Canada: DRESS Syndrome associated with Valtrex (Valacyclovir)

Last Updated on March 19, 2023 by Joseph Gut – thasso

March 18, 2023 – Valtrex (Valacyclovir) is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is a prodrug, which works after being converted to acyclovir in a person’s body. Valaciclovir was patented in 1987 and came into medical use in 1995. It is on the World Health Organization’s List of Essential Medicines. It is also available as a generic medication. In 2020, it was the 119th most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and/or anaphylaxis. In contrast, use in pregnancy appears to be safe.

Drug reaction with eosinophilia and systemic symptoms (DRESS), also termed drug-induced hypersensitivity syndrome (DIHS), is a rare reaction to certain medications. It involves primarily a widespread skin rash, fever, swollen lymph nodes, and characteristic blood abnormalities such as an abnormally high level of eosinophils, low number of platelets, and increased number of atypical white blood cells (lymphocytes). However, DRESS is often complicated by potentially life-threatening inflammation of internal organs and the syndrome has about a 10% mortality rate. Treatment consists of stopping the offending medication and providing supportive care. Systemic corticosteroids are commonly used as well but no controlled clinical trials have assessed the efficacy of this treatment.

DRESS is classified as one form of severe cutaneous adverse reactions (SCARs). In addition to DRESS, SCARs includes four other drug-induced skin reactions such as the Stevens-Johnson Syndrome (SJS),  Toxic Epidermal Necrolysis (TEN), Stevens–Johnson/Toxic Epidermal Necrolysis Overlap Syndrome (SJS/TEN); and Acute Generalized Exanthematous Pustulosis (AGEP). The SCARs disorders have similar disease mechanisms. New strategies are in use or development to screen individuals at risk for DRESS to aid them in avoiding medications that increase the risk of DRESS. Alternative medications are used in all individuals testing positive for these predispositions.

In December 2022, according to its Health Product InfoWatch December 2022 Edition, Health Canada updates the current Canadian Product Monograph for Valtrex (Valacyclovir) and includes now warnings about the risk of DRESS occurring in some patients. The following information has therefore been included into the Monograph:

– Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with Valtrex (Valacyclovir) treatment. DRESS is a serious skin reaction that may affect one or more organs and can be life-threatening or fatal.
– Patients should be monitored closely for skin reactions and advised of the signs and symptoms of DRESS, including fever, severe rash, peeling skin, facial edema, lymphadenopathy, flu-like feeling, jaundice, dyspnea, dry cough, chest pain or discomfort, dehydration, and eosinophilia.
– If signs and symptoms suggestive of DRESS appear, Valtrex (Valacyclovir) should be withdrawn immediately and an alternative treatment considered, as appropriate.
– If a patient has developed DRESS with the use of Valtrex (Valacyclovir), treatment with valacyclovir must not be restarted in this patient at any time.

According to Health Canada, GlaxoSmithKline Inc., the maker and authorization holder of Valtrex (Valacyclovir) has updated its Canadian product monograph for Valtrex (Valacyclovir) to add information about the risk of Valtrex-associated DRESS. In comparison, the Full Prescribing Information document for Valtrex (Valacyclovir) in the United States does not currently have any discussion of or warning about Valtrex-associated DRESS as a possible side effect. In contrast, according to the Electronic Medicine Compendium, warnings for possible DRESS occurrences under Valtrex (Valacyclovir) are included in the European drug label as of January 2023. It remains to see whether the American Food and Drug Administration (FDA) follows the lead of Health Canada  and the European Medicine Agency (EMA) and require a Valtrex (Valacyclovir) drug label change to add information about drug reaction with eosinophilia and systemic symptoms (DRESS) too. Needless to mention that thasso already had a variety of posts on the many aspects of DRESS such as here, or here, or here.

See here a short sequence on DRESS:

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