Antonio Clavenna

Pregnancy outcome after cabergoline treatment in early weeks of gestation

We collected information on 61 pregnancies in 50 women treated with cabergoline. These pregnancies resulted in 12 (19.7%) early terminations (five induced abortions, six spontaneous abortions, one hydatidiform mole) and 49 (80.3%) live births. In one case, malformations were suspected by a gynecologist based on ultrasound at 12 gestational weeks and the pregnancy was terminated; additional information was not available. There was one case of trisomy 18. The frequency of spontaneous and induced abortions and major congenital malformations was comparable with rates in the general population. The data did not indicate any potential adverse effect of the drug on pregnancy. The data from this study in combination with previous reports can exclude a congenital malformation risk greater than 10% associated with pregnancy exposure to cabergoline.

Adverse drug reactions in childhood: a review of prospective studies and safety alerts

Objective: To assess the incidence of adverse drug reactions (ADRs) in the paediatric population and the safety alerts concerning children and adolescents issued by international drug regulatory agencies since 2001. Methods: A bibliographic search was performed in the Medline and Embase databases for prospective studies published between January 2001 and December 2007 evaluating the ADR incidence in the paediatric population. Data were analysed by a random effect model. Moreover, the websites of nine international drug regulatory agencies were searched to collect information on safety alerts concerning the paediatric population. Results: A total of eight prospective studies were evaluated, six of which concerned the ADR incidence in hospitalised children. The overall incidence of ADRs was 10.9% (95% CI 4.8 to 17.0) in hospitalised children and 1.0% (95% CI 0.3 to 1.7) in outpatient children. The rate of hospital admission due to ADRs was 1.8% (95% CI 0.4 to 3.2). The skin and gastrointestinal system were the organs most commonly affected and antibiotics were the drugs most commonly associated with ADRs. Safety alerts in the paediatric population were retrieved for 28 drugs, five of which were for psychotropic drugs and most of which were issued by the Food and Drug Administration (20 drugs). For 12 drugs, warnings were published in the 2006–2007 period. Antidepressants were the only drugs for which alerts were issued by all the drug regulatory agencies. Conclusions: To ensure safe and effective medicines for children, efforts are needed at different levels (governments, drug regulatory agencies, pharmaceutical industries, health care professionals, and parents). Collaborative regulatory initiatives, such as the use of common warnings, can also contribute to a more rational use of drugs for children.

Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: A systematic review and meta-analysis

To evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with depressive disorder, the main electronic databases and the reference lists of retrieved articles and reviews were searched up to January 2007. Randomized controlled studies (RCT) were assessed for methodological quality, taking into consideration the specific diagnostic and severity evaluation tools used, and a meta-analysis on the efficacy of SSRIs compared placebo was undertaken. In all, 13 studies were included, covering a total of 2530 children and adolescents. Eleven studies met the criteria for inclusion in the meta-analysis. The pooled odds ratio was 1.57 (95% C.I. 1.29-1.91). Only fluoxetine appeared to offer a moderately significant benefit profile (OR=2.39). All studies differed in diagnostic tools and primary efficacy measures. SSRI treatment, especially with fluoxetine, may be effective on child and adolescent depression. Nevertheless, additional RCTs with sound methodological designs, validated diagnostic instruments, large sample sizes, and consistent outcomes are necessary to determine the role of SSRIs, alone or in combination with psychological interventions in the treatment of depression in children and adolescents.

Differences in antibiotic prescribing in paediatric outpatients.

Antibiotics represent the most widely prescribed therapeutic agents. The prevalence of drug prescription differs across age, with preschool children being most exposed to antibiotic drugs, especially in the community setting. A review with the aim to compare the profile of antibiotic drug prescription at the multinational, national and regional levels was performed. This overview of drug-utilisation studies found quantitative and qualitative differences in the antibiotic prescription profile between and within countries. Moreover, differences exist also at the local level and between prescribers. In general, second-choice antibiotic drugs (eg, cephalosporins) were more commonly prescribed in settings characterised by a high prevalence of antibiotic prescription. Geographical differences should be taken into account when monitoring antimicrobial drug resistance and when planning educational interventions for health professionals and parents with the aim to improve the rational use of antibiotic drugs.

