Adriana Ceci

The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients

Summary. In 1997, the Italian Ministry of Health created a special programme for the controlled distribution of deferiprone to collect data and to evaluate its safety and effectiveness in long‐term use. Five hundred and thirty‐two thalassaemia patients from 86 treatment centres were enrolled in this programme. One hundred and eighty‐seven patients (32%) experienced a total of 269 events that led to a temporary interruption or, in some cases, to a discontinuation of treatment. The incidence of agranulocytosis and milder neutropenias were 0·4/100 and 2·1/100 patient‐years respectively. Neutropenia occurred predominantly in younger and non‐splenectomized patients. Transient alanine transaminase increase, gastrointestinal discomfort and arthralgia were the other most commonly reported events. Ferritin levels showed a significant decrease in time after 3 years of therapy. This is the largest number of deferiprone‐treated patients to have been reported to date. These data show that the drug was effective in reducing serum ferritin levels and the incidence of adverse events was not greater than the frequency reported in clinical trials.

Drug use in children: Cohort study in three European countries

Objective To provide an overview of drug use in children in three European countries. Design Retrospective cohort study, 2000-5. Setting Primary care research databases in the Netherlands (IPCI), United Kingdom (IMS-DA), and Italy (Pedianet). Participants 675 868 children aged up to 14 (Italy) or 18 (UK and Netherlands). Main outcome measure Prevalence of use per year calculated by drug class (anatomical and therapeutic). Prevalence of “recurrent/chronic” use (three or more prescriptions a year) and “non-recurrent” or “acute” use (less than three prescriptions a year) within each therapeutic class. Descriptions of the top five most commonly used drugs evaluated for off label status within each anatomical class. Results Three levels of drug use could be distinguished in the study population: high (>10/100 children per year), moderate (1-10/100 children per year), and low (<1/100 children per year). For all age categories, anti-infective, dermatological, and respiratory drugs were in the high use group, whereas cardiovascular and antineoplastic drugs were always in the low use group. Emollients, topical steroids, and asthma drugs had the highest prevalence of recurrent use, but relative use of low prevalence drugs was more often recurrent than acute. In the top five highest prevalence drugs topical inhaled and systemic steroids, oral contraceptives, and topical or systemic antifungal drugs were most commonly used off label. Conclusion This overview of outpatient paediatric prescription patterns in a large European population could provide information to prioritise paediatric therapeutic research needs.

Defining off-label and unlicensed use of medicines for children: Results of a Delphi survey

The aim of this Delphi survey is to develop common definitions for unlicensed and off-label drug use in children to be used for research and regulatory purposes. After a literature review on the current status of unlicensed/off-label definitions, a two-stage, web-based Delphi survey was conducted among experts in Europe. Their opinion on concerns, rules and scenarios regarding the unlicensed and off-label use of medicines were obtained. Results were then consulted with the European Medicines Agency (EMEA) before the final proposal was circulated to participants. Eighty-four experts were invited to participate (scientists, health professionals, pharmaceutical companies, regulatory agencies), 34 responded to the first round questionnaire and participated in subsequent rounds. Consensus was reached for the majority of questions. The lowest level of consensus reached was for questions related to a different formulation or if a drug was given although contraindicated. At the final step, 85% of the responding experts agreed on the proposed definition for off-label (use of a drug already covered by a Marketing Authorisation, in an unapproved way) and 80% on the definition for unlicensed (use of a drug not covered by a Marketing Authorisation as medicinal for human use), respectively. Results will facilitate the conduct of pharmacoepidemiological studies and allow comparison between different countries. The Delphi panel agreed that the definitions should be circulated within the scientific community and recommended to be adopted by relevant regulatory authorities.

Treatment of acute myelogenous leukemia in children: results of the Italian Cooperative Study AIEOP/LAM 8204.

One hundred thirty-three children with acute myelogenous leukemia (AML) entered the multicenter Pediatric Branch of the Italian Association Against Leukemia trial AIEOP/LAM 8204 between July 1982 and May 1986. Induction therapy consisted of two courses of daunomycin (DNM) plus cytosine arabinoside (Ara-C). Those patients who achieved remission were given four courses of consolidation with DNM, 6-thioguanine (6-TG) and escalated doses of Ara-C followed by six courses of sequential continuation therapy using monthly pairs: etoposide (VP-16)/Ara-C, Ara-C/6-TG, and DNM/Ara-C. Periodic intrathecal Ara-C was used for CNS prophylaxis. One hundred seven (80%) children achieved complete remission (CR). Kaplan-Meier estimates of 3-year disease-free survival (DFS) and event-free survival (EFS) are 41% and 33%, respectively. Relapses occurred in 34 patients after 5 to 97 weeks (32 marrow; 2 marrow plus CNS). Overall, 14 patients died of complications during treatment (nine during induction; five during the postremission phase), mostly from infection. Risk factor analysis showed that induction failures occurred predominantly in children with French-American-British (FAB) M5 and in those with elevated leukocyte counts; by step-up Cox analysis, only FAB subtype was predictive of remission success. None of the variables examined was significant for predicting the duration of remission. Hyperleukocytosis was predictive of a significantly worse EFS rate. These results are encouraging and further support the use of intensive chemotherapy programs for childhood AML.

