Between 1999 and 2004, 19 children prescribed ADHD medications were reported to the FDA voluntary reporting system to have died suddenly, and 26 children were reported to have experienced cardiovascular events, including heart palpitations, strokes and cardiac arrests, and this prompted public concern about these medications, according to Jeffrey A. Towbin, MD, executive co-director of the Heart Institute at the Cincinnati Children’s Hospital Medical Center in Ohio.
According to Towbin, some methylphenidates have been linked with increased heart rates and blood pressures, but ECGs show little to no change. Similar results were found for other ADHD treatments containing amphetamines. Amphetamine abuse, however, was associated with certain cardiac problems, including myocardial hypertrophy and endocardial thickening.
Labeling issues
Although little evidence linked stimulants with sudden unexplained cardiac deaths in children, health officials in Canada suspended the extended-release formulation of Adderall (Shire) in 2005 based on data from U.S. marketing reports.
The FDA subsequently added a warning to Adderall XR’s label recommending against the medication’s use in patients with structural cardiac abnormalities. The warning noted that misuse may cause serious cardiovascular events and sudden death. Canadian health officials eventually reinstated marketing authorization of Adderall XR with the stipulation that the drug monograph contain the same warnings.
In a 2006 meeting of the FDA’s Drug Safety and Risk Management Committee, research suggested a high number of sudden deaths and serious cardiovascular events among children receiving methylphenidates. Consequently, the FDA recommended adding a black box warning to these products.
The FDA’s Pediatric Advisory Committee, however, did not follow the Drug Safety and Risk Management Committee’s recommendations for a black box warning, instead suggesting that the information be placed in the highlights section of a newly formatted label with warnings stating that children with structural heart defects, cardiomyopathy or heart rhythm disturbance may be at risk for adverse cardiac events.
The FDA took further action in 2007 by directing all manufacturers of drugs approved for treatment of ADHD to develop patient medical guidelines to alert patients to possible cardiovascular risks and adverse psychiatric symptoms and advise them to take precautions. Although useful for the public, these guidelines also increased the fear factor, said Towbin.
When analyzing data from a screening perspective, approximately half of individuals who experienced sudden death had generally undetected pre-existing conditions and were using multiple drugs simultaneously. These results therefore underscored the importance of following AHA screening guidelines and conducting a good physical exam and obtaining a thorough family history, Towbin said.
Controversy
Current prescribing label instructions of ADHD medications emphasize a physical exam and a review of personal and family history for relevant cardiac events before initiating stimulant treatments. If abnormalities are detected, practice guidelines recommend pretreatment ECG screening.
The AHA recommends that ECGs are reasonable but not mandatory when prescribing these medications.The AHA also notes it would be optimal for pediatric cardiologists to read the ECG results, although it is not necessary.
“Stimulants continue to play a role in chronic ADHD,” said Towbin. “Concerns regarding safety have been outlined and have reasonable theoretical basis, but data are really pretty weak for sudden death.”
More information is needed to create better guidance, Towbin noted, and hopefully future studies will provide physicians with the required data. — by Melissa Foster
For more information:
- Towbin JA. X2002. Presented at: 2010 AAP National Conference and Exhibition; Oct. 2-5, 2010; San Francisco.
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