Safety profile of oseltamivir during the 2009 influenza pandemic.

PURPOSE: This study evaluated the safety of oseltamivir during the 2009 influenza pandemic. METHODS: Case reports were obtained from the Roche safety database. The incidence of adverse events (AEs) during the pandemic (1 May 2009 to 31 December 2009) was compared with that beforehand (during previous influenza seasons) for USA and Japan only, as exposure data in other countries were collected inconsistently. Events with significantly higher reporting during the pandemic (lower bound of 95%CI for crude rate ratio >1) were analyzed further. RESULTS: Global exposure in the pandemic and prepandemic periods was 18.3 and 64.7 million patients, respectively. In USA and Japan, exposure was 15.5 (1382 cases, 2225 events) and 62.0 million (8387 cases, 12,749 events), respectively. AEs with significantly higher reporting during the pandemic were generally consistent with influenza and its complications and/or with the circulation of a novel virus strain. As might be expected in a pandemic, mortality increased (crude rate ratio, 2.83; 95%CI, 2.23-3.59) versus the prepandemic period. Medical review of serious AEs (fatal or non-fatal outcome) found that most were consistent with pre-existing risk factors, underlying disease, and/or progression of influenza or its complications. Analysis of the remainder did not suggest a causal link with oseltamivir. A review of AEs in previously underexposed subpopulations did not support an association with oseltamivir. CONCLUSIONS: During the first 8 months of the 2009 influenza pandemic, AEs reported in patients exposed to oseltamivir were consistent with the drug's labeled safety profile, underlying medical conditions, or infection with the pandemic virus.

Safety of oseltamivir in pregnancy: a review of preclinical and clinical data.

Pregnant women with influenza are at increased risk of morbidity, particularly due to respiratory complications. A high excess mortality rate among pregnant women has been observed in previous influenza pandemics and healthcare agencies have provided recommendations on the use of oseltamivir to treat pregnant women who are infected with the pandemic (H1N1) 2009 virus. This article reviews pre-clinical and clinical data to assess the safety of oseltamivir administered during pregnancy, in the context of the effects of influenza on adverse pregnancy outcomes and fetal malformations. The effects of influenza during pregnancy, whether mediated directly by the virus or by fever or other events secondary to the underlying infection, are not yet well understood, but some data indicate an increased risk of birth defects in women infected with influenza during the first trimester. Animal and toxicology studies do not suggest that clinically effective dosages of oseltamivir have the potential to produce adverse effects on fetal development. Additionally, transplacental transfer of the drug and its active metabolite was very limited and not detectable at normal therapeutic doses in an ex vivo human placenta model. To investigate the safety of oseltamivir in pregnancy, the Roche oseltamivir safety database was searched for all exposures to oseltamivir during pregnancy in the 9 years up to 14 December 2008. In addition, a search of the literature was carried out. Of 232 maternal exposures to oseltamivir in the Roche database, pregnancy outcomes were known for 115 of these exposures. The incidence of adverse pregnancy outcomes was as follows: spontaneous abortions 6.1% (7/115), therapeutic abortions 11.3% (13/115) and pre-term deliveries 2.1% (2/94 live births), values that are not higher than background incidence rates. Fetal outcomes were known in 100 of the 232 exposures. For the nine cases of birth defect that were reported, the timing of oseltamivir exposure in relation to the sensitive period for inducing the birth defect was analysed. Two cases of ventricular septal defect, a more common birth defect, and one case of anophthalmos, an uncommon birth defect, were consistent with exposure to oseltamivir during the sensitive period for these birth defects. For other birth defects, there was either no exposure to oseltamivir during the sensitive period for the defect or insufficient information for assessment. These findings were consistent with other reports in the published literature, including a series of 79 Japanese women exposed to oseltamivir during the first trimester. Together with the other evidence reviewed herein, review of the company safety database suggests that oseltamivir is unlikely to cause adverse pregnancy or fetal outcomes, but available data are limited. Clinicians who use oseltamivir in pregnant women should consider the available safety information, the pathogenicity of the circulating influenza virus strain, the woman's general health and the guidance provided by health authorities. Roche will continue to monitor all reports of oseltamivir use during pregnancy.