Comparison of antiepileptic drug prescribing in children in three European countries.

Purpose:  Antiepileptic drug (AED) use in young people is increasing. However, evidence of its use at a multinational level is limited. This study aims to characterize AED prescribing in the young in three European countries and to assess the capacity of drug safety surveillance.

Pattern of complications and burden of disease in patients affected by beta thalassemia major

Abstract Objectives: Despite the correct application of blood transfusions and chelation treatments, beta thalassemia patients have many complications. Systematic population analyses on types and frequency of these complications are very few. The aim of this study is to characterize the complications, their risk factors and their clinical and economic impact. Methods: Complications at baseline and events occurring during one observational year were analyzed in 272 patients aged >12 years. Risk factors were analyzed through chi-squared and unpaired t tests. Logistic regression was applied to perform the risk factors multivariate analysis. Results: A total of 554 complications (1–6 per patient) affected 82.3% of patients. Cardiac complications were less represented than expected. Musculoskeletal diseases were the most represented complications followed by hepatic, sexual and endocrine diseases. Splenectomized patients, born before 1970 and aged >40 years, starting iron chelation therapy when aged >4 years or after receiving more than 20 blood transfusions, presented a significantly higher number of complications. A total of 885 adverse events requiring 34125 additional medical services occurred in 1 year. Of these, 34.9% were related to treatments and 65.1% to other causes. Event numbers, additional medical interventions and cost increased progressively in patients affected by one or more complication compared to patients with no complications. Conclusions: The pattern of complications changes according to birth cohort and differentiates older from younger patients. The burden of the disease and its costs increase after the onset of the first complication, therefore prevention of complications is fundamental in these patients.

Cyclosporine A therapy for multisystem langerhans cell histiocytosis.

BACKGROUND Treatment of multisystem Langerhans cell histiocytosis (LCH) remains difficult. Various regimens of single and multiagent chemotherapy have been used, but a significant proportion of patients fail to respond to treatment. PROCEDURE We have evaluated the use of cyclosporine A (CSA) in a controlled group of patients, who had received a systematic primary therapy (LCH-I). Patients received CSA either as a single agent (10 patients) or in combination with vinblastine, etoposide, prednisolone, and/or antithymocyte globulin (16 patients). RESULTS Among the total of 26 patients treated, a single patient developed a complete response and three a partial response, whereas 85% (22 patients) had no response to CSA. CONCLUSIONS CSA is at best of limited value in the treatment of patients with multisystem LCH, particularly those who had progressive disease while receiving chemotherapy.

Databases for pediatric medicine research in Europe--assessment and critical appraisal.

To identify and describe European health care databases that can be used for pediatric pharmacoepidemiological research.

ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia in early bone marrow relapse

Seventy‐three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R‐87 protocol). This treatment programme consisted of an induction phase with intermediate‐dose cytarabine (IDARA‐C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration 12 months (P = 0.0005) and for those with a white blood cell (WBC) count at relapse <20 × 109/l (P=0.004). The estimated disease‐free survival (DFS ± SE) at 82 months was 0.18 ± 0.05 for all responders, and 0.70 ± 0.14 for allotransplanted patients versus 0.05 ± 0.05 for those autografted (P = 0.001). The estimated probabilities of survival ± SE and event‐free survival (EFS ± SE) at 83 months were 0.16 ± 0.07 and 0.13 ± 0.04, respectively, for all enrolled children. Univariate analysis showed that age <10 years at initial diagnosis and B‐lineage immunophenotype favourably influenced both DFS (P = 0.001) and EFS probabilities (P = 0.0014 and P = 0.012, respectively), whereas a first CR duration 12 months and a WBC count at relapse <20 × 109/l were associated only with a better EFS rate (P = 0.026 and P = 0.004, respectively).

The prescribing of analgesics and non-steroidal anti-inflammatory drugs in paediatric primary care in the UK, Italy and the Netherlands

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are commonly prescribed drugs which are frequently used for the treatment of various painful conditions. However, particularly for the paediatric population, there is a lack of information on effectiveness, safety and appropriate formulation resulting in off-label use and undertreatment. The aim of this study was to investigate the prescribing patterns of non-steroid anti-inflammatory drugs and opioids in children and adolescents in three European countries. A retrospective cohort study was conducted using the same protocol in three primary care databases: Pedianet (Italy), IPCI (Netherlands) and IMS Disease Analyzer (UK). User prevalence rates were calculated for opioids (N02A) and non-steroidal anti-inflammatory drugs (NSAIDs) (M01A) based on ATC therapeutic and chemical levels and stratified by country, age and gender. The prescribing prevalence for NSAIDs was lower in the Netherlands compared to Italy and the UK. Ibuprofen was the most frequently prescribed drug in this group in Italy (20.8 users/1000 PY) and the UK (30.6 users/1000 PY) whereas diclofenac was dominant in the Netherlands (1.7 users/1000 PY). Among opioids, codeine and codeine combinations were most commonly prescribed; only little use was seen for other drugs. There is a great variety of different NSAIDs and opioids prescribed to children in Europe in primary care. This is due to a varying availability of drugs in different countries but also because of differing prescribing attitudes, reimbursement scheme and a lack of data on the effectiveness of individual drugs. Further research into the rationale for prescribing these drugs to children is clearly needed.