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Prescription of off-label and unlicensed drugs for preterm infants in a neonatal intensive care unit

ABSTRACT

Objective:

To evaluate the use of off-label and unlicensed medications in preterm infants hospitalized in a neonatal intensive care unit.

Methods:

This nonconcurrent cohort study included preterm infants admitted to 3 neonatal intensive care units in 2016 and 2017 who were followed up during the neonatal period. The type and number of medications used were recorded for the entire period and classified based on the Anatomical Therapeutic Chemical. Descriptive and bivariate data analyses were performed to assess associations between the number of drugs used (total, off-label and unlicensed) and the explanatory variables of interest.

Results:

Four hundred preterm infants received 16,143 prescriptions for 86 different pharmaceuticals; 51.9% of these medications were classified as off-label and 23.5% as unlicensed. The most prescribed drugs were gentamicin and ampicillin (17.5% and 15.5% among off-label, respectively) and caffeine (75.5% among unlicensed). The results indicated significant associations between the use of off-label drugs and lower gestational age, low birth weight, lower 5-minute Apgar score, advanced resuscitation maneuver in the delivery room and death. The prescription of unlicensed drugs was associated with lower gestational age, low birth weight and 5-minute Apgar score below 7.

Conclusion:

Neonates admitted to neonatal intensive care units are highly exposed to off-label and unlicensed medications. Further studies are needed to achieve greater safety and quality of drug therapy used in neonatology.

Keywords:
Infant, preterm; Infant, newborn; Intensive care units, neonatal; Drug prescription; Off-label use

RESUMO

Objetivo:

Avaliar o uso de medicamentos off-label e sem licença em recém-nascidos prematuros hospitalizados em unidade de terapia intensiva neonatal.

Métodos:

Estudo de coorte não concorrente, incluindo prematuros admitidos em três unidades de terapia intensiva neonatais, nos anos de 2016 e 2017, acompanhados durante o período neonatal. O uso de medicamentos e o número foram registrados para todo o período e classificados segundo a Anatomical Therapeutic Chemical. Foram realizadas análises descritivas e bivariadas dos dados para avaliar associações entre o número de medicamentos utilizados (total, off-label e sem licença) e as variáveis explicativas de interesse.

Resultados:

Os 400 neonatos prematuros utilizaram 16.143 medicamentos, com 86 especialidades diferentes; 51,9% desses itens foram classificados como off-label e 23,5% como sem licença. Os mais prescritos foram gentamicina e ampicilina (17,5% e 15,5% dos off-label, respectivamente) e cafeína (75,5% dos não licenciados). O estudo demonstrou associações significativas do uso de medicamentos off-label com a menor idade gestacional, baixo peso ao nascer, menor escore de Apgar no quinto minuto, manobra de reanimação avançada em sala de parto e óbito. Com os medicamentos não licenciados, foram verificadas associações com a menor idade gestacional, baixo peso ao nascer e escore de Apgar no quinto minuto menor que 7.

Conclusão:

Os neonatos internados em unidades de terapia intensiva neonatais são muito expostos ao uso de medicamentos off-label e sem licença. Tornam-se necessários mais investimentos em estudos para alcançar maior segurança e qualidade da terapêutica medicamentosa empregada em neonatologia.

Descritores:
Recém-nascido prematuro; Recém-nascido; Unidades de terapia intensiva neonatal; Prescrição de medicamentos; Uso off-label

INTRODUCTION

The use of medications is essential in health care due to their curative, prophylactic or palliative effects; however, medications can also pose risks to patient health. When medications are prescribed, their quality, cost-effectiveness and safety should be considered. Thus, clinical trials are necessary for safe prescriptions, especially among high-risk groups such as pregnant women, the elderly and children.(11 Duarte ML, Batista LM, Albuquerque PM. Notificações de farmacovigilância em um hospital oncológico sentinela da Paraíba. Rev Bras Farm Hosp Serv Saude. 2014;5(1):7-11.,22 Magalhães J, Rodrigues AT, Roque F, Figueiras A, Falcão A, Herdeiro MT. Use of off-label and unlicenced drugs in hospitalised paediatric patients: a systematic review. Eur J Clin Pharmacol. 2014;71(1):1-13.)

Pediatric patients, especially preterm neonates, are a vulnerable group, especially when they require intensive care due to an increased need for pharmacological treatments. Drug metabolism and renal function are immature in these patients, and there are differences in the sensitivity of target organs. Thus, the half-life of a drug tends to be longer, and accumulation in the body may occur.(33 Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45(11):1077-97.,44 Schirm E, Tobi H, de Jong-van den Berg LT. Risk factors for unlicensed and off-label drug use in children outside the hospital. Pediatrics. 2003;111(2):291-5.)

