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This application is a service of the Singapore Government.

Health Sciences Authority

29 Sep 2017: Safety review on risk of serious allergic reactions with chlorhexidine

HSA would like to inform healthcare professionals about the outcome of its review on the known risk of allergic reactions, including anaphylactic reactions, with chlorhexidine-containing products. This review was conducted following recent international safety alerts regarding serious allergic reactions reported with antiseptic products containing chlorhexidine. HSA’s review of our local adverse event (AE) database did not identify any significant local signals with respect to serious allergic reactions associated with the use of chlorhexidine-containing products at this point in time. Healthcare professionals are encouraged to remain vigilant to this potential risk as such reactions could become life-threatening if not managed promptly.

Background

Chlorhexidine is a broad-spectrum antiseptic which is effective against Gram-positive and Gram-negative bacteria on the skin and is widely used to reduce the risk of bacterial infection. Chlorhexidine is present in a variety of topical and oromucosal antiseptic preparations in the form of creams, wipes, cleansers, mouthwashes, dental implants, contact lens solutions, lozenges, topical anaesthetic medicines or antimicrobial dressings. Some indwelling catheters such as urinary catheters and central venous catheters may also be coated or impregnated with chlorhexidine to prevent catheter-related infections.

International regulatory actions

(a) US Food & Drug Administration (US FDA)1

In February 2017, US FDA issued a safety communication regarding serious allergic reactions with skin antiseptic products containing chlorhexidine gluconate. Although rare, US FDA shared that the number of AE reports of serious allergic reactions to these products had increased over the last five decades and recommended that the product labels for over-the-counter (OTC) chlorhexidine gluconate-containing products be updated with a warning about the possibility of serious allergic reactions. This warning is currently present in the US labelling for prescription chlorhexidine gluconate mouthwashes for treatment of gingivitis and prescription oral chips used for periodontal disease.

US FDA identified 43 worldwide serious cases of anaphylactic reactions with the use of topical chlorhexidine gluconate-containing products. These cases were reported to the FDA Adverse Event Reporting System (FAERS) between January 1969 and June 2015, of which 24 cases (56%) were reported after 2010. Serious outcomes were reported and these include life-threatening conditions (26 cases), hospitalisation (12 cases) and death attributed to anaphylactic reaction (2 cases). All reported cases had a positive temporal association to the use of chlorhexidine gluconate-containing products, with seven cases reporting a positive allergy rechallenge. An additional nine cases of anaphylactic reaction associated with chlorhexidine were identified from medical literature and the National Electronic Injury Surveillance System: Cooperative Adverse Drug Event Surveillance (NEISS-CADES) database.

(b) Health Canada 2

Health Canada issued a safety communication in May 2016 on the risk of serious hypersensitivity reactions with the use of non-prescription topical chlorhexidine antiseptics. Its safety review took into account 53 domestic reports of serious allergic reactions with the use of non-prescription topical chlorhexidine-containing products, including three anaphylactic reactions, as well as published cases in medical literature. Health Canada concluded that although uncommon, some conditions may increase the risk of anaphylaxis, such as using chlorhexidine in the mouth, on open wounds, or immediately before or during surgery. As such, Health Canada recommended updating the product information of non-prescription chlorhexidine-containing products with these new findings.

(c) Other regulatory agencies 3-7

The Australian Therapeutic Goods Administration (TGA), UK Medicines & Healthcare Products Regulatory Agency (MHRA) and New Zealand Medicines and Medical Devices Safety Authority (Medsafe) also issued similar safety alerts between 2009 and 2013. The agencies informed healthcare professionals about the risk of serious hypersensitivity reactions with chlorhexidine-containing products, including topical anaesthetic gel and chlorhexidine-impregnated central venous catheters. They also reminded healthcare professionals that chlorhexidine is known to induce hypersensitivity, and that an alternative product should be used if they suspected a patient had an allergy to chlorhexidine. The labels and instructions for use should be checked to establish if the products or devices contain chlorhexidine prior to use on patients with a known allergy.

HSA’s review outcomes

HSA’s current review of local AE reports concluded that there was no significant increase in the total number of AE reports associated with chlorhexidine hypersensitivity received by HSA over the past years. The majority of reports described non-serious AEs such as pruritus and rash. Fifteen reports of anaphylactic reactions related to chlorhexidine (route of administration was reported as topical for two cases and not listed for the rest) were identified over a span of 36 years (1981 to 2017). No increasing trend of serious allergic reactions to chlorhexidine-containing products across the years was observed. HSA’s review did not identify any significant local safety signals regarding serious allergic reactions with the use of chlorhexidine at this point in time. Understandably, there may possibly be some cases of chlorhexidine-induced serious allergic reactions that might have gone unreported as the causality to the offending agent might not be apparent. Nevertheless, HSA will continue to monitor this safety concern and will take appropriate and timely action if further risk mitigation measures are deemed necessary.

HSA’s advisory

Chlorhexidine is known to induce hypersensitivity, including generalised allergic reactions and anaphylactic shock. Although the prevalence of chlorhexidine hypersensitivity is likely to be rare, healthcare professionals are advised to remain vigilant to the potential risk of serious allergic reactions, including anaphylaxis, with chlorhexidine-containing products. The product labels or instructions for use should be checked to establish if the products contain chlorhexidine prior to use on patients with a documented or suspected history of an allergic reaction to chlorhexidine. Healthcare professionals are advised to inform their patients to stop using the product and seek immediate medical attention if they experience symptoms of a serious allergic reaction, such as wheezing, swelling of the face, or severe rashes.

References

  1. https://www.fda.gov/safety/medwatch/safetyinformation/
    safetyalertsforhumanmedicalproducts/ucm539575.htm
  2. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-topical-antiseptic-non-prescription-chlorhexidine-products-potential-risk.html
  3. https://www.tga.gov.au/publication-issue/australian-adverse-drug-reactions-bulletin-vol-28-no-2
  4. https://www.tga.gov.au/publication-issue/medicines-safety-update-volume-3-number-3-june-2012
  5. https://www.gov.uk/drug-safety-update/chlorhexidine-reminder-of-potential-for-hypersensitivity
  6. https://www.gov.uk/drug-device-alerts/medical-device-alert-all-medical-devices-and-medicinal-products-containing-chlorhexidine-risk-of-anaphylactic-reaction-due-to-chlorhexidine-allergy
  7. http://medsafe.govt.nz/profs/PUArticles/June2013Chlorhexidine.htm