Introduction

Vomiting in children represents a common occurrence related to several conditions, such as acute gastroenteritis or gastroesophageal reflux, which stimulate the vomiting center in the bulb, but does not necessarily require drug treatment. Acute gastroenteritis (AG) represents a common cause of acute vomiting in children under 3 years old and, therefore, a major cause of access to the emergency department [24].

Several antiemetic agents may be able to prevent or reduce vomiting in children with gastroenteritis (Tables 1 and 2) [4, 8, 20, 38, 39], even if their use could be related with the development of serious side effects [2, 17]. Moreover, several drugs are prescribed outside their licensed indications with respect dosage, age, indication, or route of administration and are named as off-label [1]. Off-label use is very common among pediatricians, and the main cause is attributable to the lack of drugs specifically designed and marketed for children in different age groups (Table 2). In pediatrics, drugs are often prescribed using dosages and indications approved for adults, resulting in ineffective treatment or increased risk of serious side effects [18, 19, 37, 40]. In addition, physicians when administering drugs to children are frequently forced to deviate from the established labeling indications, by manipulating drug formulation to obtain a pediatrics dose or by changing the indicated route of administration [30].

Table 1 Antiemetic drugs and their mechanism of action
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Table 2 Antiemetic drugs administered in children
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Off-label prescribing could be related to several problems, such as safety for the patient, costs for the society, and legal risk for the physician; therefore, this practice should be used only when the benefit outweighs the risk. In this contest, the aim of present study was to assess, in pediatric emergency department, the off-label use of antiemetic drugs in children with vomiting related to AG.

Methods

This study was carried out in eight pediatric emergency departments in Italy: Paediatric Emergency Department, Institute for Child Health IRCCS Burlo Garofolo, Trieste; Paediatric Emergency Department, Institute for Child Health IRCCS Bambino Gesù, Roma; Paediatric Emergency Department and Pharmacy, Institute for Child Health IRCCS Gaslini, Genoa; Paediatric Emergency Department, Ospedale Meyer, Firenze; Paediatric Emergency Department, Ospedale Civile, Padova; Paediatric Emergency Department, Ospedale Sant’Anna, Torino; Emergency Department, Ospedale Salesi, Ancona; and Paediatric Emergency Department, Ospedale Civile, Brescia. After receiving the approval of the local ethics committee, we retrospectively analyzed the data on pharmacy records of children from 0 to 17 years old admitted to the above-reported pediatric emergency rooms from 1 January 2004 to 31 December 2007, with a primary diagnosis of acute gastroenteritis. The following data were obtained crossing the pharmacy distribution records with emergency departments’ patient data: sex and age of the patients and detailed information for each drug used (indication, dose, frequency, and route of administration).

Usually, the daily defined dose is used in adult to calculate the standard daily dosage [13], but it is not possible to use in children. Therefore, in order to evaluate the off-label use determined by dosing, we calculated a standard dose based on weight and age of children, comparing it with the median doses recorded.

In particular, formulation, such as tablets, injectable, and suppositories, was calculated as one single dose, and as regards for formulation such as syrup and drops, we calculated a media dosage; this was extrapolated from the dose range described in the leaflet, as commonly used, for a child of 4 years old, and when necessary, we considered the weight at 50th percentile referred to a child of 4 years old, in agreement with the paper of Cacciari et al. [6]. For each drug, the approved indications, dosages, and dosages by age were collected. For active substances approved in children, the characteristics of the pediatric studies included in the leaflet were also considered. The Italian National Formulary, which is consistent with the leaflet from the manufacturer, represented the reference document.

Off-label drugs

In agreement with Morales Carpi et al. [27], we considered off-label use to be the utilization of a drug at an indication, dosage, frequency, or route of administration different from those specified in the leaflet or in children outside the authorized age group. A ±10 % difference in dosing between the data obtained and leaflet was tolerated when determining the off-label status for the dose. We also considered off-label use when the leaflet did not specifically provide pediatric informations.

Literature research

Medline, PubMed, Embase, Cochrane Library, and reference lists were searched for articles published until May 2012, using the words “children,” “vomiting,” “acute gastroenteritis,” “therapy,” “antiemetics,” “off label,” and “on label.”

Statistical analysis

Following the study, data were coded and entered into a customized database in SPSS, version 17, for statistical analyses. Chi-square test analyses were used to test for significant differences between groups. A P value less than 0.05 was considered statistically significant.

