Off-label use of drugs in pediatrics

On January 26th 2007, the European Regulation on medicinal products for paediatric use (Regulation EC No 1901/2006) [1] entered into force in all the European Union countries. The aims of this regulation are to facilitate the development and the accessibility to medications specifically designed for children from 0 to 18 years old, to ensure that medicinal products used in paediatric population are subject to high quality ethical research and appropriately authorized for use in children, as well as to increase the informations availability on use of medicines for children [2].

However despite the European Regulation and initiatives put forward in this area by Agenzia Italiana del Farmaco (AIFA), still only one third of drugs available to the adult range gets to the pediatric patient and sometimes only after many years. The analysis of the current situation shows that many new drugs and most molecules already available since long time on the market, are not registered for pediatric use.

It follows that, in clinical practice, children are often treated with medications designed and tested only in the adults, according to procedures and indications not specifically envisaged nor registered for children (off-label use of the drug). Using a drug off-label means prescribing it in conditions that differ from those for which it has been authorized, in terms of age, dosage regimen (dose or frequency of administration), therapeutic indication, route of administration and formulation.

The off-label and unlicensed classification methods varied, making results difficult to compare [3,4,5]. Many studies reported high rates of off-label (9 to 78.7%) and unlicensed (0.3 to 35%) drug use in different pediatric patient settings [5]. The extent of paediatric unlicensed/off label use is higher in neonatal and paediatric intensive care units and oncology wards, compared with primary care [4]. On the paediatric hospital wards, off-label/unlicensed prescriptions ranged from 16 to 62% [3]. In the neonatal wards, rates ranged from 55 to 80% [3]. In the community setting, rates ranged from 11 to 37% [3].

This lack of adequate registration is caused by different issues:

  • There are problems of numerosity and heterogeneity of patients and clinical situations: between 0 and 18 years there are at least three different sub-populations (infants, children and adolescents) with biological and metabolic characteristics significantly different from each other, and therefore requiring specific studies and experiments [6].

  • There are ethical issues: there is in fact a kind of ethical bias to expose children to experimental clinics, although, on the contrary, this may go to harm their own interests, since it precludes the possibility of developing drugs tailored to their specific needs [7].

  • .There are finally economic reasons determined by the costs of the trials and the limited economic return: a situation that discourages investment by the pharmaceutical industry.

Since publication of the 2002 statement from the American Academy of Pediatrics on the off-label use of drugs [8], the number of drugs approved with pediatric indications or expanded labeling that informs drug use in pediatric patients has substantially increased [9,10,11]. However, despite this success and advances in both basic science and clinical trials in pediatrics, off-label drug use remains a common and important issue for children and adolescents [12].

Off-label use is in many situations the only therapeutic option [12,13,14]. Such use has in clinical practice a “crucial” and, in many situations, not deferrable role and, although unauthorized, has frequently long periods of pediatric use (clinical practice statement), as well as studies and reports in the literature that strongly support drug efficiency and safety [12, 14].

Remarkably off-label prescription has clinical, legal and ethical implications to consider [12] the chance of making mistakes in the definition of a treatment is greater, it involves the direct assumption of responsibility by the prescriber (both in terms of efficacy and possible adverse effects), it requires informed consent by a person conducting the parental authority and has an impact on drug reimbursement.

The issue of the off-label use of drugs in Pediatrics is further amplified in certain areas, where even more problems related to the difficulty of developing clinical trials for specific type of patients, features of situations and/or newness of the problema may arise [12, 15]. For example, these critical issues are greater in neonatology, in rare and complex diseases, in children with life threatening/limiting disease and/or in terminal illness, where trials are rarely conducted both for the low numerosity and high heterogeneity of the population, both for ethical reasons and sometimes for lack of economic resources.

The result is that the off-label use of drugs in these conditions represents the standard of treatment, consolidated and time honoured in the management of the young patient. In these areas the treatment choices are made on the basis of an established practice, often deduced from experience/studies completed in adults, and limited pediatric specific evidence. This is the case of pediatric palliative care [16].

Pediatric palliative care

In recent years, a slow but continuous change of the care needs of the ill infant/child/adolescent took place: new types of patients, new situations and new goals of “health”. Certainly one of these new fields is represented by the needs of Palliative care in the pediatric population.

