Adverse Reaction Report No. 324764

Submitted by: Health Professional

Date: 2009

Location: Canada

Patient: Male

Age: 15 years old

Suspect Drug: Strattera

Side Effect: Completed Suicide

This is just one of nearly 600 cases of Canadian kids suffering serious, sometimes fatal side effects suspected to have been caused by ADHD medications in the past 10 years.

A Toronto Star investigation has found a growing number of doctors, nurses, pharmacists and parents are reporting that they believe attention deficit drugs are causing major health problems in patients, many as young as 6 and 7 years old.

The federal government is not listening.

Health Canada, which collects these adverse reaction reports, does not alert the public to the magnitude of these side effects. This is because the regulator has not analyzed the data it collects. It has allowed the industry to largely police itself.

“It is primarily the (drug company’s) responsibility to monitor the safe use of their products,” Health Canada told the Star.

The regulator says the benefits of the drugs, when properly prescribed and used, outweigh the risks. Health Canada and the drug companies also say the side-effect reports show only a suspected connection between the drug and side effect but no medical proof that one caused the other.

Though ADHD doctors and experts worry the Star’s investigation will scare parents from medicating kids in need, they say Health Canada should consider the reports a “red flag” and move quickly to find out if doctors and patients know enough about the drugs’ risks.

All parties involved agree that because doctors and nurses are not required by law to report adverse effects the regulator only learns of a minority of cases.

“It boils down to a simple thing: we need good safety monitoring for medication,” said Dr. Kenny Handelman, an ADHD specialist in Oakville. “That will help us be safer in prescribing medicines to people.”

The Star’s data analysis revealed 7-year-olds were most likely to suffer a serious side effect.

Ten per cent, or nearly 60 cases, of the nearly 600 reviewed involved boys and girls 7 years old.

A nurse said a boy suffered amnesia, mania and psychotic disorder while on Concerta . A 7-year-old girl on the same drug developed Stevens-Johnson syndrome, a potentially life-threatening skin disorder, as well as 13 other side effects, a doctor reported. A boy the same age and on Strattera thought about killing himself.

Twenty-two youths aged 8 to 18 tried to kill themselves and two demonstrated suicidal behaviour. Seven completed the attempt. All boys. An 11-year-old, one 14-year-old, two 13-year-olds and three 15-year-olds. One of the 15-year-olds who ended his life was on an antipsychotic that the reporting nurse believed was partly to blame.

The reports of the 11- and 14-year-old Canadian boys were found in the U.S. government side-effect database. Tuesday, Health Canada contested the accuracy of those reports and was continuing to look into the issue.

The Star also found four deaths that were not suicides, including an 18-year-old girl who died after a cerebral hemorrhage in 2011.

“This is ugly. This is really ugly,” said a concerned Conservative MP Terence Young, when presented with the Star’s findings. Young has been pushing for stricter regulation of the drug industry since his 15-year-old daughter Vanessa died while taking Prepulsid, a digestion aid, in 2000. Health Canada pulled the drug from shelves a few months after her death.

“Every parent who makes a decision about one of these ADHD drugs for their child should be given this information that the Star found on the adverse drug reactions that other children have suffered,” Young said.

Each of the nearly 600 adverse reaction reports reviewed by the Star is the opinion of the doctor, pharmacist or parent that a particular drug has caused a side effect. Anyone can make a report but most of the time it is doctors who do so. Patients’ names are taken out of the reports to protect their privacy.

The drugs in the Star study are commonly prescribed to help manage attention deficit hyperactivity disorder, a term used to describe people with poor focus, impulsivity and hyperactivity.

Though the number of Canadian kids with the disorder is unclear — one estimate puts it at one in 20 children — parents are increasingly turning to these drugs to deal with the diagnosis.

In the 10 years reviewed by the Star, 76 kids on ADHD medications thought about killing themselves. One-third of these were children younger than 10, some as young as 6.

When presented with this number, Dr. Sohail Khattak, a behavioural pediatrician and ADHD expert in Whitby, shook his head and said: “This is an important number. I think (this) information should be available to everyone. If I am going to be on the front line of prescribing the medication, I need to know.”

In 52 of these suicidal ideation reports, the attention deficit drug Strattera is listed as the suspected cause of the side effect. In 12 of the reports, Concerta is listed as the suspected cause. It is also listed as the suspected cause of one completed suicide.

Canadian doctors also prescribe Adderall XR (an extended-release formula), Ritalin, Vyvanse, Biphentin and generic versions to treat ADHD. Unlike other ADHD medications, Strattera is not a stimulant.

“Additional scientific investigations are needed to establish a cause and effect relationship between a medication and an adverse reaction,” said a spokesperson for Eli Lilly Canada, maker of Strattera.

The reports are supposed to play a crucial role in regulating the drug companies.