In Brazil, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária - ANVISA) is the agency responsible for authorizing drug registrations in Brazil based on data and information from nationally recognized regulatory agencies. However, there is currently no specific regulation for drugs intended for the pediatric population. Because of ethical dilemmas, the field of pediatrics faces substantial challenges with regard to conducting clinical trials involving this population.(33 Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45(11):1077-97.)

In the care of newborns, the scarcity of medication studies is so substantial that many experts even consider this specialty almost “experimental” because 40% to 80% of the drugs used in neonatal intensive care units (ICUs) are off-label or unlicensed.(55 Cuzzolin L, Agostino R. Off-label and unlicensed drug treatments in neonatal intensive care units: an Italian multicentre study. Eur J Clin Pharmacol. 2016;72(1):117-23.,66 Dessì A, Salemi C, Fanos V, Cuzzolin L. Drug treatments in a neonatal setting: focus on the off-label use in the first month of life. Pharm World Sci. 2010;32(2):120-4.)

Off-label medication refers to a drug that is used for a different purpose than that described on its label or package insert in regard to indication, route of administration, dosage and age group.(77 McIntyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child. 2000;83(6):498-501.) These medications, however, are approved by regulatory agencies for use.(88 Frattarelli DA, Galinkin JL, Green TP, Johnson TD, Neville KA, Paul IM, Van Den Anker JN; American Academy of Pediatrics Committee on Drugs. Off-label use of drugs in children. Pediatrics. 2014;133(3):563-7.)

Unlicensed drugs are not approved for use because they do not have a specific dosage and are contraindicated for specific populations and are modified, such as the preparation and use of extemporaneous formulations conceived from existing pharmaceutical formulations through the grinding of tablets, dilution of oral liquids or opening of capsules.(88 Frattarelli DA, Galinkin JL, Green TP, Johnson TD, Neville KA, Paul IM, Van Den Anker JN; American Academy of Pediatrics Committee on Drugs. Off-label use of drugs in children. Pediatrics. 2014;133(3):563-7.,99 Santos L. Medicamentos potencialmente perigosos, não aprovados e de uso off label em prescrições pediátricas de um hospital universitário [dissertação]. Porto Alegre: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul; 2009.)

The prescription of these drugs has resulted in important legal and clinical debates because studies associate them with an increased risk of exposure to harmful or potentially harmful excipients, both in adults and in the pediatric population.(1010 Horen B, Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol. 2002;54(6):665-70.,1111 Eguale T, Buckeridge DL, Verma A, Winslade NE, Benedetti A, Hanley JA, et al. Association of off-label drug use and adverse drug events in an adult population. JAMA Intern Med. 2016;176(1):55-63.)

Considering the risks of this practice, the aim of this study is to evaluate the use of off-label and unlicensed drugs in preterm newborns hospitalized in neonatal ICUs.

METHODS

This is a nonconcurrent, hospital-based cohort study that is part of a broader study titled “Preterm birth cohort - survival and morbidity in preterm infants in neonatal intensive care units in the municipality of Vitória da Conquista - BA: a nonconcurrent cohort study”.

The study was conducted in Vitória da Conquista (BA). Preterm infants admitted to 3 neonatal ICUs of 3 hospitals (2 public and 1 private) were included. Each neonatal ICU offered 10 beds and had a trained multidisciplinary team for the care of high-risk newborns. The neonatal ICU units included in the study served as training sites for the Medical Residency Program in the Specialization of Pediatrics and Neonatology and had similar clinical practice protocols.

The study included all preterm infants admitted to the neonatal ICU of 3 hospitals in the municipality of Vitória da Conquista between January 1st, 2016, and December 31st, 2017. The population was monitored from the day of admission during the neonatal period, respecting censorship of 27 days (interruption of follow-up). Data were collected by analyzing the medical records of preterm infants; the records were stored in the Medical Records and Statistics Service (MRSS) of the hospitals.

The exclusion criterion was major congenital anomaly (severe anatomical changes; for this study, patients with the following conditions were excluded: complex congenital heart diseases, gastrointestinal tract atresias, abdominal wall defects, hydrocephalus, encephalocele and diaphragmatic hernia).