Pediatric Palliative Care (PPC) are that part of pediatric medicine that takes care of children with incurable disease and/or severe disabilities: the goal of palliative care is the quality of young patient’s life and symptom control [17]. Home is, in the vast majority of cases, the chosen and ideal place for care and treatment. The spectrum of diseases potentially eligible at PPC is heterogeneous and broad (neurological diseases, oncology, cardiology, respiratory, muscular, metabolic, infectious, developmental disorders, chromosomal, post anoxic) and heterogeneous and large is also the spectrum of needs, clinical and not, that they trigger, and the modality needed for the care of the patient. It is estimated that in Italy children eligible to PPC are about 30,000 [18].

The main goal for all these children is alleviating suffering and pain, while addressing and containing all the other stressful symptoms and conditions. In these contexts the scientific evidence are scant and, in order to obtain welfare objectives consistent with the situation, the prescription of drugs is off-label in the overwhelming majority of cases, for indication use and/or for age and/or modality of administration and/or formulation [19]. Minors eligible at PPC are patients at high-complexity of assistance, affected by multiple pathologies which trigger complex symptoms that require polytherapy, frequently for long periods of time.

These are often patients with complex conditions which may limit the possibility of assuming drugs through routine routes of administration, requiring alternative ways such as the intranasal, the submucosal, the inhalatory one. Often these children may have cognitive and/or relational deficits which limit the possibility for sharing, actively participate or accept the management of a treatment plan.

In the majority of cases, the management of these infants/children/teenagers takes place at home and thus the medication management is settled into a different contest from that of a hospital or outpatient setting, with different standards of recording and monitoring.

Off-label drugs and law 648/96

In Italy, the off-label use is governed by Law 648/96 that has identified a list of medications with a therapeutic indication other than that authorised, used in clinical practice for consolidated use and data from scientific literature. These drugs, once inserted in the list of medicinal products established by Law 648/96, are administered under the physician’s direct responsibility and can be reimbursed by the National Health Service [20].

In this list, there are drugs partially covering the needs of different areas of pediatric medicine such as drug listed for oncological, cardiovascular [21], gastrointestinal, anesthetics [22], anti-infective, dermatological, genitourinary tract medications and hormones.

This list lacks of some medicines frequently used to control pain and other relevant symptoms in the PPC.

Given the peculiar situations and cure aims that PPC promise, we identified a list of medications used in the PPC for which inclusion in the list established by Law 648/96, represents for patients, operators and all the health system a goal of efficacy, safety and equity.

For using such drugs, it remains mandatory to collect, by the legal representatives of the child, the informed consent at use. It’s also important to inform the child, with tool and modality appropriate to age, clinical situation and capacity of discernment, on medication and strategies of administration, in the perspective of sharing and participating to the treatment program.


A list of drugs used off-label in pediatric palliative care (PPC) and in pain therapy, deemed essential to solve, at least in part, the low availability of medicinal products studied and approved in pediatric age, has been filled out. Ten drugs have been identified that routinely, for specific indications in PPC clinical practice, are used off-label with modality that are different from those for which they have been authorized in terms of age, dosage, therapeutic indication, route of administration and formulation.

In order to derive a proposal for inclusion in the list of medications dispensed in accordance with law 648/96, the work includes information about the scientific evidence to support the off-label use (literature, RCT, any clinical studies in course) and the use of the active ingredient in the off-label indication in other Member States (United Kingdom, with reference to the British National Formulary, BNF for children, Edition 2016–17).

The list has the aim to indicate the active ingredients, for each ATC class, which can be used in children under the CPP, although their use is not approved in childhood. For some of them, there is a rational use as supported by available evidence, even in the absence of controlled trials, frequently in case of old molecules or for objective difficulties in conducting pediatric clinical trial.

Some indications applied for inclusion in the list according to Law 648/96, refer to therapies that are used for short periods of time, in the course of exacerbations and/or end-of-life. Other requests instead, refer to prolonged use (months, years), during the course of taking charge in palliative care of the child with an incurable disease.

For each of the 10 identified active ingredients a single card was formalized that lists the specific indication of on-label demand in clinical practice, the rationale of the request, the evidence in support of the request, the current situation that is approved for use from leaflet, any additional notes [23]. The drugs detected are listed in Table 1.

Table 1 The 10 drugs singled out for an authorised “off-label” use in PPC


The Agenzia Italiana del Farmaco (AIFA) and the Italian Society of Palliative Care (SICP), under the dedicated work table, drew up a document that gathers the scientific evidence available to support the off-label use of medicines more frequently used in the field of pediatric palliative care, with the goal of attesting to the off-label use of these drugs and propose their use under the law 648/96, in the absence of data from clinical trials.