After a controlled-setting clinical trial involving thousands of participants, if a drug is approved for sale, the reports are often the only way a government can monitor how a drug performs in the much-larger general population. (A clinical trial may not reveal serious drug reactions that occur infrequently or take a long time to materialize.)

The Star found the reports are piling up in Ottawa at an increasing clip: more than one-third of the 600 serious ADHD medication side-effect reports were filed in the past two years alone.

While the reports accumulate, the Canadian regulator says on its website it does not have the expertise to analyze the information for trends and is relying on the U.S. Food and Drug Administration (FDA) for help. When asked about this in late August, the regulator told the Star that the plan to partner with the FDA had been dropped and another strategy would be launched this month.

In the meantime, the drug companies note that they are required by law to forward adverse reaction reports they receive to Health Canada, and say they closely monitor these reports and consider patient safety a priority.

Janssen Inc., the maker of the drug Concerta, said, “We take adverse reaction reports seriously.” The company has a process of “collecting, analyzing and evaluating adverse reaction reports from Canada and across the world” and “proactively communicating findings” to regulators.

Toronto psychiatrist Dr. William Wehrspann, who treats kids and adults, says this regulatory system is like “the police investigating themselves.”

“What bothers me is that it’s left to the pharmaceutical companies to evaluate the effects of the drugs. That’s a conflict of interest,” he said. “It’s unfair.”

Dr. Derryck Smith, an ADHD specialist in B.C., says monitoring side effects is the government’s job. “That’s why we have Health Canada,” he said. “There’s no point in making the reports if (the regulator is) not going to be monitoring.”

Though Health Canada told the Star it does not have the technical expertise to analyze the adverse reaction reports, the regulator said it does monitor drug safety by reading the reports and scientific literature and gathering updates from other regulatory agencies.

The regulator — which a 2011 federal audit found “does not take timely action” and is “slow to assess potential safety issues” — told the Star it has not investigated whether ADHD drugs are leading to a disproportionately high number of suicide-related side effects.

“I’m almost certain no one actually evaluates these reports. Health Canada doesn’t have the resources,” said Dr. Jack Uetrecht, a professor of pharmacy and medicine at the University of Toronto who holds a Canada Research Chair in adverse drug reactions.

The Star conducted data analysis and made an unexpected discovery: ADHD medications Strattera and Concerta were the second- and third-highest suspected causes of reported serious side effects suffered by Canadian kids taking any drug in the past 10 years.

More than any cancer drug.

More than any powerful antipsychotic for kids with serious mental illness.

More than nearly 1,800 other drugs reported to have been the suspected cause of a serious side effect in a Canadian youth since 2001.

In more than 40 per cent of all cases where a youth thought about suicide, an ADHD drug is listed as the suspected cause.

The Star found side effects on most parts of the body — the brain, respiratory system, several major organs, blood, skin, eyes, ears, and hair, including:

20 kids had psychotic disorders

More than 40 kids suffered depression. A doctor reported a 15-year-old felt “worthless.” This teen, made aggressive and depressed by two different, concurrent doses of Adderall XR, hurt himself and thought about killing himself.

24 convulsions, including a 7-year-old on Adderall XR in 2010.

48 hallucinations, including 11 cases of kids hearing voices. In the antiseptic language of adverse-reaction reporting, this side effect is labelled “auditory hallucination.”

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20 overdoses, eight of those intentional, including a 10-year-old boy on Ritalin.

3 strokes: an 11-year-old boy; a 16-year-old boy; and an 18-year-old girl also on birth control

28 cases of heart problems, including irregular heartbeats, blood pressure spikes, chest pain and one ventricular fibrillation (severely abnormal heart rhythm). An 8-year-old girl suffered a heart attack.

23 cases involving side effects on the liver, including a 6-year-old boy on two ADHD drugs with abnormal liver function, and a 12-year-old who died in 2007 after developing a liver tumour.

Other side effects experienced by 7-year-olds include sleep terror, emotional disorder, moaning, convulsion, weight loss, chest pain, muscle twitching, intentional self-injury, depression, staring and fecal incontinence.

A long list of very rare but disturbing side effects, including increased intracranial pressure; muscle coordination problems that made it difficult for kids to walk or speak; involuntary and repetitive body movements; incoherent talkativeness; eyes rolling into the head; blindness in a 14-year-old girl on two ADHD drugs; rectal hemorrhage; angina; blisters covering the body; twisted neck; deafness; face swelling; a tumour in an 8-year-old girl and growth retardation.

In each of the 600 reports, the youth either went to hospital, suffered a disability or life-threatening condition, or died.

The number of serious side-effect reports is far smaller than the number of kids who take the drugs without incident. The drug companies refused, however, to say how many Canadian kids are on their medications.

