The FDA has issued new information about this safety issue, see the FDA Drug Safety Communication issued on 05-23-2018.

Safety Announcement

Additional Information for Consumers and Caregivers

Additional Information for Healthcare Professionals

Data Summary

References

Safety Announcement

[04-07-2011] The U.S. Food and Drug Administration (FDA) is warning the public that the use of benzocaine, the main ingredient in over-the-counter (OTC) gels and liquids applied to the gums or mouth to reduce pain, is associated with a rare, but serious condition. This condition is called methemoglobinemia and results in the amount of oxygen carried through the blood stream being greatly reduced. In the most severe cases, methemoglobinemia can result in death.

Benzocaine gels and liquids are sold OTC under different brand names such as Anbesol, Hurricaine, Orajel, Baby Orajel, Orabase, and store brands. Benzocaine is also sold in other forms such as lozenges and spray solutions (also see separate Drug Safety Communication on Benzocaine Sprays). These products are used to relieve pain from a variety of conditions, such as teething, canker sores, and irritation of the mouth and gums.

Methemoglobinemia has been reported with all strengths of benzocaine gels and liquids, including concentrations as low as 7.5%. The cases occurred mainly in children aged two years or younger who were treated with benzocaine gel for teething. People who develop methemoglobinemia may experience pale, gray or blue colored skin, lips, and nail beds; shortness of breath; fatigue; confusion; headache; lightheadedness; 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 applying benzocaine and may occur with the first application of benzocaine or after additional use. If you or your child has any of these symptoms after taking benzocaine, seek medical attention immediately.

Benzocaine products should not be used on children less than two years of age, except under the advice and supervision of a healthcare professional. Healthcare professionals and consumers are advised to consider the American Academy of Pediatrics’ recommendations for treating teething pain instead of using the benzocaine teething products:1,2

Give the child a teething ring chilled in the refrigerator.

Gently rub or massage the child’s gums with your finger to relieve the symptoms of teething in children.

If these methods do not provide relief from teething pain, consumers should talk to a healthcare professional to identify other treatments.

Adult consumers who use benzocaine gels or liquids to relieve pain in the mouth should follow the recommendations in the product label. Consumers should store benzocaine products out of reach of children. FDA encourages consumers to talk to their healthcare professional about using benzocaine.

Additional Information for Consumers and Caregivers

Labels of marketed benzocaine products currently do not as of yet contain warnings about the risk of methemoglobinemia, even though the use of benzocaine can cause this serious condition.

as of yet contain warnings about the risk of methemoglobinemia, even though the use of benzocaine can cause this serious condition. Benzocaine products should not be used on children less than two (2) years of age, except under the advice and supervision of a healthcare professional.

Store benzocaine products out of reach of children.

If benzocaine products are used, watch for signs and symptoms of methemoglobinemia, including pale, gray or blue colored skin, lips, and nail beds; shortness of breath; fatigue; confusion; headache; lightheadedness; and rapid heart rate. If you or your child has any of these symptoms after taking benzocaine, seek medical attention immediately.

Signs and symptoms of methemoglobinemia may appear within minutes to one or two hours after using benzocaine. Symptoms may occur after using benzocaine for the first time, as well as after several uses.

The development of methemoglobinemia after treatment with benzocaine gels and liquids has been reported to occur following a single administration of the product.

Benzocaine gels and liquids should be used sparingly and only when needed, but not more than four (4) times a day. If pain persists despite using the product as labeled, contact your healthcare professional for further evaluation and treatment recommendations.

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.

Additional Information for Healthcare Professionals

Labels of marketed benzocaine products currently do not as of yet contain warnings about methemoglobinemia, although the use of benzocaine can cause this condition.

as of yet contain warnings about methemoglobinemia, although the use of benzocaine can cause this condition. Advise patients and caregivers to use the smallest amount possible to relieve pain and not to apply the product more frequently than four (4) times daily.

Before recommending benzocaine products, discuss the signs and symptoms of methemoglobinemia with your patients. Advise patients to monitor for signs and symptoms when using benzocaine products, and to seek medical attention immediately if they suspect methemoglobinemia.

Recognize the signs and symptoms of methemoglobinemia, including pale, gray or blue colored skin, lips, and nail beds; headache; lightheadedness; shortness of breath; fatigue; 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. Symptoms may occur with the first or subsequent applications of benzocaine.

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 that will be additive to that formed by benzocaine products. 3, 4

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.

Data Summary

A search of the FDA’s Adverse Event Reporting System (AERS) database through March 16, 2011 identified 21 cases of methemoglobinemia associated with the use of OTC benzocaine gel or liquid products.

Of the 21 cases, ten cases were categorized as life-threatening, defined as those patients with a reported methemoglobin level greater than 55%. Six cases were categorized as serious, defined as those patients with a reported methemoglobin level of 30% to 55% or who were were administered methylene blue regardless of the level of methemoglobin. There was also one reported death, but it is unclear from the information provided whether the use of benzocaine gel contributed to the outcome. The last four methemoglobinemia cases associated with the use of benzocaine gel products did not provide sufficient information to determine the severity of methemoglobinemia. Methemoglobin levels were reported in 13 of the 21 cases, and were as follows: 4%, 33%, 40.5%, 42.5%, 44.6%, 45%, 46%, 55.5%, 57%, 59.1%, 64%, 69.9%, and 70.4%.

The methemoglobinemia cases generally occurred when using the OTC benzocaine products at home. The cases mainly involved pediatric patients (n=15), most of whom were two years of age or younger (n=11) and were administered benzocaine gel for teething pain. The other six cases occurred in adult patients who applied the benzocaine gel or liquid to relieve toothache.

Not all cases provided a description of the amount of benzocaine administered. Of the 14 cases that provided information regarding the amount of benzocaine administered, there were five cases that suggested the product was used in accordance with the label recommendations and nine cases in which the product was used inappropriately or excessively.

Among the five cases of methemoglobinemia reported following the labeled use of the product, two cases (one life-threatening case in an adult and one serious case in a pediatric patient) occurred following a single administration of benzocaine gel to the oral mucosa. In the pediatric case that occurred following a single exposure to the product, the reporting physician noted that the one year-old patient was found to have “normal methemoglobin reducing capacity.” Three cases described application frequencies that did not exceed the recommendations in the label (i.e., up to four times daily).

Among the nine cases in which the product was used inappropriately or excessively, six cases described unsupervised self-administration or accidental ingestion of the gel by a child and three cases suggested overuse of the product (n=3) where excessive quantities or applications of the products were administered.

The onset of symptoms or diagnosis of methemoglobinemia generally ranged from a few minutes to one or two hours following the application of the benzocaine gel. Symptoms occurred with the first or subsequent applications of benzocaine gel. For the gel and oral liquid methemoglobinemia cases, cyanosis was the most often reported sign that alerted the patients or caregivers to the condition. In particular, reports describe blue discoloration of the lips and nail beds, as well as ashen extremities. Other signs and symptoms reported included irritability, lethargy, difficulty walking, inability to feel hands and feet, and syncope.

FDA will continue to evaluate this safety issue and will take appropriate regulatory actions as warranted.

References

Markman L. Teething: facts and fiction. Pediatr Rev. 2009;30:e59-64. American Academy of Pediatrics. Teething: 4 to 7 Months. Available at: http://www.healthychildren.org/English/ages-stages/baby/teething-tooth-care/pages/Teething-4-to-7-Months.aspx. Accessed on March 28, 2011. 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.

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