Massive presence of off‐label medicines in Danish neonatal departments: A nationwide survey using national hospital purchase data

Abstract

There is currently insufficient knowledge of gestational age dependent medicine disposition in neonates. Accordingly, the use of off-label medication, i.e., use of medicines outside its approved marketing authorization, is high in the neonatal departments. By using data from the Danish National Pharmaceutical Hospital Purchase Database, we identified the most commonly occurring medications and calculated the on/off-label ratios for premature and term neonates. Data was extracted on ATC level 5 and based on defined daily doses as per WHO. Data covered the 4 high-level NICUs and 10 of 13 of the intermediate/standard level Danish neonatal departments. Of the identified medication, 87% and 70% did not have approved marketing authorization for use in premature and full-term neonates, respectively. Furthermore, one-fifth of the top 100 medicines did not have a (Danish) marketing license. Overall, off-label medication was widespread covering virtually all ATC groups and no ATC group had an off-label level lower than 50% (range 50%-100%). Finally, in 21% of medications, additives from 8 different chemical groups with potential deleterious effects for neonates were identified. In conclusion, off-label medication in the Danish neonatal departments is widespread. The pharmaceutical industry is unlikely to solve this problem, and we may for a very long time be occasionally forced to use off-label medication. Practical solution must therefore come from multidisciplinary clinical and academic collaboration. Use of formulation list as guidance for prescriptions and NICU-friendly galenic formulations may mitigate the problem temporarily while waiting for definitive studies.

Neonatal Drug Formularies: a Global Scope

“…A prospective cohort study by Costa et al [3] examined the prevalence of neonates administered off-label and unlicensed drugs and found that 96.4% of neonates and 100% of extremely preterm neonates or extremely low birth weight neonates were exposed to offlabel drugs, while 66.8%, 76.7% and 75.7% were exposed to unlicensed drugs, respectively. This high prevalence has very recently been reconfirmed in a Danish nationwide survey [4]. Moreover, a review by van der Zanden et al found that 70% and 56% of the drugs included in the Dutch Pediatric Formulary (DPF) are not authorized (i.e.…”

Establishment of a children's Drugs and Therapeutics Committee to ensure evidence‐based and cost‐effective medical treatment for children

“…Potentially harmful additives posed a challenge to the cDTC in general, as an official complete list of medicines, including benzyl alcohol, ethanol, propylene glycol and other additives, does not exist and safety limits are often unknown. It even appears that medicines developed and approved for use in the paediatric population may contain potentially harmful additives, e.g., the oral solution Pinex junior®, which contains both benzyl alcohol and propylene glycol, both of which are associated with fatal outcomes in newborns and young children 11,29 . To avoid the local pharmacy supplying a substitutable cost‐effective alternative that may contain harmful excipients, it has been stated as a note to the recommendation lists that some medicines must be explicitly noted as non‐substitutable when prescribing.…”

“…9,10 Recently a presence of up to 90% off-label medicines among the 100 most used medicines in Danish neonatal intensive care units was demonstrated. 11 To worsen the situation, a recent survey showed that even though a paediatric marketing authorization was acquired, this was no guarantee that the medicine would be available to the general paediatric population. A third of new medicines approved for children between 2007 and 2016 and up to half of all new paediatric formulations agreed on in a PIP were not marketed in the Nordic countries, Denmark, Sweden, Norway and Finland.…”

“…Regulatory approved medicines for newborns are lacking in particular 9,10 . Recently a presence of up to 90% off‐label medicines among the 100 most used medicines in Danish neonatal intensive care units was demonstrated 11 . To worsen the situation, a recent survey showed that even though a paediatric marketing authorization was acquired, this was no guarantee that the medicine would be available to the general paediatric population.…”

Antiasthmatic prescriptions in children with and without congenital anomalies: a population-based study

“…Beta-2-agonists should not be used in children with infundibular pulmonary stenosis as beta-blockers may be prescribed to prevent hypoxic spells in these children while awaiting surgery. 40 While over 50% of children in hospitals are administered ‘unlicensed’ or ‘off-label’ medicines, 41 42 a Spanish study reported that 16% of antiasthmatics dispensed by community pharmacies for use by children were ‘off-label’ and that the seasonal variations suggested that these were prescribed to treat respiratory infections in young children rather than asthma. 43 We do not have information about off-label use in our study but the indications and age limits for prescribing off-label antiasthmatics are likely to differ between countries.…”