FDA Drug Safety Communication: FDA continues to receive reports of a rare, but serious and potentially fatal adverse effect with the use of benzocaine sprays for medical procedures
[04-07-2011] The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals that the Agency continues to receive reports of methemoglobinemia, a serious and potentially fatal adverse effect, associated with benzocaine sprays. These sprays are used during medical procedures to numb the mucous membranes of the mouth and throat.
Benzocaine sprays are marketed under different brand names such as Hurricaine, Cetacaine, Exactacain, and Topex.
Methemoglobinemia is a rare, but serious condition in which the amount of oxygen carried through the blood stream is greatly reduced. In the most severe cases, methemoglobinemia can result in death. Patients who develop methemoglobinemia may experience signs and symptoms such as pale, gray or blue colored skin, lips, and nail beds; headache; lightheadedness; shortness of breath; fatigue; and rapid heart rate. In some cases, symptoms of methemoglobinemia may not always be evident or attributed to the condition. The signs and symptoms usually appear within minutes to hours of using benzocaine. Conditions such as anemia, heart disease, and lung disease (e.g., emphysema) may exacerbate the toxicity of methemoglobinemia.
In 2006, FDA issued a Public Health Advisory warning about methemoglobinemia with the use of benzocaine sprays during medical procedures. Since then, FDA has received 72 new cases of methemoglobinemia, including three resulting in death, associated with the use of benzocaine sprays, bringing the total to 319 cases (see Data Summary below).
A review of the cases indicates that the development of methemoglobinemia after treatment with benzocaine sprays may not be related to the amount applied. In many cases, methemoglobinemia was reported following the administration of a single benzocaine spray. In other cases, methemoglobinemia resulted after excessive amounts were applied. The amount of benzocaine contained in a single spray varies across the different products, and depends on the concentration of the solution, the amount of time the actuator is depressed, the residual volume in the can, and the spatial orientation of the can during spraying. Symptoms may appear within minutes to one or two hours after using benzocaine.
FDA is continuing to evaluate the safety of benzocaine (also see separate Drug Safety Communication on Benzocaine Gels and Liquids), and the Agency will update the public when it has additional information. FDA will take appropriate regulatory actions as warranted.
- Benzocaine sprays are marketed under different brand names such as Hurricaine, Cetacaine, Exactacain, and Topex.
- Be aware that benzocaine sprays may cause a serious condition where the amount of oxygen carried through the blood stream is greatly reduced (methemoglobinemia).
- Labels of marketed benzocaine sprays are not currently required as of yet to warn about the risk of methemoglobinemia.
- Know how to recognize the signs and symptoms of methemoglobinemia: pale, gray or blue colored skin, lips, and nail beds; headache; lightheadedness; shortness of breath; nausea; fatigue; and rapid heart rate.
- If you or someone you are caring for has any of these symptoms after receiving benzocaine, seek medical attention immediately. Symptoms of methemoglobinemia generally appear within minutes to one or two hours after using benzocaine spray.
- FDA encourages all patients to talk to their healthcare professional if they have concerns about any treatment they are receiving.
- Report side effects or medication errors from the use of benzocaine to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
- Labels of marketed benzocaine sprays are not currently required as of yet to warn about the risk of methemoglobinemia although the use of benzocaine can cause this condition.
- Carefully monitor patients who receive benzocaine sprays for signs of methemoglobinemia during the procedure and for at least two hours post-application. Signs include pale, gray or blue colored skin, lips, and nail beds; shortness of breath; decreased blood oxygen saturation levels; and tachycardia. These indicate a moderate to severe level of methemoglobin and a marked reduction in the oxygen-carrying capacity of the blood. A characteristic color of the blood (chocolate-brown rather than blood-red) may indicate methemoglobinemia, but this change is a late sign of the condition.
- Symptoms may appear within minutes to one or two hours after using benzocaine.
- Be aware that the development of methemoglobinemia after treatment with benzocaine spray may not be related to the amount applied; methemoglobinemia has been reported to occur following the administration of a single benzocaine spray.
