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Drug Safety Oversight Board Meeting, March 17, 2011

Public Summary

The Executive Director updated the Drug Safety Oversight Board (DSB or Board) on Drug Safety Communications posted and in development since the February 17, 2011 meeting. The following is a list of the posted risk communications:

Drug Safety Communications Posted since the January 20, 2011 DSB meeting:

  • February 22, 2011: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns: FDA issued a DSC informing healthcare professionals that it has updated the Pregnancy section of drug labels for the entire class of antipsychotic drugs. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.
  • March 1, 2011: Safety review update of abacavir and possible increased risk of heart attack: FDA issued a DSC informing the public about its ongoing safety review of abacavir and a possible increased risk of heart attack. There has been conflicting information on the potential increased risk of heart attack with abacavir treatment. An increased risk of heart attack (myocardial infarction or MI) has been seen in several observational studies and one randomized controlled trial (RCT) with abacavir. However, an increased risk of heart attack has not been seen in other RCTs and the safety database maintained by the drug manufacturer.

    FDA conducted a meta-analysis of 26 randomized clinical trials that evaluated abacavir. This meta-analysis did not show an increased risk of MI associated with the use of abacavir. Healthcare professionals should continue to prescribe abacavir according to the professional label. Patients should not stop taking their abacavir without first talking to their healthcare professional.
  • March 2, 2011: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs): FDA issued a DSC informing the public that prescription proton pump inhibitor (PPI) drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time (in most cases, longer than one year). In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.
  • March 4, 2011: Risk of oral clefts in children born to mothers taking Topamax (topiramate): FDA issued a DSC informing the public of new data that show that there is an increased risk for the development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with topiramate (Topamax and generic products) during pregnancy.

    The benefits and the risks of topiramate should be carefully weighed when prescribing this drug to women of childbearing age, particularly for conditions not usually associated with permanent injury or death. Alternative medications that have a lower risk of oral clefts and other adverse birth outcomes should be considered for these patients. If the decision is made to use topiramate in women of childbearing age, effective birth control should be used.
  • March 4, 2011: Liver injury warning to be removed from Letairis (ambrisentan) tablets: FDA issued a DSC informing the public that it is removing the warning related to liver injury from the boxed warning of the Letairis (ambrisentan) tablet label. Also, further evaluation of the clinical trial data and post-marketing safety information has led the FDA to conclude that routine monthly serum liver enzyme testing for patients taking Letairis is not necessary.
  • March 8, 2011: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution: FDA issued a DSC notifying healthcare professionals of serious health problems that have been reported in premature babies receiving Kaletra (lopinavir/ritonavir) oral solution. Kaletra oral solution contains the ingredients alcohol and propylene glycol. A safe and effective dose for babies less than 14 days of age (whether born premature or full term) has not been established.

The DSB discussed two topics:
1. Update on Stimulant Drugs Used to Treat Attention Deficit Hyperactivity Disorder (ADHD)
2. Update on Systems Biology Modeling and Drug Safety

The views expressed by non-CDER employees are those of the individual and not necessarily the opinion of their respective government agency.

Update on Stimulant Drugs Used to Treat ADHD

The Board invited a guest expert, Dr. William Cooper, Professor of Pediatrics and Preventive Medicine at Vanderbilt University School of Medicine, a principle investigator of the ADHD Medications and Serious Cardiovascular Disease Study funded by FDA/AHRQ. Dr. Cooper's epidemiology research has focused on issues related to the effects of health policy on vulnerable populations of children, including children enrolled in government insurance programs and children with chronic health conditions. In recent years, he has focused on the unexpected effects of medicine on children, including psychotropic drugs and drugs taken by pregnant women and their effect on the developing fetus. He provided an interim update on the FDA/AHRQ study.

The Board discussed the following regarding stimulant drugs used to treat ADHD:

  • Background information regarding stimulant medications used to treat ADHD and the findings which led to the concern that the ADHD medications might increase cardiovascular risk
  • The actions that FDA has taken to address this concern
  • The published and ongoing studies addressing cardiovascular risk and ADHD medications
  • The design and methods used in the FDA/AHRQ sponsored study of ADHD medications and serious cardiovascular disease
  • An interim update on the FDA/AHRQ sponsored study of ADHD medications and serious cardiovascular disease
  • Use trends for the medications used to treat ADHD

Update on Systems Biology Modeling and Drug Safety

The Board heard presentations by two speakers from CDER and discussed successes to date and a path forward for Systems Biology Modeling (SBM) and Drug Safety Predictions. When applied to drugs and drug safety, SBM is a computational approach designed to predict how effective or safe a drug might be based on known characteristics of the drug and previous experience with similar drugs. A clinical trial may be simulated with potential safety outcomes predicted.

The Board discussed the following:

  • The history of SBM in CDER and efforts in drug safety prediction
  • The sources of data and the tools for assessment in modeling efforts related to drug safety
  • How the lessons learned from a Drug Safety Workshop held at FDA in January 2011 could be applied to SBM
  • The use of safety biomarkers, intermediate endpoints and integrated endpoints, as related to modeling
  • The application of the Archimedes model in simulating the SCOUT trial, which studied sibutramine.
  • An update of the Entelos Simulation Projects on Drug-Induced Liver Injury (DILI) and the Cardiovascular (CV) Risk Model
  • A DILI-simulation model designed to improve the assessment and prediction of liver toxicity through a computer model representing healthy liver function and drug induced liver injury
  • A CV Risk Model developed to predict the clinical trial results with a specific pharmacologic drug class.
  • Future areas to explore in SBM