Safety of medicines used for ADHD in children: a review of published prospective clinical trials

Objective To assess the long-term safety of drugs for attention deficit hyperactivity disorder (ADHD). Methods A bibliographic search was performed in the MEDLINE, EMBASE and PsycINFO databases for prospective studies evaluating the incidence of adverse events (AEs) in children and adolescents treated for ADHD. Results A total of six prospective studies that monitored drug safety during therapy for at least 12 weeks were retrieved. The drugs studied were atomoxetine (two studies, 802 patients), osmotic-controlled released oral methylphenidate formulation (two studies, 512 patients), extended release formulation of mixed amphetamine salts (one study, 568 patients) and transdermal methylphenidate (one study, 326 patients). Heterogeneity was found in the duration of follow-up (ranging between 1 and 4 years) and in the way data were reported. The rate of treatment-related AEs ranged from 58% to 78%, and the rate of discontinuation due to AEs ranged from 8% to 25% of the children. Decreased appetite, insomnia, headache and abdominal pain were the most common AEs observed. Most AEs and cases of discontinuation occurred during the first few months of treatment. Conclusions Few studies evaluated the long-term safety of drugs for ADHD. Heterogeneity in follow-up duration and in data reporting made comparing different studies and drugs difficult. A systematic monitoring of long-term safety is needed.

Determinants of the drug utilization profile in the paediatric population in Italy's Lombardy Region

AIMS To evaluate the intraregional differences in drug prescribing to children and adolescents. METHODS Prescriptions reimbursed by the National Health System, involving 1543 203 children and adolescents <18 years old and dispensed during 2005 by the retail pharmacies of 15 local health units (LHU) in the Lombardy Region, were analysed. Logistic regression analysis was performed to evaluate the association between drug prescription and age, gender, prescriber, and setting. RESULTS A total of 747 790 youths (48%) received at least one drug prescription. The prescription prevalence rate was highest in children 1-5 years old (65%), decreased with increasing age to 38% in adolescents, and was slightly higher in boys than in girls. Antibiotics and anti-asthmatics were the most prescribed therapeutic classes. Amoxicillin + clavulanic acid was the most prescribed drug (18% of children; 20% of packages). Large differences were found in the drug prescription prevalence rate between the different LHUs. The rate ranged between 38.4 and 54.8%, and was not correlated to hospitalization rate in the paediatric population. Being 1-5 years old [odds ratio (OR) 4.51, 95% confidence interval (CI) 4.43, 4.58] and living in the eastern part of the region (OR 2.06, 95% CI 1.99, 2.13) were the factors associated with the highest risk of drug exposure. CONCLUSIONS The results resemble the profiles observed in other Italian contexts, in particular concerning the wide use of antibiotics and anti-asthmatics. However, large differences were found between LHUs, highlighting the need for more detailed investigations on therapeutic needs, drug use, and related variables in different geographic contexts.

Anti-asthmatic drug prescriptions to an Italian paedriatic population

To estimate the prevalence and evaluate the appropriateness of anti‐asthmatic drug prescriptions in an Italian paediatric population, drug prescriptions involving 24,407 children <18 years old, dispensed during 2003 by the retail pharmacies of the local health unit in Lecco, Italy, were analysed. Children ≥6 years old receiving anti‐asthmatics were categorized into three subgroups based on the number of boxes prescribed: occasional (one box), low (two and three boxes) and high (≥four boxes) users. A logistic regression analysis was performed to estimate the relationship between the drug use patterns and formulations, antibiotic co‐prescriptions, systemic steroid prescriptions and rate of hospitalization. Anti‐asthmatic drugs were prescribed to 6594 (12%) children and adolescents; 58% of whom received only one box of the drug. Prevalence varied according to age, with the highest values at 1 and 4 years (24% and 21% respectively), and decreased to 6% in 17‐year‐old adolescents. Inhaled steroids were the most prescribed drugs (83%). The most common of these was beclomethasone. Occasional, low and high users represented 58%, 29%, and 13%, respectively, of the treated population ≥6 years old. High users were found to be at increased risk of systemic steroid prescriptions (OR 8.6) and hospital admission for asthma (OR 6.8). This study confirms that in Italy the prevalence of anti‐asthmatic prescription is much higher than prevalence of disease, indicating that anti‐asthmatics are over‐prescribed. Moreover, steroids, especially nebulized, are mainly prescribed only once in a year, supporting the idea that are prescribed not for asthma, which as chronic disease requires a chronic therapy. The approach to create subgroups on the basis of number of boxes prescribed seems to be effective in estimating asthma severity and appropriateness of the therapies.

