Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

26th Annual Conference of the Canadian Academy of Child and Adolescent Psychiatry 2006

Toronto, Ontario / November 12-14, 2006

Following the reinstatement of the extended-release mixed amphetamine salts (MAS XR) on the Canadian market in August 2005, there are still reactions from physicians and patients alike, according to Canadian child and adolescent psychiatrists in attendance here at the meeting.

In February 2005, Health Canada unilaterally decided to withdraw the widely used amphetamine product from the Canadian market. Their decision was based on concerns generated by case reports of sudden/cardiac death or stroke in patients who were prescribed MAS immediate-release (IR) or XR formulations; neither formulation was withdrawn in any other country. At the time, physicians who were treating patients for attention deficit/hyperactivity disorder (ADHD) expressed concern over both the suddenness of the action as well as the fact that Health Canada acted without consulting any specialists in ADHD who would be better qualified to analyze the data.

This development was cause for concern to both patients and physicians directly affected by ADHD. The Canadian Attention Deficit/Hyperactivity Disorder Resource Alliance (CADDRA) is a national independent not-for-profit association consisting of physicians who support patients and their families who suffer from ADHD. As leaders in their field, CADDRA members conduct research, treat patients and design practice guidelines for ADHD.

According to Dr. Umesh Jain, CADDRA chair and child/adolescent specialist, Centre for Addiction and Mental Health, Toronto, Ontario, Health Canada officials appeared not to have taken into consideration what impact the sudden withdrawal of this medication (at the time, taken by approximately 11,000 patients in Canada) would have on patients and their ability to cope with re-emerging symptoms of ADHD as well as the physicians who needed to find alternative treatment for those patients.

After a long deliberation between a panel of ADHD experts and Health Canada, the MAS XR formulation was reinstated in August 2005.

Nevertheless, the suspension of the Notice of Compliance for MAS XR “gave us an opportunity to learn about what happened to our patients” when they were switched to alternative therapies, Dr. Jain told the audience.

CADDRA members took the initiative to develop and disseminate a fax-back questionnaire to all physicians known to prescribe MAS XR at the time of its withdrawal and asked patients or their caregivers to respond. Information was collected by an independent third party for tabulation.

Above all, CADDRA members wanted to know which alternative medication patients had been prescribed after the suspension, how the patients responded to the alternative therapy and, when reinstated seven months later, how many former MAS XR patients went back to the same medication. “This was a CADDRA-sponsored initiative, it was not sponsored by industry,” Dr. Jain emphasized, adding that they also obtained the raw data for analysis to ensure correct data entry.

They also enjoined statistician Dr. David Streiner, Professor Emeritus, Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, to validate both the analyses and conclusions from the survey.

Overall, 208 questionnaires were completed and returned. Of these, 193 respondents had been prescribed MAS XR at the time of its suspension. CADDRA members felt they constituted a representative sample of ADHD-treating physicians across the country.

“By far, the majority at 37% were switched over to a once-daily, extended-release form of methylphenidate,” reported Dr. Jain, who characterized it as a fairly predictable choice, considering that the product was widely marketed at the time. Switches to dextroamphetamine sulfate were a “very close second” at 32% of patients, followed by switches to the non-stimulant atomoxetine at 16%.

Alternative Medication

Survey participants were also asked about the effect of being on an alternative medication compared with MAS XR. Overall, 54% of patients said their symptoms worsened when they were switched to an alternative therapy; 8% said there was no change in their symptoms and 11% indicated that symptoms improved.When asked about specific symptoms, patients or caregivers also frequently indicated they preferred their medication prior to the switch off MAS XR. For example, over half of respondents felt that the quality of their social interactions was better on MAS XR than when they were taking an alternative medication, while over 60% indicated that their behaviour while on MAS XR was also improved before the switch. Some 60% also signified that overall symptom control was better on MAS XR than on alternative therapy.

Thus, as Dr. Jain observed, “When patients do well on [MAS XR], they do really well on it and when you take them off it, they would never be happy with anything else.” He explained that this would reflect the nature of the MAS XR preparation and patients often experienced a “profound effect” on treatment.

Following Reinstatement

Following reinstatement of MAS XR, 65% of patients who had been previously receiving MAS XR therapy elected to go back on it. Of those patients who remained on alternative therapy, 21% were unaware that MAS XR was available again. Another 22% of respondents said that they remained on the alternative therapy “due to safety concerns” about the previous medication. The same percentage at 22% remained on alternative therapy because they felt their symptoms were controlled and did not feel the need to change.

“We are only talking about approximately 200 out of 11,000 patients who had been on [MAS XR] so it’s not a big sample, but I think at least in the way the data was obtained, it is a fairly good representation of the regionality of the country as well as some of the issues associated with the medication itself,” Dr. Jain concluded.

At present, physicians are still reticent in their prescribing habits, according to Dr. Jain, “which is not necessarily wrong, as it is up to Health Canada to warn the public about some of the issues that may have been there. A lot of the same issues were there 40 years ago. The withdrawal made it look as if these were new symptoms that Health Canada had identified and unfortunately, it created an environment of tension.” Health Canada has recently advised that all ADHD drugs in Canada will now carry cautionary warnings of these rare but serious adverse events.