The sample was obtained by convenience (n = 400). However, the smallest sample size needed to represent the preterm population of the region was estimated at 384, considering the following parameters: infinite population size (given that it is not possible to estimate the total number of preterm infants who would require intensive neonatal care because the region contains many municipalities), expected frequency of 50% (considering the multiple outcomes evaluated), 5% accuracy and 95% confidence interval.

The instrument used to perform the collections was a questionnaire adapted from the national survey on delivery and birth in Brazil.(1212 Escola Nacional de Saude Pública (ENSP), Fiocruz. Nascer no Brasil: Inquérito Nacional sobre parto e nascimento. Instrumento para coleta de dados no prontuário. [citado 2019 Out 30]; 21p. Disponível em: https://nascernobrasil.ensp.fiocruz.br/?us_portfolio=nascer-no-brasil
https://nascernobrasil.ensp.fiocruz.br/?...
) Voluntary health researchers, under the supervision of neonatologists, were responsible for data collection using a digital questionnaire uploaded in tablets with KoBo Toolbox software, version 1.4.8. A pilot study was conducted in May 2018 using medical records of preterm infants hospitalized in the period prior to the study. The main data recovery occurred from June 2018 to May 2019.

The dependent variables of this study included the use (categorized as yes or no) and number of medications related to the length of stay in the neonatal ICU. Each pharmaceutical specialty was registered by its generic name, pharmaceutical form and route of administration. Pharmacological classification was performed based on the Anatomical Therapeutic Chemical (ATC) classification recommended by the World Health Organization (WHO).(1313 World Health Organization (WHO). Born too soon: the global action report on preterm birth. Geneva: World Health Organization; 2012. [cited 2019 Oct 30]. Available from: https://www.who.int/pmnch/media/news/2012/201204_borntoosoon-report.pdf
https://www.who.int/pmnch/media/news/201...
) For the present study, drug classifications relative to levels 1 (anatomical) and 2 (therapeutic) were used. Level 5 (chemical) was also used to describe the most commonly used products.

The drugs were also classified as off-label and unlicensed for the population in accordance with the American criteria, based on Costa,(1414 Costa HT. Utilização de medicamentos off-label e não licenciados em terapia intensiva neonatal [dissertação]. Natal: Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal do Rio Grande do Norte; 2017.) and through the international database Drug Dex-Micromedex® (https://www.micromedexsolutions.com/home/dispatch).(1515 IBM Corporation. IBM Micromedex. [cited 2019 Out 20]. Available from: https://www.micromedexsolutions.com/home/dispatch
https://www.micromedexsolutions.com/home...
) Off-label drugs were defined as those for which age, indication or route of administration differed from that authorized by the health agency, in this case the United States Food and Drug Administration (FDA).

The following independent variables were used: gestational age (moderate or late, very preterm or extremely preterm), birth weight (≥ 2,500g, ≥ 1,500g and < 2,500g, ≥ 1,000g and < 1,500g or < 1,000g), 5-minute Apgar score (≥ 7 or < 7), resuscitation in the delivery room (did not perform, positive-pressure ventilation or advanced resuscitation - positive-pressure ventilation plus cardiac massage and/or drugs) and death (yes or no).

Descriptive analyses were performed using a simple frequency distribution. The prevalence of drug use (total, off-label and unlicensed) was calculated from the number of preterm infants who had a record of use of at least 1 drug during their stay in the neonatal ICU, divided by the total number of preterm infants.

Bivariate analysis was performed to evaluate associations between the number of drugs used (total, off-label and unlicensed) and the explanatory variables of interest. For this purpose, continuous variables were described based on each explanatory variable using the median and the maximum and minimum values. The differences between the selected variables were assessed by nonparametric methods: the Mann-Whitney-Wilcoxon test for variables with 2 categories and the Kruskal-Wallis test for those with more than 2 categories, with a significance level lower than 5%. For all variables, the number of drugs used was described based on each categorization (total, off-label and unlicensed) using boxplot graphs. Stata software, version 15.0 (Stata Corporation, College Station, USA), was used for data analysis.

All phases of this study were performed in accordance with ethical and legal guidelines detailed in resolution 466/12 of the National Health Council of the Ministry of Health (Conselho Nacional de Saúde do Ministério da Saúde). The study titled “Survival and morbidity in preterm infants in neonatal intensive care units in the municipality of Vitória da Conquista - BA: a nonconcurrent cohort study” was approved by the Human Research Ethics Committee of the Instituto Multidisciplinar em Saúde of the Universidade Federal da Bahia (UFBA; CAAE: 79450717.4.0000.5556) on February 5th, 2018.

