Health Canada is reviewing risks associated with the common antidepressant
HOW DANGEROUS IS SERZONE?
Health Canada is reviewing risks associated with the common antidepressant
THOSE U.S. COMMERCIALS for some prescription drugs that occasionally turn up on TV programs seen in Canada sure can be bizarre. They tell you that, if you take a particular pill, your quality of life will improve—unless you're unfortunate enough to experience any of a long list of awful side effects. Picture what a commercial for Serzone might look like. Manufactured by New York-based Bristol-Myers Squibb Co., Serzone is prescribed in North America for moderate to severe depression. An ad could feature a smartly dressed businesswoman confidently going about her routine in a modern office setting. An announcer with a reassuring baritone would tell us Serzone can relieve depression, and that you should ask your doctor whether the drug is right for you. Then, in a rapid, clipped monotone, he might conclude: "Serzone may cause serious liver damage—symptoms include fatigue, malaise, abdominal pain, nausea, vomiting, discoloured stools, dark urine, weight loss, jaundice, confusion, brain swelling and, in some cases, death."
There is no such ad, but those side effects are real. Serzone—its generic name is nefazodone—is one of the newer drugs known as selective serotonin reuptake inhibitors (SSRIs), the class that includes Prozac. Health authorities have linked nefazodone to severe liver damage that has caused at least 18 deaths worldwide since 1994, the year it first became available in Canada. Because of what is broadly believed to be the widespread under-reporting of adverse drug reactions by health-care workers, the actual number of deaths attributable to Serzonerelated liver damage is almost certainly higher. Other patients taking Serzone have required liver transplants—including two in Canada. More than 100 Canadians—and likely many more—are known to have suffered liver damage resulting in enzyme imbalances, cell death, inflammation and bile in the blood. Again, because of spotty reporting, the exact number of cases of serious liver damage worldwide is not known.
All told, about 11 million people have
taken the drug—including 650,000 in Canada. In December 2001, the U.S. Food and Drug Administration told Bristol-Myers Squibb to add a black-box warning to nefazodone's packaging—the FDA's strongest labelling requirement—to alert doctors to the antidepressant's association with potentially life-threatening liver damage. Europeans applied pressure as well, with authorities in the Netherlands and Sweden raising the need for investigations and liver-monitoring programs for patients using the antidepressant, sold there as Dutonin. Last month, Bristol-Myers Squibb, the world's fifth-largest drug maker, said it is pulling the product from the entire European market. Adverse drug reactions, or even pressure from the regulators, weren't the cause of the withdrawal, says Dr. Darlene Jody, Bristol-Myers Squibb's Lawrenceville, N.J.-based vice-president of medical affairs, global marketing. The decision was made, she says, in response to slumping sales in Europe and the absence of a single test that could reveal different types of potential liver damage.
The company will continue selling nefazodone in the United States and Canada. (Global sales reached the $600 million range in 2001, but have dropped considerably since then.) "Since the incidence of liver failure has remained constant in spite of increased exposure to the product," says Jody, "we feel very comfortable with our decision to discontinue sales, based on business rationale, in some places, and continue selling the product in others."
For concerned patients, there are alternatives to nefazodone. Public Citizen, a Washington-based advocacy group, urged readers of its on-line newsletter (at worst
Eighteen people taking Serzone-out of 11 million users-are known to have died of liver failure. But are all cases reported?
pills.org) a year ago to ask their doctors about switching to a safer antidepressant. Pharmacist Larry Sasich, a Public Citizen research analyst, says there are about two dozen pharmacological alternatives to nefazodone that generally can work just as well, but pose less risk. "I no longer see any reason why this drug should stay on the market anywhere," he says.
Bristol-Myers Squibb first learned of a patient suffering liver failure in 1995, says Jody. "We followed up on that report," she says, "as we do all serious adverse events, to the best of our ability, by contacting the physicians reporting the information, etc." Since then Jody says, the occurrence of liver damage linked to nefazodone has not been alarming. "This is a very rare event," she says. "Since 1994, we've only had 28 reports of liver failure leading to necrosis or death."
Eighteen of those patients died, out of 11 million users, over eight years or so. That appears to be a minuscule rate. It helps, however, to put the number of deaths and serious illness into perspective. The U.S. FDA, for example, says only a fraction of adverse drug reactions get reported. "We see less than 10 per cent," says Laura Bradbard, an FDA spokeswoman, "and maybe closer to one per cent." Health Canada spokesman Ryan Baker estimates that one occurrence out of 10 gets reported. So have there been many more deaths attributable to nefazodone but never reported as drug-related? No one knows. But drug-related deaths tend to get noticed more than illnesses, Jody argues, and consequently are more likely to be reported.
Terence Young bristles at the lack of certainty. Young, a former member of the Ontario legislature and now president of a consulting firm in Oakville, Ont., has researched adverse drug reactions extensively since his daughter Vanessa, 15, died in March 2000 while taking another drug, Prepulsid, to control bloating. His conclusion: healthcare workers likely report fewer than one in 100 adverse drug reactions. Young welcomes health commissioner Roy Romanow's call
for an independent drug agency to monitor adverse reactions. The current system, which relies on doctors voluntarily reporting problems to a branch of Health Canada, is a woefully inadequate way to keep tabs on potentially lethal drugs, says Young. "What doctor with a roomful of patients wants to pause in the middle of the day," he asks,
"and send a letter to Health Canada that says he almost killed one of his patients?"
Concerns over nefazodone have circulated since as early as July 1999, when a Health Canada newsletter on adverse drug reactions briefly noted nine cases of liver dysfunction. Two years later, Bristol-Myers Squibb Canada Inc. and one of its divisions,
Montreal-based Linson Pharma Inc., mailed Canadian physicians and pharmacists a letter with "important safety information." It noted 109 incidents of serious liver injury worldwide since 1994, adding that this was generally presumed to be an underestimate.
The letter said two-thirds of those patients showed symptoms within four months of starting the drug—some within a few weeks. The manufacturers also had important information for people taking nefazodone in conjunction with other drugs. Nefazodone, said the letter, inhibits a key liver enzyme important in metabolizing a variety of drugs. As a result, some drugs could accumulate in the body and reach toxic levels even when used as directed. Health Canada also posted a warning on its Web site a month later, stating that nefazodone had "on occasion" been associated with liver damage leading to transplants or death.
Women may have particular reason to be concerned about nefazodone use. Last May, Dr. Donna Stewart reported a troubling observation in the Canadian Journal of Psychiatry. Stewart, a University of Toronto psychiatry professor and chair of women's health for several Toronto hospitals, said that out of 32 mostly severe cases of nefazodone-related liver injury, 22 were women. Why is unclear. "Every month a drug like this is on the market," says Stewart, "more people get sick."
Health Canada is now reviewing nefazodone's safety— 3 V2 years after publishing its initial concerns. "Health Canada hopes to have the review of nefazodone completed in the next couple of months," says Baker. "However, it's impossible to predict exactly how long it will take considering there's no way of knowing where the evidence will lead us."
Stewart worries Health Canada is taking too long. "Sometimes," she says, "one wonders if the lag time is not due more to bureaucratic process than careful evaluation of the material." Terence Young suggests that patients and practitioners alike take a cautious approach to new medications. "Some doctors don't recommend any drugs until they've been on the market for five years," he says. "I would suggest that's the kind of physician you want as your family doctor." Young's advice, however, wouldn't apply to Serzone—in May, for all the controversy surrounding it, the drug will have been on the market for nine years. liïï
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