Research Article: Use of off-label and unlicensed medicines in neonatal intensive care

Date Published: September 25, 2018

Publisher: Public Library of Science

Author(s): Haline Tereza Matias de Lima Costa, Tatiana Xavier Costa, Rand Randall Martins, Antônio Gouveia Oliveira, Ricardo Queiroz Gurgel.


To evaluate the use of off-label and unlicensed medicines in a neonatal intensive care unit (NICU) of a teaching maternity hospital specialized in high risk pregnancy.

A prospective cohort study was conducted between August 2015 and July 2016. All newborns admitted to the NICU who had at least one medication prescribed and a hospital stay longer than 24 hours were included. The classification of off-label and unlicensed drugs for the neonatal population was done according to the information of Food and Drug Administration.

A total of 17421 medication items were analyzed in 3935 prescriptions of 220 newborns. The proportion of newborns exposed to off-label drugs was 96.4%, and to unlicensed medicines was 66.8%. About one-half (49.3%) of the medication items were off-label and 24.6% were unlicensed. The main reason for off-label and unlicensed classification was, respectively, frequency of administration and the administration of adaptations of pharmaceutical forms.

Although there are actions to encourage the development of pharmacological studies with neonates, this study observed a high rate of prescription and exposure of newborns to off-label and unlicensed drugs in NICUs and pointed out areas of neonatal therapy that require scientific investment.

Partial Text

Newborns represent a patient population with special concerns regarding drug therapy, because prematurity and low birth weight may have a significant effect on the pharmacokinetics and pharmacodynamics of many drugs, making the administration of medicines rather delicate [1–2]. Newborns can be admitted to a neonatal intensive care unit (NICU) for several reasons, including extreme prematurity or complications from delivery, [3–5] where they receive multiprofessional care and are often administered medicines that do not have proof of safety and efficacy obtained from randomized clinical trials in this patient population [6–7].

From August 2015 to July 2016, 308 newborns were eligible for the study. From these, 14 parents refused participation and the parents of 74 newborns could not be located. The final analysis set consisted of 17421 prescribed items in 3935 prescriptions from 220 newborns, of which 101 (46.3%) were females, 43 (19.5%) were term, 134 (60.9%) preterm, and 43 (19.5%) were extremely preterm. The mean gestational age was 32.4 ± 4.4 weeks, (range 23.4 to 42.4 weeks) and the mean NICU stay was 18.3 ± 19.4 days (median = 12 days, range 1 to 106 days). The number of prescriptions and the number of prescribed medicines per patient were, respectively, 17.9 ± 19.2 (median 11, range 1 to 106) and 8.2 ± 6.2 (median 7, range 1 to 33). Of the 17421 items prescribed to the patients, 27.9% (n = 4868) were antimicrobials for systemic use, followed by agents acting on the alimentary tract and metabolism (n = 4245, 24.4%), nervous system (n = 3536, 20.3%), cardiovascular system (n = 2324, 13.3%) and respiratory system (n = 1369, 7.9%). Thirteen neonates received more than 20 different drugs and two newborns had more than 30 medicines prescribed during the hospitalization. The characteristics of the study population are summarized in Table 1.

The present study analysed prospectively the labelling status of drug therapy of newborns hospitalized in a NICU of a Brazilian teaching hospital over a whole year. The results show that during NICU stay nearly all newborns are exposed to off-label medicines and about two-thirds to unlicensed drugs. Off-label prescription of drugs is highly prevalent in NICUs, as well as prescription of unlicensed medications, occurring in about half and one-quarter of the prescriptions, respectively. Fentanyl, gentamicine and aminophylline are the drugs most commonly prescribed as off-label, and caffeine and phenobarbital the most common unlicensed drugs used in NICUs. Adaptations of drug formulations represent a significant proportion of unlicensed use of medicines.

The use of off-label medicine affects almost all neonates hospitalized in a NICU, regardless of gestational age and birth weight. The unlicensed use, which is not as frequent as off-label use, is still relevant, however, since the use of unlicensed agents increases with prematurity. Antimicrobials for systemic use, drugs acting on the nervous system, as well as respiratory system and cardiovascular drugs, are the medicines most often implicated in off-label use, while unlicensed prescriptions are mainly of the nervous, cardiovascular and alimentary tract classes.




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