Off-label drugs are off the charts in Canada

When Rachel Lavallee’s son Sam was born five years ago, she was determined to breastfeed, despite a low milk supply. She spoke to her doctor about domperidone—a drug prescribed to treat stomach ailments, that has been used for at least 30 years to help women boost milk production. “It just about doubled my milk supply,” says Lavallee, 32, a nurse in Halifax. When son Alex was born last August, she took it again. “For baby number two, it was the same,” she says.

This March, Health Canada issued an advisory, stating the risk of abnormal heart rhythms or sudden death may be higher in patients taking higher doses of domperidone, or in those over age 60, based on two new studies. A letter from the Canadian Lactation Consultant Association noted the average age of patients in the studies was 72 and 79, respectively. “When I looked at the [studies] it was based on, it has nothing to do with new mothers,” says Joan Fisher, a lactation consultant in Ottawa. Lavallee, who takes three tablets four times a day, is unfazed. “Based on my age, health, and my reasons for taking it, I feel the benefits outweigh the risks.” After discussing it with her family doctor, she continues to take the drug. Countless other women are doing the same.

When doctors prescribe domperidone to increase milk production, it’s an off-label use, meaning it hasn’t been approved by Health Canada. It’s not the only drug used this way. Quinine, an anti-malaria medication, has long been prescribed to treat nighttime leg cramps; antipsychotic drugs are frequently given to dampen some symptoms of dementia. At Apex Compounding Pharmacy in Toronto, pharmacist-owner Ara Papazian has raspberry-flavoured lollipops laced with ketamine, a powerful anaesthetic prescribed to those who suffer from chronic pain. “We make Viagra in a lozenge. As opposed to the guy taking a pill one hour before the act, he can pop this under his tongue and he’s good to go within 15 minutes.” Papazian sometimes recommends an anti-cancer drug, tamoxifen, in an ointment to help heal scars.

Prescribing off label is accepted medical practice, one that allows doctors to tailor treatments to patients who may not benefit from other forms of medication. But it carries risks. “When you go off label, one has to be really cautious,” says Dr. Tewodros Eguale of McGill University, lead author of a new paper that looks at how common these prescriptions are. “It’s not always well known whether it will give you a severe reaction.” It’s such standard practice that doctors often don’t even realize they’re doing it: one 2009 study asked 1,200 U.S. psychiatrists and primary care doctors to look through a list of medical conditions and  the drugs used to treat them. They identified whether the use was approved roughly half the time.

Eguale’s study, published in the Archives of Internal Medicine, found a little more than one in 10 drugs were prescribed off label. Using electronic health records, he and his co-authors looked at a total of 253,347 prescriptions in Quebec from 2005 to 2009 for more than 50,000 adult patients. Of the drugs prescribed off label, 79 per cent “lacked scientific evidence” that the treatment would work. Drugs that affect the central nervous system—like antipsychotics and antidepressants—were most often prescribed for an off-label use. Interestingly, women were more likely to get off-label prescriptions because they’re more often treated for conditions like anxiety and insomnia, where off-label prescribing is common. In a separate study of prescribing in the U.S., researchers found that 21 per cent of prescriptions were for off-label uses, and of that number, 72 per cent had “uncertain or inadequate” evidence the prescription would work.

“It’s a benefit-risk calculation for the physician,” Eguale says. In the case of quinine, “there’s no effective drug to treat nocturnal leg pain,” so doctors prescribe the anti-malaria drug, which has a long history of being used this way, although it isn’t approved for that use in Canada or the U.S. In April 2011, Health Canada issued an advisory that, as of the previous September, it had received 71 reports of serious adverse reactions related to quinine sulfate—41 of them were life-threatening or required hospital admission. “Only four of the 71 reports listed malaria as the indication for use of the drug,” it says. The remaining 67 were all for cramps. The letter concludes with a reminder that quinine sulfate “is not indicated for the prevention or treatment of nocturnal leg cramps.”

It seems bizarre that an anti-nausea drug could help breastfeeding, or a malaria fighter might help subdue leg cramps. But that’s the story of drug development, Papazian says. Sometimes a drug’s side effects are more beneficial than its intended purpose. Viagra was initially developed as a cardiac drug, but then manufacturer Pfizer Inc. realized it could induce erections. The first oral pill to treat impotence was approved by the U.S. Food and Drug Administration (FDA) in 1998. “Pfizer went on to make a fortune based on a side effect,” Papazian says.