Results

In this study, we calculated a total amount of 19,879 doses of antiemetic drugs administered in 19,879 children admitted to the emergency room for vomiting related to AG (Table 2; Fig. 1). Among the subjects with vomiting related to AG who received an antiemetic, almost half were 2 years or less (P < 0.01) (Fig. 1). The analysis suggests a tendency to an off-label antiemetic administration comparing to both leaflet from the manufacturer and literature data. In Table 1, we list the approved age and dose ranges for each drug, and in Fig. 2, we describe the frequency of each drug prescribed for each year under study.

Fig. 1
figure 1

Age distribution of children admitted to pediatric emergency departments and receiving an antiemetic drug in eight hospitals from 2004 to 2007, in Italy. *P < 0.01; 0–2 years respect to other years

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Fig. 2
figure 2

Percentage of antiemetic drugs prescribed in children from 2004 to 2007, in eight centers in Italy.*#P < 0.01 domperidone vs other drug treatments; #P < 0.01 metoclopramide vs granisetron, ondansetron (except on 2007), tropisetron, thiethylperazine, and prochlorperazine; *P < 0.01 ondansetron vs granisetron, tropisetron, thiethylperazine, and prochlorperazine

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Variability among centers

Antiemetic dose prescriptions were evaluated during 4 years (from 2004 to 2007) in eight Italian pediatric emergency departments; 70 % of the administered doses were label, while 30 % were off-label (10 % for indication and 20 % for age), without difference between each center. Domperidone was the only antiemetic used labeled for AG treatment in children in all years studied and in seven of eight centers (P < 0.01) (Fig. 3). Metoclopramide and ondansetron have been used off-label for both age and indications in all involved centers. In particular, metoclopramide was administered off-label in seven of eight centers (P < 0.01; 87.5 %) and in all years studied (Fig. 3), while ondansetron was prescribed off-label in five of eight centers (P < 0.01) and meanly in three of 4 years (Fig. 3).

Fig. 3
figure 3

Antiemetic drugs administered from 2004 to 2007, at each child with vomiting related to acute gastroenteritis admitted at each of the eight centers enclosed in this study

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Discussion

In our paper, we evaluated the off-label use of antiemetic drugs in children admitted in eight pediatric emergency departments in Italy. Previously, Albano et al. [1] evaluated the antiemetic prescribing rates by Italian pediatricians, through a questionnaire study distributed at a pediatric national conference, and documented that the use of antiemetics in children is common. In our study, we reported that 30 % of the antiemetic prescriptions for children in emergency room are off-label.

Off-label use is widespread in different countries worldwide and across medical disciplines and is more common in some restricted clinical populations, such as human immunodeficiency virus-infected patients, children, pregnant women, patients with psychiatric disorders, and cancer patients [5, 7, 22, 23, 28, 33, 35].

Italian legislation on the use of off-label drugs is based on law no. 648/1996. Off-label use is allowed for drugs included in a specific list (known as L.648 list). This list includes innovative drugs not yet marketed in Italy, drugs still undergoing clinical trials, and medicines administered for a different therapeutic indication not included in the leaflet, in case of absence of therapeutic alternatives and previous written consent of the patient. None of these antiemetic drugs are included in this list.

Italian Law no. 94/1998 allows the physician, in individual cases, to use an off-label drug on the basis of evidence of efficacy, under his/her direct responsibility, and after obtaining written informed consent from the patient. This law does not allow widespread off-label use but permits the physicians to prescribe the appropriate therapy based on data published on the international valuable literature and previously documented demonstration of the absence of other therapeutic alternatives.

Since 2006, in Italy, the use of off-label drugs has been greatly restricted by law no. 296 of 27/12/2006 (provided by the Italian National Financial Plan for 2007) which forbade the widespread use of drugs outside of the approved conditions allowed by law no. 94/1998. Law no. 244 of 24/12/2007 (provided by the Italian National Financial Plan for 2008) subsequently specified that the use of an off-label drug should be possible only if supported by phase III or, in exceptional cases, phase II clinical trials, and if the related data are sufficient to provide a favorable opinion on its efficacy and tolerability. A recent review of worldwide publications on off-label prescribing for children, from 1985 to 2004, reported that up to 80 % of medicines prescribed to children are prescribed in an off-label manner [30]. The concerns about pediatric off-label prescribing revolve around a reported higher rate and severity of adverse drug reactions, the potential for treatment failure, and a general lack of long-term safety and efficacy [18, 19, 37, 40]. Even if antiemetics treatment in children with vomiting may be related to the development of side effects [17], physicians frequently prescribe antiemetic agents [23] because they are interested to increase the effects of oral rehydration solutions, reducing the discomforts of vomiting. Antiemetic agents commonly used in the 1990s such as promethazine and prochlorperazine [21, 23] are associated with frequent and potentially life-threatening side effects [34], which resulted in a negative perception of all antiemetics and a reduction in their use in children with gastroenteritis.