RESULTS

During the study period, a total of 592 preterm infants were admitted to the neonatal ICU units, of whom, 37 were excluded because they had major congenital malformations, and 155 were excluded because of missing or incomplete records, leaving 400 preterm infants who were included in the study.

Among the participants, the gestational age ranged from 230/7 to 366/7 weeks, with 59.3% being moderate or late preterm, 29.2% being very preterm and 11.5% being extreme preterm. More than half of the participants had a weight greater than or equal to 1,500g (67.0%), had a 5-minute Apgar score of 7 or higher (86.0%) and did not require resuscitation in the delivery room (54.3%), while 16.0% died during hospitalization (Table 1).

Table 1
Characteristics of the studied population

The prevalence of prescribed medications in the population was 89.8% (95% confidence interval - 95%CI 86.3 - 92.4%). Regarding the use of at least 1 off-label product, the prevalence was 79.0% (95%CI 74.7 - 82.7%). Unlicensed medications were prescribed to 55.5% (95%CI 50.5 - 60.3%) of preterm infants.

The number of medications prescribed per patient ranged from zero to 217, with a median of 30. For off-label medications, number of medications prescribed per patient ranged from zero to 161, with a median of 13, and for unlicensed medications, it ranged from zero to 56, with a median of 4.

Overall, the preterm infants included in this study received 16,143 prescriptions for 86 different pharmaceuticals. Among these prescriptions, 8,372 (51.9%) were for products classified as off-label, and 3,790 (23.5%) were classified as unlicensed. The most used pharmaceutical classes were systemic anti-infectives (36.9%) and drugs that acted on the nervous system (27.6%) and on the digestive system and metabolism (24.5%). Among the off-label medications, systemic anti-infectives predominated (63.8%), especially those of the therapeutic subgroup systemic antibacterials (56.0%). Most unlicensed products acted on the nervous system (91.5%), mainly in the psychoanalytic subgroup (75.4%) (Table 2).

Table 2
Distribution of pharmaceutical classes used by preterm neonates, based on anatomical and therapeutic classification (Anatomical Therapeutic Chemical levels 1 and 2)

Considering the fifth level of the ATC classification, the most prescribed off-label drugs were gentamicin (17.5%), followed by ampicillin (15.5%) and amikacin (8.9%). Among the unlicensed drugs, the most prescribed were caffeine (75.5%), phenobarbital (15.6%) and ferrous sulfate (5.6%) (Table 3).

Table 3
Distribution of the most prescribed off-label and unlicensed drugs in decreasing order of use

Bivariate analysis revealed statistically significant associations between the number of medications used (total, off-label and unlicensed) and the explanatory variables of interest. The very preterm and extremely preterm groups, with lower birth weights and 5-minute Apgar scores less than 7, who required advanced resuscitation maneuvers in the delivery room and who died required a higher median of products, considering both the total number of drugs and off-label drugs. Unlicensed medications were mostly used by very preterm newborns, with birth weights between 1,000g and less than 1,500g and 5-minute Apgar scores less than 7 (Table 4 and Figure 1).

Figure 1
Boxplot of the relationships of the explanatory variables of interest with the number of drugs used (total, off-label and unlicensed) by gestational age (A); birth weight (B); 5-minute Apgar score (C); resuscitation maneuvers in the delivery room (D) and death (E). PPV - positive-pressure ventilation.

Table 4
Relationship of the explanatory variables of interest with the number of drugs used (total, off-label and unlicensed)

DISCUSSION

The results of this study showed a high prevalence of off-label and unlicensed medication use among preterm infants admitted to neonatal ICUs in a rural region in the State of Bahia. The use of a greater number of these medications was associated with greater vulnerability of these individuals, who had lower gestational age and birth weight, in addition to an Apgar score less than 7. A higher number of off-label drugs was also associated with advanced resuscitation maneuvers in the delivery room and progression to death.

