The use of unlicensed and off-label medicines in the neonate

doi:10.1016/j.siny.2004.11.003

Seminars in Fetal and Neonatal Medicine

Volume 10, Issue 2, April 2005, Pages 115-122

https://doi.org/10.1016/j.siny.2004.11.003 Get rights and content

Summary

The use of unlicensed and off-label medicines in neonates in intensive care is common and widespread. Up to 93% of babies receive at least one unlicensed or off-label medicine during their stay in intensive care. Such practice is an essential part of their care and should be done based on the best evidence available. However, problems arise – on an every-day basis – because of the lack of appropriate information and licensed medicine formulations for neonates. These problems include the selection of appropriate medicine and dose, administration and the increased risk of medication errors. Initiatives to improve the situation are underway in the US and are proposed in Europe. However, more urgent action is required to stop these babies continuing to be deprived of their basic human rights to safe, effective and high-quality therapy.

Section snippets

Background

Most medicines used in adults are licensed products used in a licensed manner. This implies that they have been through the rigorous regulatory processes that demand evidence to support all aspects of the medicine's safety and efficacy in the approved doses, indications, routes and methods of administration and patient populations. This detailed information will have been provided by the pharmaceutical company seeking the licence. A medicine's quality – in terms of content, physical, chemical

Unlicensed medicines

Unlicensed medicines are required when no suitable commercially available formulation exists to facilitate administration of a neonatal or paediatric dose in a form that the patient is able to take. Unlicensed medicines include the following:

Off-label medicine use

A medicine is used off label when it is used outside the strict conditions of the license or marketing authorisation. This might occur because of:

Incidence and nature of unlicensed and off-label medicine use in neonates

The incidence and nature of unlicensed and off-label medicine use in neonates and children has been investigated by a number of studies examining different therapeutic and geographical areas where children are treated. Table 2 summarises studies conducted in neonatal intensive care units (NICUs).

Differences in classification of unlicensed and off-label medicines between authors mean that these studies are not necessarily directly comparable but they still give a good overall picture of the

Primary care

This situation is not confined to intensive care and hospital settings. A number of studies have reported that the highest incidence of unlicensed and off-label prescribing in primary care is also in neonates and infants. A one-day survey of prescriptions written by office-based French paediatricians found that off-label prescribing occurred in 70% of 49 neonates (5% of the total study population).²⁴ This represented 81 prescriptions and was double the off-label prescribing rate found in the

Risks associated with unlicensed and off-label medicine use in neonates

Practical problems are experienced every day with the use of unlicensed and off-label medicines; these include the lack of suitable child-friendly formulations, difficulty in finding medicine information and problems at the primary/secondary care interface, but is there a risk of harm? The little evidence we have as to the real risks of using unlicensed and off-label medicines in neonates comes from the paediatric population and suggests that we are justified to be concerned and that urgent

United States

In the early 1990s, the US Food and Drug Administration (FDA) introduced a number of mainly voluntary measures to encourage the pharmaceutical industry to submit paediatric labelling information.³⁵ However, these initiatives were not sufficient to improve the situation substantially. The FDA Modernisation Act (FDAMA) was subsequently introduced in 1997. This provided economic incentives in the form of a 6-month extension of any existing exclusivity or patent protection on a medicine for which

Summary

The use of unlicensed and off-label medicines in neonates is common and widespread. It is an essential part of neonatal care because of the lack of availability of suitable licensed medicines for this population. Practical problems are encountered on an everyday basis and result in delays in therapy, inconvenience and increased workload for healthcare professionals and families. More worrying is the increased risk of medication errors and adverse reactions stemming from the use of these

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Cited by (87)

Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018
2022, Journal of Pediatrics
Citation Excerpt :
However, our definition of “labeled for use” was necessarily broad and unable to account for differences in approval for specific indications or of specific gestational ages but not others; thus, the percentage of FDA-approved drugs in the ELBW population is likely lower than our estimate. Nearly all infants admitted to the NICU receive at least 1 medication that is unlicensed or used off-label, and it is estimated that >70% of infants in the NICU are exposed to drug–drug interactions.1,3,10 Off-label use exposes infants to many risks, including overdosing, increasing the risk of adverse reactions, or underdosing, leading to ineffective treatment.11
To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time.
We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies.
The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem + cilastatin, and amikacin.
Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.
Dosing regimens of antibiotics in neonates: Variations in clinical practice and what should be done?
2016, Archives de Pediatrie
La prescription néonatale des antibiotiques pose le problème d’une grande variabilité de pratiques tant au niveau national qu’international. Ceci reflète un manque d’évaluation de cette classe thérapeutique, pourtant largement utilisée. Face à ce constat, un travail d’optimisation de la prescription s’impose pour assurer chez le nouveau-né l’efficacité et la sécurité du traitement et pour diminuer les risques d’acquisition de résistances microbiennes. La prescription doit être sous-tendue par la connaissance des données de pharmacocinétique/pharmacodynamie du développement. Les études rigoureuses, conduites en collaboration entre néonatologues et pharmacologues pédiatres, sont indispensables pour disposer de schémas posologiques validés en néonatologie.
There is wide variation in neonatal dosages of antibiotics in clinical practice, both nationally and internationally. This reflects the lack of evaluation of drugs in this therapeutic class, although widely prescribed. Given this situation, optimization of antibiotic prescription is required to ensure efficacy and safety of neonatal treatment and reduce microbial resistance. Rational prescription should be based on the knowledge of developmental pharmacokinetics and pharmacodynamics. Rigorous studies, conducted in collaboration between neonatologists and pharmacologists, are essential to develop and validate evidence-based neonatal dosage regimens.
Comparative Assessment of Off-label and Unlicensed Drug Prescriptions in Children: FDA Versus ANSM Guidelines
2016, Clinical Therapeutics
Citation Excerpt :
The majority of drugs used in children are either not licensed for use (unlicensed [UL]) or are prescribed outside the terms of the product license (off-label [OL] prescribing),1,2 a policy which increases the potential for medication errors and is a risk factor for adverse drug reactions.3
The main objectives of this study were to assess the incidence of off-label (OL) and/or unlicensed (UL) prescriptions in a sample of pediatric Lebanese patients by using US Food and Drug Administration (FDA) and the French Medical Regulatory Authority (ANSM) regulations. The goal was to analyze the divergences between regulations and to identify those drugs most commonly involved in OL-UL utilization.
This study was a retrospective analysis (500 pediatric files) conducted in a Lebanese University hospital in 3 pediatric wards (chronic diseases, acute diseases, and the pediatric intensive care unit).
The frequency of OL-UL drug use was significantly different between pediatric wards (P < 0.001), with the highest incidence occurring in the intensive care unit. The most frequent OL-UL prescriptions occurred with cancer (oncology) admissions. Age was significantly related to OL-UL frequency (highest incidence in children aged between 0 and 1 year). The number of drugs prescribed per patient ranged between 1 and 20 (mean [SD], 4.13 [2.6]). The incidence of OL-UL prescriptions was significantly higher in patients treated with a greater number of medicines (P < 0.001). Overall, 58.9% of drug prescriptions were authorized according to ANSM and 50.7% according to FDA regulations; 11.1% (ANSM) and 15.8% (FDA) were UL, and 30.2% (ANSM) and 33.5% (FDA), respectively, were OL use (where OL for the indication were the most common). The highest percentage of OL-UL prescriptions was seen with the following groups: blood and blood-forming organs, genitourinary system, and sex hormones. Divergence between FDA and ANSM was mainly observed for OL medicines. UL prescriptions assessed according to both regulations showed similar results.
This study highlights the need for prescribers to continuously examine updates to official regulations to avoid using an OL-UL drug whenever possible. It also calls for better harmonization between worldwide official guidelines concerning drugs used in children to reduce risk factors for adverse drug reactions.
Development and Evaluation of the Impact of Validated Drug Dosing Pocket Guide in Pediatric Intensive Care Unit (PICU)
2024, Malaysian Journal of Medicine and Health Sciences
Current Status of Pharmacokinetic Research in Children: A Systematic Review of Clinical Trial Records
2024, Current Reviews in Clinical and Experimental Pharmacology
“A hard-won capability”: the experiences of parents managing their babies' medicines after discharge from a neonatal unit
2023, Frontiers in Communication

View all citing articles on Scopus

View full text

The use of unlicensed and off-label medicines in the neonate

Summary

Section snippets

Background

Unlicensed medicines

Off-label medicine use

Incidence and nature of unlicensed and off-label medicine use in neonates

Primary care

Risks associated with unlicensed and off-label medicine use in neonates

United States

Summary

Lancet

Arch Pediatr

J Pediatrics

Status of new medicines approved by the European Medicines Evaluation Agency regarding paediatric use

Br J Clin Pharmacol

Medicines for children licensed by the European Agency for the Evaluation of Medicinal Products

Eur J Clin Pharmacol

Information for paediatric use of medicines in a product information compendium

Paediatr Perinatal Drug Ther

Indian Medical Association wants off-label prescribing

Br Med J

Unapproved uses of approved drugs: the physician, the package insert, and the FDA

Pediatrics

Unapproved uses of approved drugs: the physician, the package insert, and the Food and Drug Administration: subject review

Pediatrics

The prescription and supply of drugs in children from a legal viewpoint

Paediatr Perinatal Drug Ther

Medicines for Children

The Use of Unlicensed Medicines or Licensed Medicines for Unlicensed Applications in Paediatric Practice. Policy Statement

Birth of a formulary

Arch Dis Child

Editorial: medicines for children

J Pharm Med

Extemporaneous (magistral) preparation of oral medicines for children in European hospitals

Acta Paediatr

Unlicensed and off-label drug use in Australia

Paediatr Perinatal Drug Ther

Optimal dosing schedules with gentamicin are needed for premature neonates

Br Med J

The use of gentamicin in the neonate

JPPT

Unlicensed and off label drug use in neonates

Arch Dis Child Fetal Neonatal Ed

Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study

Acta Paediatr