Expanding Armamentarium

Since there is a potential for drug abuse or diversion of ADHD compounds, researchers are trying to discover different avenues to limit the risk of substance abuse among ADHD patients. At the present time, an optimal strategy might be to prescribe long-acting or XR preparations. This issue was addressed here in a separate session by Dr. Robert Findling, Professor of Psychiatry and Pediatrics, Case Western Reserve University, Cleveland, Ohio. He reviewed novel formulations of various stimulants that are likely to find a niche in the future treatment of ADHD.

SPD465 is a 16-hour sustained-release MAS that has an IR, delayed-release and further delayed-release mechanism of action. “SPD465 is meant to look as much as possible as MAS XR,” Dr. Findling explained, “while at the same time providing an extra dose of IR MAS eight hours later.” In a study evaluating the new triple-bead preparation, both doses of SPD465 provided superior results in terms of the mean numbers of math problems adolescents were able to solve compared with IR MAS. As expected, insomnia and anorexia did occur in conjunction with the new 16-hour MAS formulation but none of the patients withdrew from the study because of side effects.

Another formulation that has been developed is lisdexamfetamine (LDX). As a prodrug, LDX must undergo chemical conversion before the active ingredient becomes bioavailable and as such, should significantly curtail its diversion and subsequent abuse. In laboratory animals, no lethal dose of LDX has yet been identified, as Dr. Findling confirmed. In an outpatient study, LDX titrated up to 70 mg reduced ADHD rating scale (ADHD-RS) symptom scores by a mean of 26.9 points compared with baseline in children who had previously received ADHD therapy. This represents an average improvement of more than 60% on the rating scale. Investigators also used the Clinical Global Impressions-Improvement scale to rate patients symptoms. After only six months, 95% of patients were evaluated as “much improved” or “very much improved.”

In another naturalistic study, children assigned to the methylphenidate transdermal system (MTS) or osmotic-release methylphenidate had significantly greater changes in their ADHD RS-IV total scores at the end of seven weeks compared with placebo, with very similar effect sizes being noted for the two active agents. It has several attractive features, as Dr. Findling outlined, including the fact that it is a clear, thin patch that is applied like a bandage and which adheres to the skin surprisingly well. This patch is designed to stay on during the normal daily activities of a child such as swimming, exercising or bathing. This is the first non-oral medication for ADHD.

Based on nine-hour wear times, significant improvement in Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) scores were demonstrated in children treated with the patch compared with placebo over the nine-hour wear time, with clinically meaningful effects being observed out to 12 hours, as Dr. Findling noted.

No serious adverse events were noted in this trial and there were no abnormalities on ECG, vital signs or any other laboratory values. Erythema at the patch site did occur but it was almost uniformly mild and most children did not report being bothered by dermatological symptoms.

Another formulation of methylphenidate, dexmethylphenidate, is available in the US in both IR and XR formulations. The latter is administered as once-daily treatment.

This delivery system is an advance in single-isomer technology and is formulated by isolating the active d-isomer of methylphenidate. Researchers believe that the d-isomer is responsible for the management of the symptoms of ADHD.

According to study results in children and adolescents, the new preparation is effective in treating ADHD symptoms, based on both teachers’ and parents’ reports, producing a response rate approaching 70% “consistent with response rates achieved in all of the stimulant studies,” Dr. Findling observed.

A multilayer-release formulation of methylphenidate is already available in Canada and the capsules produce effects that are comparable to those achieved with twice-daily IR methylphenidate. Duration of effect for the controlled-release capsules is between 10 and 12 hours.

Questions and Answers

The following question-and-answer session is based on discussions with Dr. Robert Findling, Professor of Psychiatry and Pediatrics, Case Western Reserve University, Cleveland, Ohio; and Dr. Lily Hechtman, Professor of Psychiatry and Pediatrics, McGill University Health Centre, Montreal, Quebec, during the scientific sessions.

Q: How well does the MTS patch adhere to the skin?

Dr. Findling: Parents always ask about how well the patch is going to stick and whether their children can swim or go to the gym. For most of the children in the study, the patch stuck on really quite well even though we placed no restrictions on their activity. But once it is taken off, it doesn’t really stick very well any more.

Q. What do you believe would be the optimal use for the novel formulations of stimulant preparations?

Dr. Hechtman: I think the long-acting MAS XR that lasts 16 hours is more geared toward the adult and adolescent ADHD patients, where even the 12-hour medication does not address the needs of these people; often, you have to supplement it with short-acting preparation towards the latter part of the day for homework, projects, etc. because the 10- to 12-hour preparations don’t cover them. So the 16-hour MAS XR is meant to cover that need. LDX was meant to decrease abuse, not by patients themselves, but by others who buy the drugs and inject them. As for the patch, my colleagues in the US who have used it feel that it provides parents with some control over how long their child is on medication. So if they decide they want the child covered for the time they go to church, for example, they can tailor the medication to the needs of their children.

Note: At the time of printing, SPD465, lisdexamfetamine dimesylate, methylphenidate transdermal system and dexmethylphenidate are not available in Canada.