FDA ALERT [10/2007]:  FDA has received reports of deaths and serious cardiopulmonary reactions following the administration of ultrasound micro-bubble contrast agents used in echocardiography.  Four of the 11 reported deaths were caused by cardiac arrest occurring either during infusion or within 30 minutes following the administration of the contrast agent; most of the serious but non-fatal reactions also occurred in this time frame.  FDA has requested that a Boxed Warning and other warnings emphasizing the risk for serious cardiopulmonary reactions be added to the labeling for these products and that use of these products be contraindicated in patients with unstable cardiopulmonary status, including patients with unstable angina, acute myocardial infarction, respiratory failure, or recent worsening congestive heart failure. 

 

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Considerations

Physicians who administer echocardiographic micro-bubble contrast agents should consider the following:

• Assess all patients for the presence of the following conditions that would preclude the use of these agents:
  • Right-to-left, bi-directional, or transient right-to-left cardiac shunts
  • Clinically unstable or recent worsening congestive heart failure
  • Acute myocardial infarction
  • Serious ventricular arrhythmias or at high risk for arrhythmias due to QT prolongation
  • Respiratory failure
  • Severe emphysema, pulmonary emboli or other conditions that compromise pulmonary arterial vasculature
    
    
• Monitor all patients receiving micro-bubble contrast agents for serious cardiopulmonary reactions during the infusion and for 30 minutes following completion of administration.

Information for the Patient

• Tell the physician performing the echocardiogram if you:
  • have a congenital heart defect
  • have a heart or lung condition that has recently gotten worse
  • have ever had a reaction to a drug given to you during an echocardiogram

Data Summary

Micro-bubble ultrasound contrast agents are a sterile suspension of perflutren gas microspheres that are indicated for use in patients with suboptimal echocardiograms.  These products are used to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border.  Definity and Optison are the only micro-bubble products approved for use in the United States.  FDA approved Optison in 1997.  The manufacturer of Optison voluntarily temporarily suspended marketing the product in 2005.  Definity has been marketed since FDA approval in 2001.  Most postmarketing reports are associated with the use of Definity.

FDA received postmarketing reports of 10 deaths following the administration of Definity and one death following Optison administration.  Most of the reported deaths were patients with severe underlying conditions and occurred one to 12 hours following administration of the contrast agent.  Some patients were also being treated with other medications that could have contributed to their death. Four deaths, following cardiac arrest, occurred either during or within 30 minutes of the administration of Definity.  One patient received Definity and underwent a cardiac stress test while two patients had severe congestive heart failure and one patient was undergoing mechanical ventilation for respiratory failure. 

FDA also received approximately 190 reports of serious non-fatal reactions following the administration of Definity and nine reports of serious non-fatal reactions following Optison administration.  Many of these reports describe the acute onset of symptoms suggestive of an anaphylactoid reaction including dyspnea or urticaria.  Other reports describe cardiopulmonary reactions with cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias (atrial fibrillation, suprarventricular tachycardia, ventricular tachycardia or fibrillation), cardiac ischemia, hypotension, respiratory distress, and oxygen desaturation without signs or symptoms typical of an allergic reaction.  Many of these serious reactions occurred either during or within minutes of administration of the ultrasound contrast agent. 
The manufacturers of Definity and Optison have agreed to revise the labeling for these products in order to optimize their safe use by adding the following:

• Boxed Warning for cardiopulmonary reactions and Warnings for cardiopulmonary and hypersensitivity reactions that include recommendations to monitor vital signs, cardiac rhythm, oxygen saturation and to have equipment for resuscitation and trained personnel readily available.
  
  
• Contraindications for use in patients at particular at risk from cardiopulmonary reactions specifically patients with known cardiac shunts, clinically unstable or recent worsening of congestive heart failure, symptomatic arrhythmias or at high risk for arrhythmias due to QT prolongation, respiratory failure, severe emphysema, pulmonary emboli or other conditions that compromise pulmonary arterial vasculature. 
  
  
• A statement in the Indications section cautioning that the safety and efficacy of the use of Definity with exercise or pharmacological stress testing have not been established.

The manufacturers will also conduct a postmarketing safety study to further assess the risks of serious cardiovascular reactions

Date created: October 12, 2007