Off-Label Drugs Use in Pediatrics
Off-label use is the use of pharmaceutical drugs outside the product licence for an unapproved indication, an unapproved age group, unapproved dosage, or unapproved form of administration and the use of medication that is not approved for use by the relevant national authority is referred to as unlicensed drug use. 8 Both prescription drugs as well as over-the counter drugs can be used in off-label ways, although most of the studies focus on off-label use of prescription drugs. Off-label is generally legal unless it violates the ethical guidelines or safety regulations, but it does carry health risks and differences in legal liabilities.
In comparison to adults, there is limited data pertaining to the dosing, efficacy, and safety of medications in children. This relative lack of data can be attributed to many causes, including unfamiliarity with age-related developmental pharmacology in pediatric patients, ethical considerations with conducting pediatric research, and a lack of financial incentive for the pharmaceutical industry. As a result, over the years there have been many significant therapeutic misadventures with off-label use of medications involving children with thalidomide and chloramphenicol being prominent examples. The literature review demonstrates the incidence of off-label use is higher among younger populations, especially neonates as reflected in the neonate intensive care unit-specific articles with off-label prescription rates of at least 26%. While our local study was not focused primarily on the neonate population, we did find a significant number of off-label prescriptions were due to patient age and the risk of receiving an off-label prescription decreased as age increased.Finally, none of the studies we reviewed addressed the issue of parental consent for off-label use despite two studies reporting an adverse drug reaction secondary to off-label medication use. This may in part be secondary to the above-referenced American Academy of Pediatrics adopted policy that specifically states providers do not need parental consent if the medication use is supported by current evidence in the literature or a practitioners experience with the medication. Additionally, there may be a lack of knowledge among prescribers about the on label indications for commonly used pediatric medications. Practitioners should be aware of the off-label medications they commonly use in children and be mindful of known potential adverse reactions and side effects but also be wary of possible new unreported drug reactions or side effects.
The therapeutic drug categories that are most commonly used off‐label in our hospital were general antimicrobials and drugs acting on central nervous system. This finding was in agreement with study conducted in Sweden. However, in the majority of studies, the highest proportion of off‐label drug use in children was topically administered drugs such as dermatological and eye drops (Kimland and Odlind 2011). Several studies had shown high rate of off‐label prescribing in respiratory (Jong et al. 2004), antibiotics (Ekins‐Daukes et al. 2003), analgesics (Conroy and Peden 2001), and antiepileptics (Novak et al. 2005). Ceftriaxone, cloxacillin, and gentamyicin were the top three medications which are frequently used in off‐label manner. This finding was different compared to the report from Sweden, which reported morphine, paracetamol and salbutamol as the most common off‐label medications used. The variation could be explained by the fact that the most prevalent diseases, prescribing trend and availability of medications varies across different countries. The most frequent category of off‐label use in our study was inappropriate dosing and/or frequency (42.3%). Similar findings were reported from the survey in pediatric ward of European countries, Germany, Brazil and Scotland (Conroy et al. 2000; Daukes et al. 2004; Porta et al. 2010; Hildtraud 2013). Off‐label medicine use, such as under‐ and/or overdosing, could bear the risk of potential health hazards. Inappropriate dosing is of particular concern for antibiotic use with respect to the development of resistances. If medication is underdosed, there may be no therapeutic benefit but carries a risk for ADRs. Among all pediatric patients surveyed, those receiving care for the most frequent diagnosis, which is community acquired pneumonia (CAP), are the leading recipients of off‐label medicines.
In brief, there is need for strict drug regulation for pediatric population to ensure safety and effectiveness of pharmacotherapy. Further studies are needed to examine why there are inadequate dosing guidelines and generation of more clinical data especially in respiratory medicines. Understanding various risk factors and spectrum of off-label medicine use can assist developing prevention strategies. Off-label prescribing is a reality and will not go soon. Implementing evidence based approach can significantly improve rationality of pediatric pharmacotherapy.
Mukattash T, Trew K, Hawwa AF, McElnay JC (2012). Children's views on unlicensed/off‐label paediatric prescribing and pediatrics clinical trials. Eur J Clin Pharmacol 68: 141–148.
Novak PH, Ekins‐Daukes S, Simpson CR, Milne RM, Helms P, McLay JS (2005). Acute drug prescribing to children on chronic antiepilepsy therapy and the potential for adverse drug interactions in primary care. Br J Clin Pharmacol. 59:712–717.
Jong GW, Eland IA, Sturkenboom JM, van den Anker JN, Stricker BH (2004). Unlicensed and off label prescription of respiratory drugs to children. Eur Res J 23: 310–313.
Kimland E (2010). Drug Treatment in Children with focus on Off‐label drug use, Stockholm. Karolinska Institutet, 169 solna Stockholm.