The prevalence rates for the use of off-label (79.0%) and unlicensed (55.5%) medications was higher than those reported in national and international studies. A cohort study published in Spain in 2019, conducted with newborns admitted to neonatal ICUs, found that 57.1% of patients received at least 1 off-label drug, while 32.1% received at least 1 unlicensed drug.(1616 Sucasas Alonso A, Avila-Alvarez A, Combarro Eiriz M, Martínez Roca C, Yáñez Gómez P, Codias López A, et al. [Use of off-label drugs in neonatal intensive care]. An Pediatr (Barc). 2019;91(4):237-43. Spanish.) Conversely, in an Italian study conducted in 2010 with newborns in neonatal ICUs, of the 88 treatments offered, 54.0% were off-label or unlicensed.(55 Cuzzolin L, Agostino R. Off-label and unlicensed drug treatments in neonatal intensive care units: an Italian multicentre study. Eur J Clin Pharmacol. 2016;72(1):117-23.) In 2015, a study conducted in the Slovak Republic with newborns showed that out of 962 prescribed medications, 43% were classified as off-label and 4.8% as unlicensed.(1717 Schweigertova J, Durisova A, Dolnikova D, Ondriasova E, Balazova M, Slezakova V, et al. Off label and unlicensed use of medicinal products in the neonatal setting in the Slovak Republic. Pediatr Int. 2016;58(2):126-31.)

In a national cohort lasting 1 year in a neonatal ICU with 220 newborns, 49.3% of prescriptions were off-label, and 24.6% were unlicensed.(1818 Costa HT, Costa TX, Martins RR, Oliveira AG. Use of off-label and unlicensed medicines in neonatal intensive care. PLoS One. 2018;13(9):e0204427.) Gonçalves et al.(1919 Gonçalves AC, Reis AM, Marçal AC, Bouzada MC. Use of unlicensed and off-label drugs in neonates in a Brazilian university hospital. Braz J Pharm Sci. 2017;53(3):e00252.) studied newborns admitted to the neonatal ICU of a university hospital in Brazil and found that 95.5% of newborns were prescribed at least 1 off-label drug and that 30.6% received at least 1 unlicensed drug. Notably, most of the available studies on this subject include neonates of all gestational ages admitted to the neonatal ICU, which differs from the methodology used in this cohort, in which only preterm infants were selected.

The literature shows that the use of off-label and unlicensed drugs is very common in pediatrics, with a high prevalence in neonatal ICUs.(55 Cuzzolin L, Agostino R. Off-label and unlicensed drug treatments in neonatal intensive care units: an Italian multicentre study. Eur J Clin Pharmacol. 2016;72(1):117-23.,1919 Gonçalves AC, Reis AM, Marçal AC, Bouzada MC. Use of unlicensed and off-label drugs in neonates in a Brazilian university hospital. Braz J Pharm Sci. 2017;53(3):e00252.,2020 Aamir M, Khan JA, Shakeel F, Asim SM. Unlicensed and off-label use of drugs in pediatric surgical units at tertiary care hospitals of Pakistan. Int J Clin Pharm. 2017;39(4):860-6.) Some of these drugs have well-established use in protocols, clinical trials and meta-analyses but have not been investigated in controlled clinical trials that meet FDA criteria.(2121 Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes M Jr, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. J Pediatr (Rio J). 2012;88(6):465-70.) The severity of the condition of neonates and the need for intensive care may explain the prescription of these drugs because these individuals are usually prescribed a large number of medications per day.(2222 Kalikstad B, Skjerdal Å, Hansen TWR. Compatibility of drug infusions in the NICU. Arch Dis Child. 2010;95(9):745-8.)

In the present study, the off-label pharmaceuticals most commonly prescribed to preterm infants were systemic anti-infectives (63.8%), especially gentamicin and ampicillin, corroborating the findings of other studies.(55 Cuzzolin L, Agostino R. Off-label and unlicensed drug treatments in neonatal intensive care units: an Italian multicentre study. Eur J Clin Pharmacol. 2016;72(1):117-23.,1717 Schweigertova J, Durisova A, Dolnikova D, Ondriasova E, Balazova M, Slezakova V, et al. Off label and unlicensed use of medicinal products in the neonatal setting in the Slovak Republic. Pediatr Int. 2016;58(2):126-31.

