Since 2010 CADDAC has shared our concerns about the direct substitution of methylphenidate ER-C, a generic medication, for OROS® methylphenidate (Concerta) with Health Canada. This was done through documentation, caregiver and patient survey results and several face to face meetings.
A Canadian research paper reviewing data on this issue, was recently published in the Clinical Therapeutics Journal on drug therapy. The new paper, “Differences in Adverse Event Reporting Rates of Therapeutic Failure Between Two Once-daily Extended-release Methylphenidate Medications in Canada: Analysis of Spontaneous Adverse Event Reporting Databases” looked at treatment failure adverse events of generic versions of OROS® methylphenidate (Concerta).
The research paper reported that a 10-fold higher reporting rate of therapeutic failure adverse events was found with the Canadian generic product, methylphenidate ER-C (Teva product) as compared to OROS® methylphenidate (Concerta). Although adverse events are more typically thought of as additional unwanted effects of a drug (e.g. a headache or rash), if a product fails to produce its expected intended clinical effect, or fails to produce its clinical effect for the intended duration, there may be an adverse outcome for the patient, including an exacerbation of the condition for which the product is being used. The Health Canada Guidance on Reporting Adverse Reactions to Marketed Health Products provides the example of a patient whose condition is well-stabilized, but deteriorates when the patient changes to a different brand or receives a new prescription as an example of an unusual failure in efficacy, which is a reportable adverse event.
Additionally, the study compared Canada-US data and demonstrated that this 10-fold increase in Canadian therapeutic adverse events was very similar to data seen with a US generic product by Mallinckrodt. This US product’s bioequivalence status has been removed by the FDA and it is being considered for further regulatory action. Adverse consequences for patients, such as disruptions in academic performance, school suspensions, and onset of adverse social behaviors, showed similarities between the US and Canadian generics. The Canadian study data reported that “Impacts on social functioning, such as disruption in work or school performance or adverse social behaviors, were found in 22.2% of cases.” US reports for the methylphenidate ER generic product identified adverse impacts on social functioning in more than 30% of cases.
The paper also highlighted differences in the generic medication from the brand Concerta Plasma (blood) concentrations. The generic product concentrations peaked approximately 2 hours earlier and declined more rapidly than those of Concerta. As one would expect, adverse event time of day data, showed “overdose like” symptoms to be more common in the morning and lack of efficacy to be more common in the afternoon. Methylphenidate ER-C, was reported not to be effective throughout the duration of the day in 42.6% of Canadian cases, with this early loss of efficacy occurring in the afternoon for 64.3%. Signs or symptoms of too much methylphenidate exposure were also reported in 13.5% of the cases with 58.1% occurring in the morning. Therapeutic failure occurred within one week of starting treatment with methylphenidate ER-C in 72.1% of the cases.
CADDAC’s experience was included as well, “Since the market approval of the first generic drug in Canada, the Centre for ADHD Awareness Canada (CADDAC), a patient advocacy group, has received reports of issues with generic methylphenidate ER medications, including shortened or reduced clinical effects and adverse events.”
The paper concluded that “The results of the current study are consistent with a growing literature pointing to a potential safety issue with the methylphenidate ER-C generic product. Taken together, this information suggests that an investigation should be conducted by Health Canada, to evaluate the potential differences between methylphenidate ER-C and OROS® methylphenidate. If important differences are identified, this would further suggest that the bioequivalence metrics currently used to support the interchangeability of OROS® methylphenidate with methylphenidate ER-C may not be adequate.”
Earlier this year Health Canada (HC) released a notice regarding consultation on the proposed modification to bioequivalence standards for this type of medication. In September, CADDAC contacted HC expressing our pleasure with this review, but asked whether any decisions made would also impact medications that had already been approved for bioequivalency. This is information is important because the medication for ADHD in question would fall under this category. If this was not to be the case, CADDAC wanted to know whether labeling informing patients that this medication was approved under old guidelines would be required. CADDAC has yet to hear back from Health Canada.