- Be aware that the amount of benzocaine contained in a single spray varies among different manufacturers and depends on the concentration of the solution, the amount of time the actuator is depressed, the residual volume in the can, and the spatial orientation of the can during spraying.
- Methemoglobinemia can cause unreliable oxygen saturation readings on a standard 2-wavelength pulse oximeter when used to assess the amount of oxygen bound to hemoglobin. If blood is drawn to check for methemoglobinemia, an FDA-approved co-oximeter should be used to reliably measure methemoglobin.
- Patients who have breathing problems such as asthma, bronchitis, or emphysema, patients with heart disease, and patients who smoke are at greater risk for complications related to methemoglobinemia.
- Infants less than four months of age, elderly patients, and patients with certain inborn defects such as glucose-6-phosphodiesterase deficiency, hemoglobin-M disease, NADH-methemoglobin reductase (diaphorase 1) deficiency, and pyruvate-kinase deficiency may also be at greater risk of developing methemoglobinemia.
- Medications, foods, and water containing nitrites and nitrates may also induce methemoglobin formation, which will be additive to that formed by benzocaine products.1, 2
- Report adverse events or medication errors involving benzocaine to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.
On February 10, 2006, FDA issued a Public Health Advisory warning about the risk of methemoglobinemia associated with benzocaine sprays used to locally numb mucous membranes of the mouth and throat for medical procedures. At the same time, the Veterans Health Administration (VHA) announced its decision to stop using benzocaine sprays for these purposes. Since the issuance of the Public Health Advisory in 2006, FDA has received 72 new cases of serious adverse events, including three deaths, associated with methemoglobinemia after the use of benzocaine sprays, bringing the total to 319 cases.
Of the 319 total cases, there were seven cases of death and 32 cases that were categorized as life-threatening, defined as those patients with a reported methemoglobin level greater than 55%. Two hundred and sixteen cases were categorized as serious, defined as those patients with a reported methemoglobin level of 30% to 55% or who were administered methylene blue regardless of the level of methemoglobin. Methemoglobin levels were reported in 227 cases. The values range from 0.3% to 77% (average 35.2%, median 34.5%).
In the cases, topical benzocaine spray was used for medical procedures such as transesophageal echocardiogram, endoscopy, bronchoscopy, intubation, and feeding tube placements.
Not all cases provided a description of the amount of benzocaine administered. Of the 137 cases that provided information regarding the amount of benzocaine administered, 65 cases contained information that suggested overuse of the product. Sixty-two cases reported that methemoglobinemia occurred following the administration of a single application of benzocaine. Very few of these cases reported the duration of the spray, but those that did indicated the duration of the spray was one second or less.
Seventy-three cases described the timeframe in which the symptoms of methemoglobinemia occurred or methemoglobinemia was diagnosed. The onset of symptoms or diagnosis of methemoglobinemia ranged from a few minutes to days following the application of the benzocaine spray, with most cases diagnosed within one to two hours (n=55). Because the cases of methemoglobinemia generally occurred while the patients were sedated for a procedure, symptoms experienced by the patients were generally not reported. Most commonly, the signs that alerted healthcare professionals to the patients’ condition included increased respiratory rate, shortness of breath, decreased blood oxygen saturation levels, and changes in the patients’ physical appearance (“ashen,” “cyanotic,” “dusky,” and “bluish”). In particular, many cases noted the bluish appearance of the lips. These signs persisted despite treatment with 100% oxygen supplementation. Additionally, many reports noted that when the blood sample was drawn, the blood appeared “dark in color” or “chocolate-brown.”
FDA will continue to evaluate this safety issue and will take appropriate regulatory actions as warranted.
- Greer FR, Shannon M; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Committee on Environmental Health. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005;116:784-6.
- Ash-Bernal R, Wise, R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83:265-73.
- FDA Drug Safety Communication: Reports of a rare, but serious and potentially fatal adverse effect with the use of over-the-counter (OTC) benzocaine gels and liquids applied to the gums or mouth