18 Costa HT, Costa TX, Martins RR, Oliveira AG. Use of off-label and unlicensed medicines in neonatal intensive care. PLoS One. 2018;13(9):e0204427.
-1919 Gonçalves AC, Reis AM, Marçal AC, Bouzada MC. Use of unlicensed and off-label drugs in neonates in a Brazilian university hospital. Braz J Pharm Sci. 2017;53(3):e00252.,2121 Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes M Jr, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. J Pediatr (Rio J). 2012;88(6):465-70.,2323 Arocas Casañ V, Cabezuelo Escribano B, Garrido-Corro B, De la Cruz Murie P, Blázquez Álvarez MJ, De la Rubia Nieto MA. Off-label and unlicensed drug use in a Spanish neonatal intensive care unit. Farm Hosp. 2017;41(3):371-81.,2424 Mazhar F, Akram S, Haider N, Hadi MA, Sultana J. Off-label and unlicensed drug use in hospitalized newborns in a Saudi tertiary care hospital: a cohort study. Int J Clin Pharm. 2018;40(3):700-3.) Gentamicin, despite being approved for use in newborns, according to the product specifications, should be administered every 8 hours.(2525 American Academy of Pediatrics. Summaries of Infectious Diseases. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, American Academy of Pediatrics. Red Book: 2012. Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2012.) However, in local protocols, which are based on specific pediatric references,(2626 Taketomo CK, Hodding JH, Kraus DM. Pediatric & neonatal dosage handbook with international trade names index. São Paulo: Lexi-Comp; 2014.) this drug is administered according to birth weight and can be used every 24, 36 or 48 hours. The use of ampicillin is approved only from 1 year of age, but there are pediatric clinical protocols that recommend its use in neonates, both for prophylactic and therapeutic purposes.(2626 Taketomo CK, Hodding JH, Kraus DM. Pediatric & neonatal dosage handbook with international trade names index. São Paulo: Lexi-Comp; 2014.) A study conducted in Saudi Arabia in 2018 found that the most frequently used off-label antimicrobial was the combination of piperacillin and tazobactam.(2424 Mazhar F, Akram S, Haider N, Hadi MA, Sultana J. Off-label and unlicensed drug use in hospitalized newborns in a Saudi tertiary care hospital: a cohort study. Int J Clin Pharm. 2018;40(3):700-3.) In another study conducted in Italy, the most commonly used off-label drugs were gentamicin, cefixime, ceftriaxone, piperacillin and amoxicillin.(66 Dessì A, Salemi C, Fanos V, Cuzzolin L. Drug treatments in a neonatal setting: focus on the off-label use in the first month of life. Pharm World Sci. 2010;32(2):120-4.)

The heterogeneity of the use of antibacterial subgroups used in neonatal ICUs in different countries reflects the lack of a consensus based on clinical trials for the treatment and prophylaxis of the most prevalent neonatal infections, such as sepsis. Thus, this selection depends on the clinical experience and prescription policy of each hospital.(2323 Arocas Casañ V, Cabezuelo Escribano B, Garrido-Corro B, De la Cruz Murie P, Blázquez Álvarez MJ, De la Rubia Nieto MA. Off-label and unlicensed drug use in a Spanish neonatal intensive care unit. Farm Hosp. 2017;41(3):371-81.)

The present study and others have shown that fluconazole, fentanyl, domperidone and ranitidine are widely used off-label drugs.(1616 Sucasas Alonso A, Avila-Alvarez A, Combarro Eiriz M, Martínez Roca C, Yáñez Gómez P, Codias López A, et al. [Use of off-label drugs in neonatal intensive care]. An Pediatr (Barc). 2019;91(4):237-43. Spanish.,1717 Schweigertova J, Durisova A, Dolnikova D, Ondriasova E, Balazova M, Slezakova V, et al. Off label and unlicensed use of medicinal products in the neonatal setting in the Slovak Republic. Pediatr Int. 2016;58(2):126-31.,2121 Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes M Jr, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. J Pediatr (Rio J). 2012;88(6):465-70.,2323 Arocas Casañ V, Cabezuelo Escribano B, Garrido-Corro B, De la Cruz Murie P, Blázquez Álvarez MJ, De la Rubia Nieto MA. Off-label and unlicensed drug use in a Spanish neonatal intensive care unit. Farm Hosp. 2017;41(3):371-81.,2727 de Souza AS Jr, dos Santos DB, Rey LC, Medeiros MG, Vieira MG, Coelho HL. Off-label use and harmful potential of drugs in a NICU in Brazil: a descriptive study. BMC Pediatr. 2016;16(1):13.) Fluconazole was approved by the European Medicines Agency (EMA) for term newborns. This drug is also routinely used for antifungal prophylaxis in preterm infants, with controversial efficacy in the prevention of disseminated candidiasis. However, scientific societies have supported its use for preterm infants below 1,000g admitted to neonatal ICUs with a high prevalence of fungal infections.(2828 Kaguelidou F, Pandolfini C, Manzoni P, Choonara I, Bonati M, Jacqz-Aigrain E. European survey on the use of prophylactic fluconazole in neonatal intensive care units. Eur J Pediatr. 2012;171(3):439-45.)

