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A new drug safety signal “Acyclovir or valaciclovir – Acute generalised exanthematous pustulosis”, identified by the UMC (Uppsala Monitoring Center), a WHO Collaborating Centre for international service and scientific research within the field of pharmacovigilance. This drug safety signal is identified from the VigiBase, a global drug safety database maintained by UMC on behalf of WHO.

Acute generalised exanthematous pustulosis association with the use of acyclovir or valaciclovir

Acyclovir is an antiviral class of medication which is used in the treatment of herpes simplex and zoster infections. It inhibits DNA polymerase enzyme of herpes virus and prevents viral DNA synthesis and replication, thus showing the antiviral therapeutic effect. It is slowly and poorly absorbed and widely distributed in various body tissues and fluids. Valaciclovir is the L-valine ester form of acyclovir which is converted to acyclovir and valine inside the body.

“Acute generalised exanthematous pustulosis” (AGEP) is a severe cutaneous adverse drug reaction attributed mainly to drug exposure. Some of the common medications that could cause this reaction are beta-lactam antibiotics such as penicillin’s, cephalosporins, quinolones, pristinamycin, tetracyclines, sulfonamides, oral antifungals, diltiazem, and hydroxychloroquine.

Ideally, the time to onset of reaction (temporal relationship) for this type of adverse drug reactions ranges from ‘2 days to 10 days.’

In Dec 2018, UMC identified a new-drug combination for (acyclovir-AGEP) from the VigiBase, as part of their routine screening for signal detection activities. The total number of case reports observed with this drug-ADR combination are 16 which is not proportionate (disproportionate association) with the total number of case reports expected from the combination (5 cases).

Analysis of case reports with “acyclovir-AGEP” combination:

10 cases were included in the analysis after excluding two suspected duplicate cases.

  • Age group: 20 to 96 years (median age: 65 years)
  • Gender: 5 males & 5 females
  • Temporal relationship: 1 to 21 days
  • Dechallenge: Positive in 8 cases and not reported for other two case reports
  • Rechallenge: Positive in 1 case; negative in 1 case and not reported for remaining cases
  • Alternative explanations: Concomitantly used co-suspected medicinal products

In Dec 2019, UMC observed that total number of case reports for another drug-ADR combination (valaciclovir- AGEP) as 14 which is not proportionate with the expected number of cases-3.

Analysis of case reports (14) with “valaciclovir-AGEP” combination:

  • Age group: 6 geriatric patients; 6 adult patients and 2 cases concerning patients of unknown age group
  • Gender: 7 males & 7 females
  • Temporal relationship: 1 day to 6 months
  • Dechallenge: Positive in 10 cases; negative in one case and not reported/unknown for remaining case reports
  • Rechallenge: Not reported/Unknown
  • Alternative explanations: Concomitantly used co-suspected antibiotics

Listedness for ‘AGEP’ in acyclovir and valaciclovir product labels:

The safety finding AGEP is not documented in the prescribing information documents for these products. However, other cutaneous adverse drug reactions- SJS and TEN were mentioned in the product labels of acyclovir 200 mg tablets (Wockhardt UK Ltd,) and acyclovir 800 mg tablets (Accord) with the frequencies of ‘not known’ and ‘rare’, respectively.

Classification of Drug-ADR combinations into signal:

Acyclovir-AGEP: Based on the below strength of evidence, UMC classified this combination as ‘a signal’ to warn that Acyclovir could potentially cause this skin reaction-AGEP.

  • Two case reports having good patient narratives and with no alternative explanations for the cause of AGEP.
  • Two published case reports in medical literature in which suspicion was confirmed by skin patch test.
  • Temporal relationship for the onset of reaction symptoms is consistent with the “expected time to onset” for the reaction.

Valaciclovir-AGEP: This drug-ADR combination is classified into signal based on the below strength evidence available at UMC from VigiBase database.

  • The time-to onset for the reactions are very shorter for few case reports demonstrating a strong temporal relationship.
  • Other case reports with longer time relationships have oral corticosteroids like dexamethasone, which are concomitantly reported-(corticosteroids were suspected of contribution to the delay of onset of reactions).
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