Thrombocytopenia from Combination Treatment with Oseltamivir and Probenecid: Case Report, MedWatch Data Summary, and Review of the Literature

Abstract

The possibility of an avian flu pandemic has spurred interest in preventive treatments with antivirals such as oseltamivir. Combining treatment with probenecid to delay excretion may extend limited supplies of oseltamivir. We previously conducted a pharmacokinetic study of oseltamivir plus probenecid among healthy volunteers. In this article, we describe a 68-year-old woman who, during the pharmacokinetic study, developed severe thrombocytopenia 2 weeks after starting oseltamivir plus probenecid. She was receiving no other drug therapy at the time. Her platelet count decreased from 200 to 15 x 10(3)/mm(3), although no clinically evident bleeding abnormalities were noted. The two drugs were discontinued. One week later, without any therapeutic intervention, her platelet count returned to normal. By using the Naranjo adverse drug reaction probability scale to assess the strength of the association between the drugs and the adverse event, a score of 7 was derived for both drugs, indicating that the association was probable. We found no previous literature reports of thrombocytopenia associated with either drug. However, a review of the United States Food and Drug Administration's Adverse Event Reporting System database found 93 cases of thrombocytopenia and/or decreased platelet counts associated with oseltamivir and 24 cases associated with probenecid administration. Signal detection analyses were significant for oseltamivir (p=0.001), but not probenecid. The underlying mechanism of thrombocytopenia with these drugs is unknown. Clinicians should be aware that the use of oseltamivir and probenecid has been reported to be associated with thrombocytopenia.

Antimicrobial Drug-Induced Thrombocytopenia: A Review of the Literature

“…99 Although oseltamivir is not generally associated with significant thrombocytopenia, there have been 93 cases of thrombocytopenia reported; the risk appears to be slightly increased when coadministered with probenecid. 100 This represents an exceptionally rare complication considering that millions of doses of oseltamivir have been prescribed.…”

“…Several [97][98][99][100] Risk for ganciclovir and its analogues associated with prolonged exposure, higher doses, and renal insufficiency. Foscarnet associated with thrombocytopenia due to direct bone marrow toxicity.…”

Prophylactic oseltamivir treatment for prevention of donor–recipient influenza A H1N1 virus transmission does not compromise stem cell mobilization or engraftment

“…During close follow-up, in repetitively collected nasopharyngeal swabs, viral RNA of H1N1 2009 virus could not be detected. A further concern was the influence of oseltamivir on engraftment, which is currently unknown; cases of pronounced thrombocytopenia associated with oseltamivir administration have been described recently; 9 however, in our allo-SCT recipient, the median time for neutrophil and plt recovery was 16 and 11 days, respectively, which is comparable to that in other allogeneic peripheral stem cell transplant recipients, suggesting no detrimental effect of neuraminidase-inhibitor therapy on engraftment. mobilization or engraftment.…”

Evaluation of Diagnostic and Therapeutic Approaches for Suspected Influenza A(H1N1)pdm09 Infection, 2009–2010

“…Antimicrobial drug dosing errors are common ( 34 , 35 ), and a failure to adjust for renal impairment is a frequent underlying reason ( 36 , 37 ). Although controlled data are not available, oseltamivir has been associated with the development of thrombocytopenia, particularly when renal clearance is artificially lowered by concomitant administration of the drug probenicid ( 38 ). Attention should be given to patients’ renal function, particularly in the elderly (diminished renal clearance) and in those for whom higher doses may be recommended, such as the severely ill or obese ( 8 ).…”