Methemoglobinemia may be associated with benzocaine topical anesthetics

NEWSLETTER 17: METHEMOGLOBINEMIA MAY BE ASSOCIATED WITH BENZOCAINE TOPICAL ANESTHETICS

February 14, 2006

ST LOUIS (MD Consult) - On February 10, 2006, the US Food and Drug Administration (FDA) issued a public health advisory regarding benzocaine sprays marketed under different names, including Hurricaine, Topex, and Cetacaine. (Anbesol contains 20% Benzocaine). This advisory applies only to benzocaine sprays used in the mouth and throat, not to other benzocaine products or to benzocaine sprays applied to exterior skin.

Benzocaine sprays are used in medical practice for locally anesthetizing mucous membranes of the mouth and throat for minor surgical procedures or when a tube must be inserted into the stomach or airways. Their use is known to be occasionally associated with methemoglobinemia. However, cases of methemoglobinemia have also resulted from medication errors caused by incorrect use of benzocaine sprays (eg, longer duration or more frequent sprays than recommended). On February 8, 2006, the Veterans Health Administration (VA) announced its decision to stop using benzocaine sprays for these purposes. The FDA is aware of the reported adverse events and is reviewing all available safety data, but at this time is not planning action to remove the drugs from the market. Up until now, the FDA has concluded that the number of reported adverse events with these sprays has been low and, when properly used, these products can help make important procedures less uncomfortable for patients.

With its new public health advisory, the FDA is again highlighting safety information previously addressed by the agency and will make further announcements or take action as warranted by the ongoing review. At present, the FDA suggests considering the following points about the use of benzocaine sprays in procedures requiring that a tube be inserted in the larynx or pharynx or in minor surgical procedures performed in these locations.

Benzocaine sprays used in the mouth and throat can result in potentially dangerous levels of methemoglobinemia.
Patients with heart disease, patients who smoke, and patients who have breathing problems such as asthma, bronchitis, or emphysema are at greater risk for complications related to methemoglobinemia and may be candidates for other forms of therapy.
Patients who may have greater tendency for elevated levels of methemoglobinemia, such as all children younger than 4 months and older patients with certain in-born defects (eg, glucose-6-phosphodiesterase deficiency, hemoglobin-M disease, reduced nicotinamide adenine dinucleotide–methemoglobin reductase [diaphorase 1] deficiency, and pyruvate-kinase deficiency) may benefit from products with different active ingredients such as lidocaine.
Patients who receive benzocaine sprays should be given the minimum amount needed to reduce the risks associated with methemoglobinemia.
Patients who receive benzocaine sprays should be carefully observed for signs of methemoglobinemia including pale skin, gray- or blue-colored skin, headache, lightheadedness, shortness of breath, anxiety, fatigue, and tachycardia.
Methemoglobinemia renders unreliable a standard device used to assess the amount of oxygen bound to hemoglobin (2-wavelength pulse oximetry). If blood is drawn to check for the condition, a CO-oximeter is needed to reliably detect methemoglobinemia.
A characteristic color of the blood (chocolate-brown rather than dark red) can be a danger sign, but these changes are a late sign of the condition.
Patients suspected of having high levels of methemoglobinemia should be promptly treated.

Methemoglobinemia is a condition in which too much of the hemoglobin in red blood cells becomes unable to bind and carry oxygen. Although treatment is available, until the condition is reversed oxygen is not effectively delivered throughout the patient's body. Patients with methemoglobinemia can experience effects ranging from headache to cyanosis that can be life-threatening in the most severe cases. Patients with underlying breathing problems, such as asthma or emphysema, patients with heart disease, and those who smoke may be more susceptible to the problems from methemoglobinemia and may experience adverse effects from this condition at lower levels of methemoglobin than healthy persons. Similarly, some patients may lack or have reduced level of enzymes that help reverse the methemoglobinemia, and they are also more susceptible to risks associated with benzocaine sprays.

The VA health system has announced its decision to remove benzocaine sprays from their practice because they believe other topical anesthetics are less likely to cause methemoglobinemia and because the procedures themselves might cause similar signs, suggesting that methemoglobinemia may occur but go unrecognized in some cases. The FDA has received adverse event reports involving benzocaine sprays together with symptoms that probably indicated methemoglobinemia. However, the agency notes that these cases were received over a period of many years, and this is an uncommon adverse event. The FDA will continue to review all available safety information for these affected products.

January 2003

Anesthetic Sprays and Methemoglobinemia
FDA Patient Safety News: Show #11, January 2003

In a recent report, the Institute for Safe Medication Practices warned that overuse of topical anesthetic sprays can cause methemoglobinemia. This is a potentially life-threatening complication that may result in cyanosis, confusion, hemodynamic instability and coma. The report points out that these sprays, most of which contain benzocaine, are probably used millions of times each year in preparing patients for endoscopic procedures and endotracheal intubation.

