Zanamivir is a neuraminidase inhibitor that has demonstrated effectiveness against the
pandemic H1N1 virus. Zanamivir was first authorized in Sweden in June 1999 and is approved in
the European Union (EU) through mutual recognition. It is indicated for treatment and
prevention of influenza in adults and children over the age of 5 years.
Zanamivir animal studies, conducted primarily in rabbits, showed a trend towards increased
post-implantation loss, decreased fetal body weight, and increased minor fetal skeletal
changes, although these effects were not statistically significant. Given the frequency,
pattern and distribution of these effects, it was concluded that they were not related to
zanamivir treatment. The summary of product characteristics for zanamivir states that it
should not be used during pregnancy unless the potential benefit to the mother justifies the
risk to the fetus.
Postmarketing data have shown no higher risk of malformation with oseltamivir than in the
general population, but data on zanamivir are scarcer. Limited data are available on
pregnancy outcomes with maternal exposure to zanamivir during pregnancy. From 01 August 2003
through 31 January 2009, 133 women were reported to have been treated with zanamivir while
pregnant. Of these 133 pregnancies, 83 pregnancies were on-going or had been lost to
follow-up (62.4%) at the time of the report; 43 resulted in a live birth with no apparent
congenital anomalies (32.3%), 4 represented spontaneous abortions with no apparent congenital
anomalies (3.0%), 2 were elective terminations with no apparent congenital anomalies (1.5%),
and 1 was an ectopic pregnancy (<1%). The European Medicines Agency (EMA) has concluded that
exposure to zanamivir during pregnancy does not represent a new safety risk to the fetus.
Published research has suggested that early antiviral treatment of pregnant H1N1 patients can
improve outcomes. In a Center for Disease Control and Prevention (CDC) surveillance
population of 788 pregnant influenza patients with disease onset between April and August
2009, the 384 with data on timing of antiviral treatment were observed to have significantly
higher risk of adverse outcomes with later treatment ('intermediate', i.e. 3-4 days, n=84;
'late', i.e. > 4 days: n=81) than with early treatment (< 2 days: n=219). Compared with those
given early treatment, those given intermediate treatment had almost 10 times the risk of
death, and those given late treatment, more than 50 times. Intensive Care Unit (ICU)
admission showed more than a 2-fold risk elevation with intermediate treatment and a six-fold
elevation with late treatment, Respective elevations in risk of need for mechanical
ventilation were almost 4-fold and more than 12-fold. The authors noted that the reason for
treatment delays in this population are unknown, but could include reluctance on the part of
clinicians and patients to expose the fetus to antiviral medications, as well as use of rapid
influenza tests, which have shown low (10%-70%) sensitivity for H1N1.
As part of their ongoing epidemiologic safety monitoring initiatives requested by the EMA
during the influenza pandemic of 2009-2010, GSK seeks to conduct a pregnancy safety study to
better understand the safety of zanamivir in women exposed during pregnancy for either the
treatment or prevention of influenza. This safety study will collect information from
existing European databases with records of pregnant women exposed to these products and
their pregnancy outcomes in order to assess the safety of these treatments in this
population.
GSK is working with PPD as the contract research organization (CRO) to oversee conduct of
this study, including data source management and payment, study design input, epidemiological
advice, data transfer oversight and overall project management. The CRO will keep a record of
all relevant personnel involved in the study. Additionally, PPD has a strategic alliance with
World Health Information Science Consultants, LLC (WHISCON) (www.whiscon.com), an
internationally recognized organization conducting post-approval drug safety and risk
management epidemiology. WHISCON will be providing services related to protocol development
as well as database-specific work plans, and will assist in analysis and interpretation of
data.
The primary objective of this study is to evaluate the safety of zanamivir taken during
pregnancy on 1) the outcome of the pregnancy, 2) congenital anomalies identifiable at or
shortly after birth, and 3) treatment-emergent diagnoses in the mother occurring within 28
days of receipt of zanamivir.
The secondary objectives of this study are 1) to develop techniques for identifying
influenza-like illness (ILI) in the participating data sources, and 2) to identify the
characteristics of zanamivir recipients.