The Impact of Unlicensed and Off-Label Drug Use on Adverse Drug Reactions in Paediatric Patients

Neubert, Antje; Dormann, Harald; Weiss, Jutta; Egger, Tobias; Criegee-Rieck, Manfred; Rascher, Wolfgang; Brune, Kay; Hinz, Burkhard

doi:10.2165/00002018-200427130-00006

Cited by 151 publications

(113 citation statements)

References 21 publications

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Section: Discussionsupporting

confidence: 55%

“…Previous inpatient studies report 27-45% of prescriptions being OLUL, 3,75,76 and two previous community-based studies report 7% and 43% of prescriptions being off-label; 77,78 compare this to 28% of prescriptions in this study. With the exception of Neubert et al 75 these studies all found an increased ADR risk associated with OLUL medicine use. In this study, OLUL medicines were more likely to be implicated in an ADR than medicines used within the terms of their MA; however, it is important to highlight that 87.2% of ADRs that involved at least one OLUL also involved at least one other medicine; in some cases the OLUL medicine may not have caused the ADR in the absence of an approved medicine.…”

Section: Discussionsupporting

confidence: 55%

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ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

Smyth

Peak

Turner

et al. 2014

Programme Grants for Applied Research

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AimsTo comprehensively investigate the incidence, nature and risk factors of adverse drug reactions (ADRs) in a hospital-based population of children, with rigorous assessment of causality, severity and avoidability, and to assess the consequent impact on children and families. We aimed to improve the assessment of ADRs by development of new tools to assess causality and avoidability, and to minimise the impact on families by developing better strategies for communication.Review methodsTwo prospective observational studies, each over 1 year, were conducted to assess ADRs in children associated with admission to hospital, and those occurring in children who were in hospital for longer than 48 hours. We conducted a comprehensive systematic review of ADRs in children. We used the findings from these studies to develop and validate tools to assess causality and avoidability of ADRs, and conducted interviews with parents and children who had experienced ADRs, using these findings to develop a leaflet for parents to inform a communication strategy about ADRs.ResultsThe estimated incidence of ADRs detected in children on admission to hospital was 2.9% [95% confidence interval (CI) 2.5% to 3.3%]. Of the reactions, 22.1% (95% CI 17% to 28%) were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44 out of 249 (17.7%) of ADRs, the remainder originating from hospital. A total of 120 out of 249 (48.2%) reactions resulted from treatment for malignancies. Off-label and/or unlicensed (OLUL) medicines were more likely to be implicated in an ADR than authorised medicines [relative risk (RR) 1.67, 95% CI 1.38 to 2.02;p < 0.001]. When medicines used for the treatment of oncology patients were excluded, OLUL medicines were not more likely to be implicated in an ADR than authorised medicines (RR 1.03, 95% CI 0.72 to 1.48;p = 0.830). For children who had been in hospital for > 48 hours, the overall incidence of definite and probable ADRs based on all admissions was 15.9% (95% CI 15.0 to 16.8). Opiate analgesic drugs and drugs used in general anaesthesia (GA) accounted for > 50% of all drugs implicated in ADRs. The odds ratio of an OLUL drug being implicated in an ADR compared with an authorised drug was 2.25 (95% CI 1.95 to 2.59;p < 0.001). Risk factors identified were exposure to a GA, age, oncology treatment and number of medicines. The systematic review estimated that the incidence rates for ADRs causing hospital admission ranged from 0.4% to 10.3% of all children [pooled estimate of 2.9% (95% CI 2.6% to 3.1%)] and from 0.6% to 16.8% of all children exposed to a drug during hospital stay. New tools to assess causality and avoidability of ADRs have been developed and validated. Many parents described being dissatisfied with clinician communication about ADRs, whereas parents of children with cancer emphasised confidence in clinician management of ADRs and the way clinicians communicated about medicines. The accounts of children and young people largely reflected parents’ accounts. Clinicians described using all of the features of communication that parents wanted to see, but made active decisions about when and what to communicate to families about suspected ADRs, which meant that communication may not always match families’ needs and expectations. We developed a leaflet to assist clinicians in communicating ADRs to parents.ConclusionThe Adverse Drug Reactions In Children (ADRIC) programme has provided the most comprehensive assessment, to date, of the size and nature of ADRs in children presenting to, and cared for in, hospital, and the outputs that have resulted will improve the management and understanding of ADRs in children and adults within the NHS. Recommendations for future research: assess the values that parents and children place on the use of different medicines and the risks that they will find acceptable within these contexts; focusing on high-risk drugs identified in ADRIC, determine the optimum drug dose for children through the development of a gold standard practice for the extrapolation of adult drug doses, alongside targeted pharmacokinetic/pharmacodynamic studies; assess the research and clinical applications of the Liverpool Causality Assessment Tool and the Liverpool Avoidability Assessment Tool; evaluate, in more detail, morbidities associated with anaesthesia and surgery in children, including follow-up in the community and in the home setting and an assessment of the most appropriate treatment regimens to prevent pain, vomiting and other postoperative complications; further evaluate strategies for communication with families, children and young people about ADRs; and quantify ADRs in other settings, for example critical care and neonatology.FundingThe National Institute for Health Research Programme Grants for Applied Research programme.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionsupporting

confidence: 55%

ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

Smyth

Peak

Turner

et al. 2014

Programme Grants for Applied Research

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“…It is likely that the use of unlicensed or "off label" drug prescriptions is associated with a greater risk of ADRs in the paediatric population [17,18].…”

Section: Introductionmentioning

confidence: 99%

Active surveillance of adverse drug reactions in children in five Italian paediatric wards

