Summary Safety Review - Azithromycin - Drug Reaction/Rash with Eosinophilia and Systemic Symptoms (DRESS)

Review decision

A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.


Issued: 2014-10-21

issue

A safety review was initiated to evaluate the possible link between a medical condition called DRESS which stands for Drug Reaction/Rash with Eosinophilia and Systemic Symptoms, and the antibiotic azithromycin (Zithromax®, Zmax® and its generics). This review was prompted from an adverse reaction report submitted to Health Canada.

Background

Approved use of azithromycin in Canada

Azithromycin belongs to a group of antibiotics called macrolides. It is approved by Health Canada to treat mild to moderate infections in adults or children depending on the type of infection (e.g., pneumonia, influenza and sinus infections). Azithromycin is available as an oral liquid, a tablet and an injectable product.

Drug Reaction/Rash with Eosinophilia and Systemic Symptoms (DRESS)

DRESS describes a group of rare but serious and potentially life-threatening adverse reactions to medications. These reactions usually occur two weeks to two months after starting a medication. Patients may experience symptoms such as a fever, a severe skin rash with swollen face or peeling of the skin over large areas of the body. Abnormal changes in blood cells or organ function such as the liver and kidney may also occur. The reasons why DRESS can occur with some medications are unknown.

Objective

To review the available evidence concerning the risk of DRESS associated with the use of azithromycin. The evidence that was considered included Canadian patient reports, scientific and medical literature on the use of azithromycin both in Canada and internationally.

Key findings

Use of azithromycin in Canada1

Azithromycin was prescribed approximately 2 million times a year in Canada from 2008 to 2012. The group that received the greatest number of prescriptions for azithromycin was patients aged 19 years and younger with an average of 500 000 prescriptions a year from 2008 to 2012.

Canadian reports of DRESS associated with the use of azithromycin in Canada

At the time of the review, Health Canada had received 1 report of DRESS associated with the use of azithromycin in Canada.

Scientific reports

Four cases of DRESS involving azithromycin have been reported in the literature. However, as of the time of this review, no clinical or larger scale population studies have been published on the association of DRESS and azithromycin.

International data2

At the time of the review, the WHO Adverse Reaction Database, also known as Vigibase, contained 14 cases of DRESS associated with the use of azithromycin.

After review of all of the Canadian and foreign cases, the development of DRESS was found to be possibly associated with azithromycin in 3 of the cases, including the Canadian case and 2 foreign pediatric cases. Three of the 14 foreign cases resulted in death.

Conclusions and actions

  • The current available evidence suggests the possibility that DRESS may occur with azithromycin use. Furthermore, DRESS is a known risk for a similar antibiotic, clarithromycin. Other serious, rare, allergic skin reactions such as Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) are described in the prescribing information for azithromycin. Common features between all three conditions may make it more difficult for early diagnosis.

    The prescribing information for Zithromax® and Zmax® has been updated to include the possible risk of DRESS. Manufacturers of generic versions of these drugs will also update their product information.

    It is important for healthcare professionals and patients to be aware of the possibility of these rare serious reactions, and for steps to be taken for early detection of DRESS due to the fact that the treatment of TEN and SJS is different from DRESS. Health Canada has previously communicated with health professionals to raise awareness about this possible risk.

References

  1. Walsh S, Diaz-Cano S, Higgins E, et al. Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases. Br J Dermatol 2013;168(2):391-401.
  2. Criado PR, Avancini J, Santi CG, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. Isr Med Assoc J 2012;14(9):577-82.
  3. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg 1996;15(4):250-7.
  4. Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013;169(5):1071-80.
  5. Shiohara T, Iijima M, Ikezawa Z, et al. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007;156(5):1083-4.
  6. Rajan TV. The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation. Trends Immunol 2003;24(7):376-9.
  7. Kelemen JJ, III, Cioffi WG, McManus WF, et al. Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995;180(3):273-8.
  8. Halebian PH, Corder VJ, Madden MR, et al. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986;204(5):503-12.
  9. Bauer KA, Brimhall AK, Chang TT. Drug reaction with eosinophilia and systemic symptoms (DRESS) associated with azithromycin in acute Epstein-Barr virus infection. Pediatr Dermatol 2011;28(6):741-3.
  10. Cascaval RI, Lancaster DJ. Hypersensitivity syndrome associated with azithromycin. Am J Med 2001;110(4):330-1.
  11. Pursnani A, Yee H, Slater W, et al. Hypersensitivity myocarditis associated with azithromycin exposure. Ann Intern Med 2009;150(3):225-6.

Footnotes

  1. IMS utilization data provided by: IMS Health Canada Inc. An external party cannot refer to nor use IMS data, which have been generated by Health Canada, without a Third Party Agreement in place.
  2. World Health Organization (WHO) adverse reaction information provided by: The WHO Collaborating Centre for International Drug Monitoring. This information is not homogenous with respect to the sources of the information or the likelihood that the health product caused the suspected adverse reaction. Also, this information does not represent the opinion of the WHO.

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