4 DISCUSSION
In this study, drug prescriptions were evaluated in NICUs of Henan,
China. To the best of our knowledge, this is the first large-scale
multicenter study conducted in China and the data would be
representative of the regional distribution of Henan, demonstrating high
rates of off-label use in neonates.
Due to lack of evidence on drug use in neonates and therapeutic
alternatives, off-label drug use is widespread in NICUs throughout the
world 3-8, 17, 18, with a incidence rate ranging from
14% in an academic Dutch Children’s hospital 17 to
95.6% in a level III NICU in Brazil 4. Regulations
and guidelines related to off-label drug use are different in global.
For example, the rational off-label drug use is allowed in Unite States,
France, Japan and UK,2, 19-21 but is abandoned in
India 22. Laws and regulations related to off-label
drug use are unavailable in China. Chinese Expert Consensus of
Pediatric Off-Label Drug Use was established to regulate pediatric
off-label drug use in 2016 by Chinese Journal of Pediatrics with great
efforts of Chinese pediatric healthcare experts.11However, there are still barriers to implement the Chinese expert
consensus of pediatric off-label drug use in clinical
practice,23 resulting in high prevalence for off-label
drug use. The percentage of prescriptions found to be off label in our
study was 84.62%, which was higher as compared to previous reports
ranging from 25.61% to 78.52% in China.12-14
Among the 5813 prescriptions, 63.03% was off label in relation to age.
In an Italian multicenter study, the proportion of off-label
prescriptions in relation to age was 34.4%.6 The
study performed in Germany showed that only 38% had information
regarding the use in patients aged less than 1 month in their SmPC among
the 102 prescribed drugs.24 In the current study,
76.11% (86/113) of the prescribed drugs are in the absence of
information for neonates, leading to the higher prevalence of off-label
prescriptions associated with neonatal age. Historically, clinical
trials evaluating the safety and efficiency of drugs and published
information such as journal articles, practice guidelines, consensus
statements in neonates are always unavailable.20Indeed, a large number of policies have been implemented to encourage
the clinical evaluation in pediatric population, resulting in more than
500 pediatric labeling changes and the increase of prospective pediatric
drug testing.20, 25 Despite this, less than 50% of
products had pediatric information in labeling, indicating that labeling
with pediatric information is still insufficient.26Additionally, as a vulnerable subpopulation, neonates are always
excluded from studies under the incentive legislative measures.
Therefore, neonatal information such as safety, efficiency and
appropriate dose in labeling is especially scarce.27Between 1997 and 2010, only forty-one studies referred to 28 drugs in
neonates were completed resulting in 24 related labeling
changes.27 Consequently, numerous efforts are still
required to overcome the current limitations and improve the efficiency
in neonatal drug evaluation,28 thus increasing the
scientific evidence of drug use and alleviating the situation of
off-label drug use in this population.
In our study, the abnormal diagnosis such as ‘preterm’ was common
(14.29%), which was defined as off label for indication. In addition,
the clinical diagnosis was incomplete, for example, phosphocreatine for
neonatal respiratory distress syndrome, phenobarbital for acid reflux,
fructose diphosphate sodium for pneumonia. Therefore, 47.17% of the
prescriptions resulted off label for indication.
Obviously, the exposure to antibiotics is very common in hospitalized
neonates. In a one-day point prevalence study of the Antibiotic
Resistance and Prescribing in European Children project, 31% (532/1712)
of the neonates were exposed to antibiotics, ranging from 19.9% in a
general neonatal ward to 39% in a neonatal intensive care
setting.29 In the current study, systemic
anti-infectives were most prescribed to neonates, which was quite
similar to the results of recent studies by Neubert et al24 , de Souza et al 4 and Costa et
al 3. However, a great variation regarding the
anti-infective drugs prescribed in each NICU has been widely observed.
Aminoglycosides such as gentamicin and amikacin, the preferred empirical
treatment of suspected neonatal sepsis,30, 31 were
most frequently prescribed in UK32,
Australia8, USA33,
Italy34 and Brazil4. In contrast,
our data indicated that beta-lactam antibiotics including
piperacillin-tazobactam, cefoperazone-sulbactam and cefotaxime were most
prescribed antibiotics. This heterogeneity indicates that neonatologists
prescribed antibiotics to the extensive variability in NICUs across
globe, due to the lack of consensus regarding empirical antibiotic
regimens in neonatal infections. To rationally use antibiotics,
different and important aspects such as the pathogens and the resistance
pattern, the PK and PD characteristics of antibiotics, and the neonatal
pharmacology, should be considered.35
The analysis of off label based on CNFC exhibited a lower rate (65.16%)
compared to Mcdex (84.62%) due to the differences of drug information
between CNFC and Mcdex. For example, Mcdex recommend aminophylline for
the treatment of asthma rather than
neonatal
apnea, while CNFC does. These results indicated that pediatricians are
prone to making therapeutic decisions guided by the available evidence
and the benefit for the individual patient in their medical practice,
thus adhering to CNFC.
Undoubtedly, this study had some limitations. First, as a retrospective
study, detailed demographic information of neonates such as the
gestational ages was unavailable, due to lack of corresponding data
collected from hospital information system. However, recent studies have
shown that a higher proportion of off-label prescriptions were
associated with increased postmenstrual age.5, 34Second, off-label conditions were analyzed according to Mcdex database
rather than country-specific licensing information in the package
leaflets, regardless of the difference from different pharmaceutical
enterprises with different trade names, leading to heterogeneity. Third,
participating NICUs in this study were from a specialized region in
China. Prospective, large sample, multicenter and nationwide studies
would be required to understand the status of off-label drug use in
neonates in the future.