International trends in clozapine use: a study in 17 countries

There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis.

Oral ondansetron versus domperidone for symptomatic treatment of vomiting during acute gastroenteritis in children: multicentre randomized controlled trial

BackgroundVomiting in children with acute gastroenteritis (AG) is not only a direct cause of fluid loss but it is also a major factor of failure of oral rehydration therapy (ORT). Physicians who provide care to paediatric patients in the emergency department (ED) usually prescribe intravenous fluid therapy (IVT) for mild or moderate dehydration when vomiting is the major symptom. Thus, effective symptomatic treatment of vomiting would lead to an important reduction in the use of IVT and, consequently, of the duration of hospital stay and of frequency of hospital admission. Available evidence on symptomatic treatment of vomiting shows the efficacy of the most recently registered molecule (ondansetron) but a proper evaluation of antiemetics drugs largely used in clinical practice, such as domperidone, is lacking.ObjectivesTo compare the efficacy of ondansetron and domperidone for the symptomatic treatment of vomiting in children with AG who have failed ORT.Methods/DesignMulticentre, double-blind randomized controlled trial conducted in paediatric EDs. Children aged from 1 to 6 years who vomiting, with a presumptive clinical diagnosis of AG, and without severe dehydration will be included. After the failure of a initial ORS administration in ED, eligible children will be randomized to receive: 1) ondansetron syrup (0,15 mg/Kg of body weight); 2) domperidone syrup (0,5 mg/Kg of body weight); 3) placebo. The main study outcome will be the percentage of patients needing nasogastric or IVT after symptomatic oral treatment failure, defined as vomiting or fluid refusal after a second attempt of ORT. Data relative to study outcomes will be collected at 30 minute intervals for a minimum of 6 hours. A telephone follow up call will be made 48 hours after discharge. A total number of 540 children (i.e. 180 patients in each arm) will be enrolled.DiscussionThe trial results would provide evidence on the efficacy of domperidone, which is largely used in clinical practice despite the lack of proper evaluation and a controversial safety profile, as compared to ondansetron, which is not yet authorized in Italy despite evidence supporting its efficacy in treating vomiting. The trial results would contribute to a reduction in the use of IVT and, consequently, in hospital admissions in children with AG. The design of this RCT, which closely reflect current clinical practice in EDs, will allow immediate transferability of results.Trial RegistrationClinicalTrials.gov: NCT01257672

Burden of psychiatric disorders in the pediatric population

In order to estimate the burden of mental disorders in a representative Italian pediatric population, an epidemiological study was performed using three administrative databases: a drug prescription, a hospital discharge form, and an outpatient ambulatory visit database. The population target was 1,616,268 children and adolescents under 18 years living in the Lombardy Region, Italy. A youth was defined as a case if during 2008 he/she received at least one psychotropic drug prescription or was hospitalized for a psychiatric disorder (International Classification of Disease codes 290-319), or attended a child neuropsychiatric outpatient unit for a visit and/or a psychological intervention or rehabilitation at least once. Epileptic children were excluded. In all, 63,550 youths (39.3 per 1000; 95%CI 39.1-39.7‰) were identified as users of health care resources for a putative mental disorder. The prevalence was higher in boys than in girls (47.0‰ versus 31.3‰) and the highest value was recorded in children 8 years old (60.2‰). A total of 59,987 youths (37.1‰) attended a child and adolescent neuropsychiatry service at least once, 3605 (2.2‰) were admitted to hospital, and 2761 (1.7‰) received at least one psychotropic drug prescription, 57% of which did not attend a child neuropsychiatry service. In all, 14,741 youths (23.1% of users) had a disorder that required a high intensity of care (e.g. recurrent prescriptions for drugs and/or ambulatory care). The proportion of youths who received care for mental disorders in the Lombardy Region seems lower than in other countries. However, the fact that many children were prescribed psychotropic drugs without the supervision of a child psychiatrist is a reason for concern.