Canada Reverses Ban On ADHD Medication

Health Canada has informed Shire BioChem Inc. that the company can resume production and distribution of its medication for treatment of attention-deficit/hyperactivity disorder (ADHD), mixed amphetamine salts–extended release, sold under the brand name Adderall XR.

The decision was announced a little over six months after Canadian sales of the stimulant were suspended out of concern about reports of serious adverse events, including sudden cardiac death and stroke.

Canada's Health Products Directorate, equivalent to the U.S. Food and Drug Administration (FDA), ordered Adderall XR off the Canadian market in February after reviewing safety information voluntarily submitted by Shire. That information included 20 international reports of sudden death in patients taking mixed amphetamine salts. None of the deaths occurred in Canada. The data indicated the deaths were not linked to overdose, misuse, or abuse. Fourteen of the deaths occurred in children, six in adults.

The FDA, as well as other regulators around the world, reviewed the same dataset. The Canadian agency was the only regulator to pull the drug off the market (Psychiatric News, March 4).

Following the suspension of Canadian sales, Shire requested review of the decision by a committee made up of independent outside consultants. Health Canada formed the Adderall XR New Drug Committee, which included a pediatric cardiologist, a physician specializing in pediatric developmental and behavioral disorders, and a pharmacoepidemiologist.

The Adderall XR New Drug Committee reviewed extensive documentation supplied by both Health Canada and Shire, ultimately concluding that “an increased risk of sudden cardiac death and/or stroke with Adderall XR compared to alternate active treatments has not been proven.”

As a result, the committee recommended that Health Canada rescind its suspension order and allow the the product to be returned to the market.

The committee also noted, however, that “such an increase [in risk of sudden cardiac death associated specifically with Adderall XR use] has not been ruled out due to limitations in the data currently available for analysis.” Therefore, the committee recommended several steps be taken prior to the product's going back on pharmacy shelves.

In particular, the committee members stressed that, theoretically, an increased risk of sudden cardiac death or stroke potentially exists with all drugs used to treat ADHD. Thus, they recommended that Health Canada seek expert consultation “on the appropriateness of potential additional cautions (e.g., strenuous exercise, use of other stimulants, family history of sudden cardiac death) in patients treated with any ADHD drug (stimulant or non-stimulant) that might be considered in the assessment of benefit versus risk for an individual patient.”

The Adderall XR New Drug Committee also recommended that Health Canada approve revised product labeling submitted by Shire in November 2004. That proposed labeling (virtually identical to the approved labeling in the United States) includes warnings regarding reports of sudden death in patients taking therapeutic doses of amphetamines, particularly children with structural cardiac abnormalities. The new Canadian labeling will also add myocardial infarction, sudden death, and stroke to the list of potential adverse events.

Lastly, the label will include the statement, “Adderall XR generally should not be used in patients with structural cardiac abnormalities.”

The committee further recommended that Health Canada “enhance postmarketing surveillance for all stimulant drugs used in the management of ADHD,” but did not list specific steps they thought should be taken. The committee also noted that while an increased risk of adverse cardiac events associated with stimulant medications “is lacking, even in the absence of this information, it may still be prudent for a baseline EKG be obtained prior to implementing drug therapy” for patients who are involved in strenuous exercise, use more than one stimulant medication, or have a family history of sudden cardiac death.

Shire's letter to Canadian health care professionals is posted at<www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/adderall_xr2_hpc-cps_e.pdf>. The report of the Adderall XR New Drug Committee is posted at<www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ndca_rep_cnma_rap_2005-08-25_e.pdf>.▪