Fentanyl is among the most prescribed opioids in neonatal ICUs as it is well-established that pain is a factor that contributes to increased morbidity and mortality in neonates. However, according to the Institute for Safe Medication Practices (ISMP), this pharmaceutical belongs to the maximum alert group because, if administered incorrectly, it can cause serious health risks.(2929 Instituto for Safe Medication Practices (ISMP). List of High-Alert Medications in Acute Care Settings. [cited 2020 Mar 16]. Available from: https://www.ismp.org/sites/default/files/attachments/2018-08/highAlert2018-Acute-Final.pdf
https://www.ismp.org/sites/default/files...
)

Ranitidine is used for the treatment of gastroesophageal reflux disease, but its safety and efficacy are not well established for newborns, and its use is associated with longer hospitalization, necrotizing enterocolitis and death.(3030 Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega L, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics. 2012;129(1):e40-5.,3131 Santana RN, Santos VS, Ribeiro-Júnior RF, Freire MS, Menezes MA, Cipolotti R, et al. Use of ranitidine is associated with infections in newborns hospitalized in a neonatal intensive care unit: a cohort study. BMC Infect Dis. 2017;17(1):375.)

Caffeine is a widely used drug in preterm infants admitted to neonatal ICUs and is the treatment of choice for apnea of prematurity. It reduces the need for mechanical ventilation and bronchopulmonary dysplasia and improves neurodevelopmental outcomes. In this study, caffeine was the most frequently used unlicensed drug, corroborating data from other studies.(1616 Sucasas Alonso A, Avila-Alvarez A, Combarro Eiriz M, Martínez Roca C, Yáñez Gómez P, Codias López A, et al. [Use of off-label drugs in neonatal intensive care]. An Pediatr (Barc). 2019;91(4):237-43. Spanish.,1717 Schweigertova J, Durisova A, Dolnikova D, Ondriasova E, Balazova M, Slezakova V, et al. Off label and unlicensed use of medicinal products in the neonatal setting in the Slovak Republic. Pediatr Int. 2016;58(2):126-31.,2121 Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes M Jr, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. J Pediatr (Rio J). 2012;88(6):465-70.,2323 Arocas Casañ V, Cabezuelo Escribano B, Garrido-Corro B, De la Cruz Murie P, Blázquez Álvarez MJ, De la Rubia Nieto MA. Off-label and unlicensed drug use in a Spanish neonatal intensive care unit. Farm Hosp. 2017;41(3):371-81.) It was used in formulations manipulated by the surveyed units, as the hospitals did not have the licensed product available on the market, possibly due to its higher cost.

Dipyrone, also found among unlicensed drugs prescribed to preterm infants, is an analgesic not approved by the FDA because of the risk of inducing aplastic anemia and agranulocytosis(2121 Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes M Jr, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. J Pediatr (Rio J). 2012;88(6):465-70.) and because there are no pharmacological and clinical studies on its use in neonates.(3232 Guinsburg R. Avaliação e tratamento da dor no recém-nascido. J Pediatr (Rio J). 1999;75(3):149-60.) Paracetamol is the only safe analgesic for neonates, but it is available only for oral use, which hinders its use in patients with contraindications to this administration route, and the onset of action is slow and of little effect in intense painful processes.(3232 Guinsburg R. Avaliação e tratamento da dor no recém-nascido. J Pediatr (Rio J). 1999;75(3):149-60.)

The association between the increased use of off-label drugs and lower gestational age and birth weight is consistent with the finding from other international and national studies. Sucasas Alonso et al.(1616 Sucasas Alonso A, Avila-Alvarez A, Combarro Eiriz M, Martínez Roca C, Yáñez Gómez P, Codias López A, et al. [Use of off-label drugs in neonatal intensive care]. An Pediatr (Barc). 2019;91(4):237-43. Spanish.) found that the use of these products occurred in all preterm infants with a gestational age < 32 weeks. A similar result was found by Costa et al.,(1818 Costa HT, Costa TX, Martins RR, Oliveira AG. Use of off-label and unlicensed medicines in neonatal intensive care. PLoS One. 2018;13(9):e0204427.) for whom 100% of preterm infants with extremely low birth weight were exposed to at least 1 off-label drug and 75.5% of the neonates in this classification were administered unlicensed medications.(1818 Costa HT, Costa TX, Martins RR, Oliveira AG. Use of off-label and unlicensed medicines in neonatal intensive care. PLoS One. 2018;13(9):e0204427.) In Brazil, the frequency of use of at least 1 off-label drug for preterm infants with gestational ages less than 28 weeks and 32 weeks was 100% and 92.9%, respectively.(1919 Gonçalves AC, Reis AM, Marçal AC, Bouzada MC. Use of unlicensed and off-label drugs in neonates in a Brazilian university hospital. Braz J Pharm Sci. 2017;53(3):e00252.) Other studies did not find the same results.(55 Cuzzolin L, Agostino R. Off-label and unlicensed drug treatments in neonatal intensive care units: an Italian multicentre study. Eur J Clin Pharmacol. 2016;72(1):117-23.,2424 Mazhar F, Akram S, Haider N, Hadi MA, Sultana J. Off-label and unlicensed drug use in hospitalized newborns in a Saudi tertiary care hospital: a cohort study. Int J Clin Pharm. 2018;40(3):700-3.)

