The Health Sciences Authority (HSA) and its Pharmacovigilance Advisory Committee (PVAC) will be strengthening the cardiovascular (CV) labelling of Attention Deficit Hyperactivity Disorder (ADHD) drugs following a review of the data of the reports of sudden death and CV risks of from the US Food and Drug Administration (FDA) 1,2 and the UK Medicines and Health products Regulatory Agency (MHRA) 3. The labelling changes will caution on using ADHD drugs in patients with structural cardiac abnormalities or other serious heart problems and to recommend assessment by a cardiologist for these patients before initiating treatment.
The ADHD drugs that are available locally include methylphenidate (a CNS stimulant) and atomoxetine (a norepinephrine re-uptake inhibitor). There are three licensed products carrying methylphenidate namely, Ritalin® (Novartis), Concerta® (Johnson & Johnson) and Rubifen® (Zyfas Medical) and one product containing atomoxetine, Strattera® (Eli Lilly).
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Findings and actions taken by international regulatory agencies
A) US Food and Drug Administration (FDA)
From the US FDA Adverse Event Reporting System (AERS) safety database, there were 14 paediatric and four adult sudden death cases reported with methylphenidate for the period of January 1992 to February 2005. Of these 14 paediatric cases, six had a documented structural CV abnormality that may have increased the risk of death. As a result of these findings, the US FDA strengthened the labels for methylphenidate-containing products to include warnings of sudden death in patients with structural cardiac abnormalities. For atomoxetine, a total of seven cases of sudden death were reported in three children and four adults taking atomoxetine at therapeutic doses. The US labelling for atomoxetine has also been strengthened to include the above warnings.
B) UK Medicines and Health products Regulatory Agency (MHRA)
The UK MHRA was concerned with the 25 cumulative serious cases of QTc prolongation reported in Eli Lilly's overview report (covering November 2004 – May 2006) on spontaneous adverse event reports, studies and literature reports. The review of this data led the UK MHRA to strengthen the label of atomoxetine to include precautions on use in patients with a history of CV problems including QTc prolongation.
C) Australian Therapeutic Goods Administration (TGA)
The Australian Drug Evaluation Committee (ADEC) of the Therapeutics Goods Administration (TGA) has also separately reviewed the safety of ADHD drugs, examining the sudden death, CV disease and psychiatric adverse events associated with these medicines 4. The ADEC recommended the inclusion of warnings relating to the use of these drugs in patients with CV disease including cardiac structural abnormalities. It also included the recommendation that these patients require the assessment by a cardiologist before the initiation of treatment.
Assessment by HSA’s PVAC and follow up actions by HSA
To date, HSA has not received any ADR reports associated with atomoxetine or reports of sudden death associated with methylphenidate.
Nevertheless, based on the PVAC's assessment of the pharmacology of the drugs and the plausibility of the ADR occurrences, HSA advises healthcare professionals to exercise caution when using ADHD drugs in patients (including children) with structural cardiac abnormalities or other serious heart problems. An assessment by a cardiologist is recommended in patients with existing structural cardiac abnormalities or other serious heart problems before initiating treatment with ADHD drugs, followed by supervision of cardiac function throughout treatment. Caution in using ADHD drugs should also be exercised in CV conditions such as severe hypertension, heart failure, recent myocardial infarction and atherosclerosis. In addition, atomoxetine should also be used with cautious in patients with congenital or acquired QT prolongation and those with a family history of QT prolongation.
The local package inserts of the affected ADHD drugs will be updated to include the above CV safety information.
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References
- US FDA safety review. 27 Apr 2004.
- US FDA safety review. 28 Feb 2006.
- MHRA: Strattera (Atomoxetine) – Preliminary assessment report December 2005.
- ADEC 247th Meeting minutes, 4 Aug 2006.