The analysis of our data revealed that 30 % of antiemetic prescription in children is off-label, and that the off-label prescription is more common in children with an age less than 2 years old. These data are in agreement with other studies that evaluated the off-label prescription of drugs in children [3, 32].

In particular, Baiardi et al. [3], evaluating the label prescription of respiratory drugs in children, documented that the mean off-label rate is of 19 and 56 %, by age and indication, respectively, and that the majority of off-label uses is among the children under the age of 2.

Similarly, Porta et al. [32] described that 27.5 % of antibiotic prescriptions for patients admitted to pediatric wards in Italy were off-label for dose, while 30 %, for indication, and these results were similar in all center involved in the study.

In our study, we documented that domperidone, registered for acute vomiting from any cause, is the most used drug (14,114.33 doses), even if Marchetti et al. [24] reported that only a few studies were published regarding the effect of domperidone in the treatment of vomiting during acute gastroenteritis in children, and these were characterized by small sample sizes, low methodological quality, and produced inconsistent results. Domperidone does not cross the blood–brain barrier and therefore should not cause extrapyramidal side effects unlike metoclopramide, but its use in infants has been associated in some studies, for QT prolongation on the ECG, potentially leading to serious ventricular arrhythmias and sudden cardiac death [9]. The dose of domperidone required by international guidelines is 0.2–0.4 mg/kg up to a maximum of 2.4 mg/kg/day. There is not a formulation appropriate for different age groups; in particular, the suppository formulation of 30 mg is appropriate for a child of 15 kg (approximately 2 years old), and the adjustment of dosage is hardly feasible.

In our study, metoclopramide has been prescribed off-label in 4,027.89 doses in seven of eight centers, even if it is contraindicated in Italy, under the age of 16 years for evidence of severe extrapyramidal reactions derived from spontaneous reports and surveillance studies of case–control [26]. Ondansetron is an antiemetic known for its safety profile, and it may be used in children with serious emesis that is not responsive to other treatment. There have been a few case reports of extrapyramidal adverse effects and seizures from this drug [31]. In our study, we recorded that this drug has been used in 1,593.00 doses in children, in five of eight centers, and its use was always off-label. In fact, in agreement with leaflet, ondansetron is indicated to treat people with vomiting related to surgery or to anticancer treatment.

This result is in agreement with a previous paper documenting that approximately 16 % of medications prescribed off–label in pediatrics were associated with dose changes [36]. Akathisia and dystonia are the most common reported side effects in children in up to 44 % of patients treated with prochlorperazine [10, 29]. Its use is very limited, since it is not recommended in pediatric patients, and there is no scientific evidence that supports its use in children. However, we recorded that it has been used in five doses in children with emesis. So, the misuse of off-label drugs could induce an unjustified increase of costs for the health care system, but we are not able to document it.

The impact of off-label use is important because it could represent a safety risk for children and a legal risk for the prescribing physician if patients have an unwanted or bad outcome from treatment; in every time, physician must obtain informed consent from both parents of each children, including information on the proposed treatment, alternatives, potential risks, and expected benefits.

Previously, it was described that the on-label use of drugs could be related with an age-related development of adverse drug reactions [12, 15, 16], and that the off-label prescription may be able to induce the development of side effects [14, 25]. However, since it has been reported that off-label use could be related to potentially negative consequences, in our study, we did not evaluate the clinical response to the treatment or development of adverse drug reactions.

In fact, as well previously reported (see “Methods”) and in agreement with the paper of Franceschi et al. [11], we analyzed the pharmacy distribution records and not the clinical records; therefore, we are not able to evaluate the data related to the development of adverse drug reactions, and this, together with the country, the enrolled children, and the time of the study, could represent a limitation of our study. In conclusion, we reported that 30 % of antiemetics prescription is off-label, and in agreement with national laws, physicians should prescribe off-label drugs only when the potential toxic effects are outweighed by the potential benefit.

Therefore, clinical trials as well as retrospective studies may be performed in order to clarify appropriate patterns of off-label use of antiemetics, in setting areas where prescribing antiemetics is inappropriate and in identifying fields of study that could be improved.