monitor in charge of Reglan, and Wyeth's knowledge that Reglan was frequently being prescribed longer than three months, Wyeth never took any action to strengthen the Reglan label. In addition, Wyeth never took any action to otherwise warn physicians that the therapeutic benefits of Reglan with use longer than three months had never been documented, there was a significantly increased risk of tardive dyskinesia with use of Reglan greater than three months and that as a result, the risk/benefit analysis for Reglan did not justify using Reglan long-term to treat GERD.
*Taken from motions and pleadings in the Reglan litigation
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