In Finland, a study conducted in a pediatric hospital also found that the chances of using off-label drugs increased significantly with the lower birth weight of the neonate, while a higher birth weight decreased the use of these drugs.(3333 Laine N, Kaukonen AM, Hoppu K, Airaksinen M, Saxen H. Off-label use of antimicrobials in neonates in a tertiary children's hospital. Eur J Clin Pharmacol. 2017;73(5):609-14.)

Blumer and Reed(3434 Blumer J, Reed M. Principles of neonatal pharmacology. In: Yaffe SJ, Aranda JV, editores. Neonatal and pediatric pharmacology: therapeutic principles in practice. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2004. p 146-58.) argue that the physiological immaturity of preterm infants affects the absorption and distribution of drugs due to the composition of body compartments and to hemodynamic and metabolic factors. In addition, polypharmacy predisposes patients to greater pharmaceutical incompatibility or interaction between products and, consequently, brings greater risks of intoxication or adverse effects of drugs.

A Canadian cohort study conducted with preterm infants with a gestational age less than 31 weeks showed an association of better 5-minute Apgar scores with early use (less than 3 days of life) of caffeine, a drug considered unlicensed.(3535 Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, Shah PS; Canadian Neonatal Network. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr. 2015;169(1):33-8.) In this study, it was found that the lowest 5-minute Apgar scores were associated with the greater use of off-label and unlicensed drugs, a finding that is probably related to neonates with fetal distress or neonatal asphyxia and who consequently had a greater need for the use of drugs.

In this cohort, preterm infants who required resuscitation in the delivery room, using positive-pressure ventilation alone or combined with cardiac massage and/or drugs, demanded a broader use of medications in general, including off-label and unlicensed drugs during the neonatal ICU stay. This finding is probably related to greater clinical instability and vulnerability of these preterm infants. A positive association was also demonstrated between the use of off-label drugs and death, a result observed by Carvalho et al.,(2121 Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes M Jr, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. J Pediatr (Rio J). 2012;88(6):465-70.) who identified an association between the use of off-label and unlicensed prescriptions for patients with high median Neonatal Therapeutic Intervention Scoring System (NTISS) severity scores, i.e., patients whose condition was more severe.

Among the limitations of this study, there is possible information bias due to difficulty in obtaining data related to maternal characteristics, pregnancy, and the time of delivery in the medical records. Thus, we prioritized information on the health conditions of preterm infants and the neonatal care received, as these are more solid and reliable data obtained from medical records.

During the study period, the evaluated units did not perform calculations of any severity scores, such as the NTISS. Despite the possibility of its retrospective estimation, some necessary information was not obtained from the medical records, making it difficult to make comparisons between the population characteristics of different ICUs and in the service itself over time.

CONCLUSION

The current study is unprecedented in the region and describes the characteristics of preterm infants admitted to neonatal intensive care units exposed to the use of medications. The prevalence of neonates exposed to off-label or unlicensed drugs during hospitalization was high and was associated with earlier prematurity, lower weights, lower 5-minute Apgar scores, receiving neonatal resuscitation and death. Antibiotics and caffeine were the most used off-label and unlicensed drugs, respectively. High exposure of neonates to off-label or unlicensed drugs in neonatal units is worrisome. Therefore, more studies are needed to achieve greater safety and quality of drug therapy used in neonatology.

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Edited by

Responsible editor: José Roberto Fioretto

Publication Dates

  • Publication in this collection
    05 July 2021
  • Date of issue
    Apr-Jun 2021

History

  • Received
    11 May 2020
  • Accepted
    01 Aug 2020
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