The relationship between aciclovir and acute generalized exanthematous pustulosis (AGEP) was identified during routine screening for signals in the VigiBase database in December 2018. Valaciclovir was later added to the assessment.
Most reports stated the age range, the dates of starting and discontinuing the drug, and the clinical picture of AGEP. However, in the case series with valaciclovir there was little information, and there were other suspect medicinal products that could cause a skin rash; these factors complicated the case assessment. In many reports in both case series, manifestations of AGEP and other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, were noted for the drugs used. Stevens-Johnson syndrome and toxic epidermal necrolysis are listed in some package leaflets of aciclovir drugs. It is quite possible that the initial manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis can be confused with AGEP.
Aciclovir is an antiviral drug used to treat herpes simplex and infections caused by herpes zoster. The antiviral effect is due to inhibition of the herpes virus DNA polymerase enzyme, thereby suppressing viral DNA synthesis and replication. When taken orally, aciclovir is absorbed slowly and poorly. Aciclovir is well distributed into body tissues and fluids, including the brain, kidneys, lungs, liver, muscles, spleen, uterus, vaginal mucosa, vaginal secretions, cerebrospinal fluid, and the fluid of herpetic vesicles. Valaciclovir, the L-valine ester of aciclovir, is almost completely converted into aciclovir and valine in the body.
Acute generalized exanthematous pustulosis (AGEP) is a severe skin reaction characterized by acute onset (usually within 48 hours) of mainly small non-follicular pustules on erythematous skin. Systemic involvement sometimes occurs in about one fifth of cases. The reaction is usually associated with the use of medicinal products, and more than 90% of AGEP cases are triggered by drugs. Most often these are β-lactam antibiotics (penicillins, cephalosporins, quinolones) and other medicinal products, including pristinamycin, tetracyclines, sulfonamides, oral antifungal drugs, diltiazem, hydroxychloroquine, carbamazepine and paracetamol. However, AGEP is not listed in the package leaflet for all of these medicinal products. Treatment of AGEP consists of discontinuing the suspected medicinal product and using potent topical or systemic steroids, as well as managing symptoms and preventing infection. Spontaneous resolution of the disease usually occurs within two weeks after discontinuation of the drug that caused AGEP.
AGEP is classified as a severe cutaneous adverse reaction, which is a very rare but potentially life-threatening delayed-type hypersensitivity reaction.
The association between aciclovir and AGEP was identified in a routine VigiBase signal detection review conducted in December 2018. As of 6 October 2019, 16 cases with the aciclovir-AGEP combination had been registered. After removing duplicates, 10 cases remained.
Conclusion
A number of reports describe several cases in which the use of aciclovir and, to a lesser extent, valaciclovir can undoubtedly be suspected as the cause of GGEP. In two literature reports this was confirmed by patch tests. Since this condition can be mistaken for a herpetic rash, it is probably important to warn that aciclovir can also potentially cause a skin reaction.
More detailed information on the cases and their analysis is provided in the document Uppsala Monitoring Centre “Aciclovir or valaciclovir – Acute generalised exanthematous pustulosis”.
List of medicinal products containing aciclovir and valaciclovir that are authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 31.03.2020).