Even though a drug’s side effects can be profitable, as Viagra shows, there are plenty of reasons a drug company might not bother seeking regulatory approval of off-label uses. “It’s very expensive to pull data together and present it to Health Canada or the FDA,” Eguale says. “If a drug is old and its patent is about to expire, the pharmaceutical companies won’t bother.” And if side effects promise to help only a small segment of the population, it might not be worthwhile either.

Children are often prescribed medication off label because, for ethical and other reasons, companies have historically been reluctant to include them in clinical trials, says Dr. Randall Stafford, associate professor of medicine at the Stanford Prevention Research Center and co-author of the U.S. study on off-label prescribing. “But many would argue that if a drug is going to enter the market and be used in children, there’s an obligation to test it,” Stafford says. The FDA has started offering incentives to do studies in children, like a longer period of market exclusivity—meaning companies would have more time without having to face competition with generics.

Once a drug is approved, doctors are free to prescribe it based on its official use, a scientific paper, a conversation with a colleague, or even a hunch. If Papazian encounters a doctor who’s hesitant to try a drug off label, and the pharmacist believes it could help, “I’ll fax him the latest research to convince him,” Papazian says. “Nine times out of 10, the doctor says yes.” Even though drug companies profit from the off-label use of their products, they aren’t allowed to advertise unofficial uses. But many have found ways to do it anyway—and have faced hefty fines when caught.

In 2009, Pfizer was charged $1.19 billion, the largest health care fraud settlement in U.S. history, for promoting the anti-inflammatory drug Bextra to treat pains of all kinds, at dosages the FDA never approved (it was pulled from the market in 2005). It illegally promoted three other drugs, too. In 2004, Warner-Lambert, which merged with Pfizer in 2000, pleaded guilty and agreed to pay more than $430 million to resolve criminal charges and civil liabilities after promoting epilepsy drug Neurontin to treat everything from bipolar disorder to migraines to restless leg syndrome.

In some cases, off-label use becomes standard, like Aspirin for patients at high risk of coronary artery disease. Dr. Joel Lexchin, a professor of health policy at York University who’s also worked as an emergency room doctor for 30 years, says he sometimes sees people with headaches “that have a particular trigger point. You press one point in the back of their head, typically where the muscles go into the skull, and they say, ‘That really hurts.’ So you take a bit of lidocaine freezing and inject it into that spot. A couple of millilitres of lidocaine isn’t going to do any harm, unless they’re allergic.” In other cases, when off-label drugs are prescribed for long periods of time or carry significant side effects, “you really would worry about [prescribing it]. At least, I would,” he says.

The use of antipsychotics to treat symptoms of dementia has been especially controversial. “They are prescribed very frequently, too frequently,” says Dr. Nathan Herrmann, head of geriatric psychiatry at Sunnybrook Health Sciences Centre and a professor in the University of Toronto’s faculty of medicine. “They do reduce the agitation, aggression and psychotic symptoms, like hallucinations and delusions,” but they can have harmful side effects, including an increased risk of stroke and mortality. Beyond that, “they can be very sedating. They cause movement disorders. They can make memory and other cognitive functions worse.”

Antipsychotics have been used this way for decades, and for now, they’re still sometimes the best option, Herrmann says—but they should only be doled out for severe problems, like aggression or psychosis, when the patient might harm themselves or others. “Some people are getting them for mild anxiety, or to help with sleep, or because they’re shouting,” which is inappropriate, he says. According to Lexchin, who’s preparing a chapter in a forthcoming book about this, studies suggest about one in three patients in Canadian nursing homes are prescribed antipsychotics, almost always off label.

In 2002, following the death of a six-year-old New Brunswick girl, a coroner’s jury made a recommendation to Health Canada to formally monitor off-label use of drugs. (The anaesthetic in question in the case, propofol, was ruled out as the cause of death.) Health Canada, which regulates drugs, insists it can’t control what doctors prescribe, a position the FDA also maintains. To Stafford and others, this is cause for concern. “It’s something that should be monitored,” he says. “When you talk about drugs being used by millions of Americans or Canadians, we’d better be pretty certain what we’re doing.” A shocking number of prescriptions are written on hazy evidence. “Although some drugs prescribed off label are done so appropriately,” Lexchin says, “most of the off-label prescribing in Canada doesn’t have a scientific basis.”

Monitoring would have many benefits, Lexchin notes: We might be able to pinpoint beneficial uses for drugs that are currently unapproved. We might get a better idea of the harmful effects of others. Until patients across Canada have electronic health records, for one thing, it’s unlikely we’ll be able to do a very good job tracking it, even if Health Canada did take on that role.

If domperidone was officially approved to boost breast milk production, Lavallee says that would be ideal. For those taking off-label drugs, it can feel like a gamble, but for moms nursing new babies, it is one many are willing to take.

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