Gallo¹,

Clavenna²,

Bonati³

et al. 2012

OJPed

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Adverse drug reactions (ADRs) are an important clinical problem and contribute significantly to mortality and morbidity. Scant data on the safety of drug use in children are usually available at the time of marketing authorization, due to the limited number of trials performed in the paediatric population. Few studies monitored the incidence of ADRs in Italian hospitalized children, that cannot be compared for methodological reasons. A 6-month prospective observational study was, therefore, conducted on the paediatric wards of five hospitals in the Campania Region, Italy. Data were collected on all patients admitted to the wards during the study period through a structured questionnaire administered to the mothers and through a hospital chart review. Of the 752 patients enrolled, 86.2% were exposed to one or more drugs during hospitalization. The therapeutic class most prescribed was systemic antibacterial agents (47%). Six ADRs occurred during hospitalization (incidence 0.9%; 95% CI 0.2% -1.7%). In addition, one child was admitted to a hospital for an ADR. Five out of seven ADRs occurred in girls. The skin was the most affected organ. The medications implicated were amoxicillin, acyclovir, ibuprofen, ceftriaxone, paracetamol, and ranitidine. According to the Naranjo probability criteria, six ADRs were probably, and one possibly, related to the suspected drug. In conclusion, this study reveals that ADRs may be under-reported in children hospitalized in the Campania Region. Consequently, healthcare personnel should be alert to the possibility of ADRs. More accurate reporting of ADRs in children would result in safer use of drugs in such patients.

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“…This practice may bring beneficial results, indicating new ways for scientific research on the standardization of indications and dosages. On the other hand, in addition to lack of therapeutic effect, it can also result in adverse reactions (Di Paolo et al, 2006;Naubert et al, 2004).…”

Section: Off-label Indications and Drug Promotional Practicesmentioning

confidence: 99%

“…This study revealed that most off-label uses happen without scientific support. It is estimated that 23% to 60% of these medications are responsible for adverse reactions in children (Naubert et al, 2004;Patel et al, 2007).…”

Section: Off-label Indications and Drug Promotional Practicesmentioning

confidence: 99%

Critical evaluation of the off-label indication and of the risks associated to the use of multi-dose vials on the treatment of age-related macular degeneration

Barbosa

Tavares

et al. 2014

Braz. J. Pharm. Sci.

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Age-related macular degeneration (AMD) is an ocular inflammatory diseases treated mainly by means of a bevacizumab (Avastin ® ) or ranibizumab (Lucentis ® ) intravitreal injection. Among these drugs, only ranibizumab has a specific therapeutic indication for AMD. Considering that, the off-label use on ophthalmic therapy seems to become a rule when it should be an exception. Furthermore, bevacizumab presentation consists of multi-dose vials although it does not contain preservatives in its formula. The current literature review aimed at assessing the risks for the patient related to the use of off-label indication and multi-dose vials on AMD treatment. Considering this, the proposal related to the Brazilian Public Consultation no.10, dated September 12, 2012, which proposes the Clinical Protocol and Therapeutic Guidelines for AMD treatment, was evaluated. This systematic review allowed to conclude that the bevacizumab off-label indication results in increased risks for the patient when compared to the product with specific therapeutic indication for AMD treatment (ranibizumab), especially referring to the significant raise in the adverse events. The risks for the patient related to the multi-dose vial use, referring to the microbiological stability and dose precision, were also made clear.Uniterms: Age-related macular degeneration/treatment. Ranibizumab/intravitreal injection. Bevacizumab/ intravitreal injection. Ophthalmic therapy/off-label use. Off-label indication/patients risks. Multi-dose vials/patients risks.A degeneração macular relacionada à idade (DMRI) é uma doença ocular inflamatória tratada principalmente por injeção intravítrea de bevacizumabe (Avastin ® ) ou de ranibizumabe (Lucentis ® ). Entre os medicamentos citados, apenas o ranibizumabe tem indicação terapêutica específica para uso oftálmico. Considerando essa realidade, o uso off-label na terapia oftálmica parece constituir regra quando deveria ser exceção. Ademais, a apresentação do bevacizumabe consiste em frascos de múltipla-dose, embora esse medicamento não contenha conservante em sua fórmula. A presente revisão da literatura avaliou os riscos ao paciente relativos ao uso indicado off-label e de frascos de múltipla-dose no tratamento de DMRI. Nesse sentido, avaliou-se a proposta relativa à Consulta Pública Brasileira nº 10, de 12 de setembro de 2012, que propõe o Protocolo Clínico e Diretrizes Terapêuticas para o tratamento de DMRI. O levantamento sistemático de trabalhos científicos e de informações relevantes de banco de dados eletrônicos permitiu concluir que a indicação off-label do bevacizumabe acarreta riscos maiores ao paciente, quando comparado ao produto com indicação terapêutica específica para o tratamento de DMRI (ranibizumabe), especialmente quanto ao aumento significativo de eventos adversos. Evidenciaramse, também, os riscos ao paciente relativos ao uso de frascos de múltipla-dose, quanto à estabilidade microbiológica e à precisão da dose.Unitermos: Degeneração macular /tratamento. Ranibizumabe/injeção intravítrea. Bevacizuma...

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The Impact of Unlicensed and Off-Label Drug Use on Adverse Drug Reactions in Paediatric Patients

Cited by 151 publications

References 21 publications

ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

Active surveillance of adverse drug reactions in children in five Italian paediatric wards

Critical evaluation of the off-label indication and of the risks associated to the use of multi-dose vials on the treatment of age-related macular degeneration

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