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Real-World Issues: Nomifensine

Nomifensine (Merital) was first used as an antidepressant in Germany in 1976, in the United Kingdom in 1977, and in the United States in 1985. From 1978 to 1985, some 165,000 to 251,000 prescriptions were written each year. Between 1978 and 1979, the manufacturer received four reports of hemolytic anemia. A case report was published in the medical literature in 1979. From 1981 to 1982, three more cases in the United Kingdom were reported. From 1979 to 1980, the company did immunologic studies of some 300 patients. In 1981, the United Kingdom labeling was changed to indicate that rare cases of hemolytic anemia were reported.

At this time, the labeling also stated that rare cases of liver enzyme elevation were noted. In the 1980s, the use of nomifensine increased, and by 1986, 296 adverse event (AE) reports were received by the manufacturer, including 16 positive Coombs’ tests and 45 hemolytic anemias, as well as 27 jaundice reports, 12 abnormal liver function tests, 6 hepatitis reports, and 1 hepatic necrosis report. The first United Kingdom fatalities were reported in 1985. Further case reports were published from 1980 to 1985, noting hemolytic anemia (with and without renal failure), thrombocytopenia, hepatitis, fatal alveolitis, a systemic lupus erythematosus-like fatal reaction, and fatal immune hemolysis. By June 1985, the estimated incidence of hemolytic anemia was 1 in 20,000. Further reports were received, and by November, the estimated rate was 1 in 4,000.

“Dear Doctor” letters were sent out in 1985 in the United Kingdom, and the drug was withdrawn from all worldwide markets in January 1986 (Stonier, Pharmacoepidemiology Drug Safety. 2002;1:177–185; Stonier, Edwards, Nomifensine and haemolytic anemia, in Pharmacovigilance, Wiley, Hoboken, NJ, 2002).

During this time (late 1970s to the 1980s), the state of drug safety and pharmacovigilance reporting was markedly different from today. The International Conference on Harmonization, European Medicines Agency, and MedWatch were not yet in existence, and many countries had disparate or nonrigorous AE reporting systems.

The drug was approved by the U.S. Food and Drug Administration (FDA) in 1984 (after some 6 years reviewing the dossier), and marketing began in the United States in July 1985. Up to 10,000,000 patients were exposed to the drug by then. The drug was withdrawn from all markets (including the United States) in January 1986.

In the United States, the question then arose regarding how the FDA could have approved the product and then permitted marketing while the crescendo of cases was building up, especially in 1984–1985. Hearings in the U.S. House of Representatives (Congress) were held in early 1986, and the FDA launched an investigation in August 1986.

A summary report was issued by the FDA (Kurtzweil, FDA Consumer, September 1991, p. 42). The FDA investigation revealed that two deaths, an Italian in 1980 and a French woman in 1984 (before the approval in the United States), were known to the company but not reported to the FDA until 1986, months after the drug was withdrawn from the market. Nine other deaths, including three in the United States, also occurred. As the FDA notes in its report: “The investigation, which lasted a year and a half, was lengthy because officials of the US company refused to allow personnel who had been directly involved in analyzing and reporting adverse drug reactions to speak to FDA investigators. In addition, months often passed before they provided written answers to investigators’ questions.”

The FDA was able to gather evidence showing that the company, Hoechst AG in Germany, and a former medical director of the clinical research division “had been aware of the deaths of the two European women shortly after they had occurred but had failed to report them to FDA as required.” The FDA found no evidence that the U.S. division of the company (Hoechst-Roussel) had withheld information from the FDA. In December 1990, the U.S. federal attorney in New Jersey charged Hoechst AG and the medical director by name with failing to report the two European deaths. No charges were filed against Hoechst-Roussel. In April 1991, Hoechst AG and the medical director pleaded guilty to the charges and were fined the maximum amount allowed by law. Nomifensine became something of a worldwide cause célèbre.

Several safety lessons were learned:

• Always do the right thing.
  
• Do not withhold safety data from the FDA and other health authorities.
  
• The company should speak with one voice and say the same (correct) thing to all health authorities at the same time.
  
• Report all data in a proper and timely manner and document it with meticulously kept records.
  
• Proper written procedures must be in place to ensure that all safety data are reported to all branches of the company (especially multinational companies) that need these data. The company should perform periodic internal audits to ensure that this is happening. Any deficiencies should be remedied immediately, and data that should have been reported must be reported to the health authorities as soon as the issue is discovered (painful though this may be).
  
• Cooperate with all health authority investigations.
  
• The senior officers of the company must understand the significance of the drug safety function and put their full weight, support, and resources into ensuring that safety is done correctly.
  
• Maintain a high index of suspicion that AEs may be due to the drug and not to other causes.
  
• Physicians and those in positions of senior responsibility in the company should be aware that they may be held personally liable (criminally and civilly) if they do not do their safety duties.

Ensure that safety information is reported to the health authorities as required before, during, and after Marketing Authorization submission.

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