Once completed, the reports are sent to Health Canada, where officials take out much of the information, leaving only the barest of details, before dumping the reports in a massive public database so difficult to search that doctors and parents have little hope of extracting meaningful information.

The name of the doctor who treated the affected child? Hidden from public view.

Information about whether side effects went away after the child stopped taking the ADHD drug? Though doctors are asked to include this detail, none of the vetted reports in the database included this information.

The city, or even the province, where the child suffered the side effect? Health Canada doesn’t want you to know.

The regulator says it is one of the few in the world to provide adverse-reaction data and that the database increases transparency of drug safety. “Health Canada’s priority remains the health and safety of Canadians.”

The drug companies say they face appropriate scrutiny and oversight by Health Canada once their products hit the market. They point out that important cardiac and psychiatric risk information is contained in their product information document, called a monograph. (Strattera’s monograph carries warnings of increased risk of suicidal thoughts or actions in some kids taking the drug.)

The monographs — lengthy documents, filled with medical jargon — also stress the importance of swift reporting of side effects by doctors and patients. Yet none of the ADHD drugmakers’ monographs mention specifics or numbers of suspected serious side effects, especially psychiatric and heart-related ones, occurring in Canadian kids and reported to Health Canada.

And when presented with the Star’s database analysis, showing their drugs are among the leading causes of side effects in Canadian kids, several companies questioned the value of the reports.

Eli Lilly, maker of Strattera, and Purdue Pharma, maker of Biphentin, and other drug companies, suggested the reports have so many information gaps as to be unusable in terms of drawing any statistical or medical conclusions.

In a letter to the Star, Eli Lilly said the side-effect reports: may show side effects that occurred “spontaneously” and not as a result of the drug; must not be used to compare ADHD drugs based on the number of side effects reported in the database; and contain a “bias” because they do not say whether a patient has other diseases that could have contributed to the adverse reaction.

Strattera is listed as a “suspect” drug in the highest number of reports of serious side effects in children and teens, with 174. Yet it is among the least prescribed, say several ADHD doctors in the Greater Toronto Area.

“Lilly takes patient safety very seriously. We work to ensure that health-care professionals and the public have the most up-to-date information on our products,” the company said the letter.

None of the drug companies responded to Star requests to meet with company officials in person.

The total number of reports the Star found, 575, represents only a fraction of side effects actually occurring in the youth population.

Health Canada acknowledges that side effects are under-reported.

This is in part the result of a flawed federal drug safety law that does not require doctors to report serious side effects. Reporting — for doctors, nurses and pharmacists — is voluntary. Several ADHD doctors told the Star the federal government should change the law.

“The more you report, the more red flags you can see,” said Khattak. “Severe adverse event (reporting) should be made mandatory. This type of information is very crucial.”

Thumbing through a stack of side-effect reports, Khattak was troubled by how many Canadian kids were on multiple ADHD medications. The Star found 61 kids were on more than one ADHD drug, some of them on three, when they experienced side effects. A 16-year-old boy on two ADHD drugs suffered delusion, morbid thoughts and heard voices.

“I really, personally, pharmacologically, don’t understand the reason behind that,” Khattak said. “If you find that the one medication is not adequate, then stop using it and move to something else.”

Khattak worries that the cases involving multiple ADHD drugs are the result of doctors rushing into writing a prescription without first looking for other pre-existing problems like anxiety, obsessive compulsive disorder or depression. Such conditions could explain why the drugs do not work the way they should, he said.

In less than 10 per cent of the cases, an ADHD medication and at least one other drug taken for a separate condition were suspected to have jointly caused the side effect.

Dr. Lily Hechtman, an ADHD expert in Montreal, said the reports in the database are missing crucial information, such as the rate at which suicidal behaviour regularly occurs in the general youth population. Without such information, she said, “these reports have no credit.”

With a voluntary reporting system, the Star found it impossible to compare the rate of suicidal behaviour on ADHD medication with the youth population as only a minority of adverse effects are reported.

Hechtman, who has been treating and researching ADHD since 1975, added that the reports do not reflect another important detail: “The way in which medication is given is really lousy . . . An average dose, for some children, is way too much. You’re supposed to start very low and go up very slowly. To cut corners, to respond to very huge demands of patient loads, sometimes physicians start with an average dose.”

The younger a child, the more difficult it is to definitively diagnose ADHD, said Khattak, who wonders if 6- and 7-year-olds suffering side effects were misdiagnosed and incorrectly medicated. “That is probably where the problem is coming in. I think it’s a diagnostic (issue).”

The drug companies say their medications should not be used in children younger than 6.

The Star found 19 cases of side effects in kids aged 4 and 5. Ten of those reports were serious, including a 5-year-old boy hallucinating and crying and a 5-year-old girl suffering amnesia, anxiety and a speech disorder.