The problem occurs when practitioners use multiple sprays, and sprays of longer duration than recommended. Part of the reason, according to the report, may be that clinicians don't realize that these topical anesthetics are significantly absorbed. An earlier report by ISMP notes that up to 35 percent of benzocaine applied to mucous membranes can be absorbed.

That report also cautions that in teaching hospitals, inexperienced fellows and technicians who are performing bronchoscopies may not be aware of the absorption and toxicity of topical benzocaine, and it recommends issuing reminders to new members of the house staff.

The ISMP report also points out that some of these local anesthetic products are available over the counter in the form of gargles and sprays, so that methemoglobinemia could also occur in consumers who over-use them to treat sore throats and minor injuries.

The report recommends alerting clinicians and patients about proper dosing with topical anesthetics and about the possibility of methemoglobinemia. It points out that inflamed areas absorb more of the drug. It also notes that certain patients are especially at risk, including infants under six months old, patients with cardiac problems, and those with certain hemoglobin and enzyme abnormalities.

Additional Information:

ISMP Medication Safety Alert: Benzocaine-containing topical sprays and methemoglobinemia

Benzocaine-containing topical sprays and methemoglobinemia

From the October 3, 2002 issue

PROBLEM: Topical anesthetic sprays such as CETACAINE (benzocaine 14%, tetracaine 2%) and HURRICANE (benzocaine 20%) have been implicated in cases of methemoglobinemia. Because methemoglobin is a form of hemoglobin that is unable to carry oxygen, the condition can be life-threatening, causing cyanosis, confusion, hemodynamic instability, and coma if not recognized and treated appropriately. The FDA MEDWATCH database contains about 100 reports of methemoglobinemia related to the use of benzocaine, the most common topical anesthetic associated with this reaction.1 However, this is probably only a small fraction of actual cases experienced in the US. It's well known that spontaneous reports sent to MEDWATCH severely underestimate the actual number of occurrences of specific drug-related problems.2 For example, methemoglobinemia has been estimated to occur in one out of every 7,000 bronchoscopies.3 Given that millions of doses of topical anesthetics are used each year during endoscopic procedures and endotracheal intubation, methemoglobinemia is unlikely to be a rare occurrence.

In reviewing reported cases of methemoglobinemia, clinicians often used multiple sprays of benzocaine and sprays of longer duration than recommended. Doses administered during endoscopic procedures may exceed manufacturer's recommendations for several reasons. First, unclear package instructions for using the products may lead to overdoses. In our February 6, 2002 issue, we mentioned that the directions for use of Cetacaine topical spray are prone to misinterpretation and could result in patient harm. One portion of the label states, "Spray in excess of two seconds is contraindicated," but the directions state, "To activate spray, press Jetco-Spray Cannula in any direction with forefinger for approximately one second. Maximum anesthesia is produced in one minute." This could be misinterpreted to mean that a continuous spray of up to one minute is permitted, even desirable, for maximum anesthesia (Cetylite Industries is clarifying this wording). Another problem is that clinicians may not be familiar with the significant absorption of topical anesthetics, so they may not realize just how much medication they are giving patients when using the sprays. See our May 15, 2002, edition of the newsletter for additional information on this problem. Patients also could self-administer topical anesthetics in doses that exceed manufacturer's recommendations. Since some products are available without a prescription (e.g., Hurricane), a patient could, for example, apply too much spray or gargle too often with a liquid formulation (or swallow the solution), especially since the directions for use may be vague (e.g., "apply a small amount").

SAFE PRACTICE RECOMMENDATION: Alert clinicians and patients to the proper dosing of topical anesthetics and the possibility of methemoglobinemia when these products are used. These drugs should not be used in high doses, especially in patients who may be predisposed to methemoglobinemia. Predisposing factors include age (infants under 6 months of age and older patients with cardiac problems may be sensitive to even low methemoglobin levels); the status of the area that is being sprayed (inflamed areas absorb more drug); concomitant use of other drugs which also have been implicated in causing methemoglobinemia; and the genetic make-up of the patient (due to altered hemoglobin, G6PD deficiency, or methemoglobin reductase enzyme deficiency).4,5 Therefore, patients who may receive topical anesthetics should be asked about their past medical history to determine if any of the risk factors are present.

References:
(1) Ajayi T, Gropper MA. Methemoglobinemia. Pulmonary Perspectives. 2001;18:1-7. v (2) Scott HD, Rosenbaum SE, Waters WJ, Colt AM, Andrews LG, Juergens JP, et al. Rhode Island physicians' recognition and reporting of adverse drug reactions. RI Med J. 1987;70:311-6.
(3) Douglas WW, Fairbanks VF. Methemoglobinemia induced by a topical anesthetic spray (Cetacaine). Chest. 1977;71:587.
(4) Wurdeman RL et al. Benzocaine-induced methemoglobinemia during an outpatient procedure. Pharmacotherapy. 2000;20:735-38.
(5) http://link.springerny.com/link/service/journals/00464/contents/00/20083/paper/index.html

FDA Patient Safety News is available

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Member, ACFEI (American College of Forensic Examiners Institute of Forensic Science)
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