Pharmacovigilance of antiepileptic drug toxicity in children

Several of the available antiepileptic drugs (AEDs) were approved in the last 25 years. These new generation AEDs have not been shown to be more effective than the old ones and their safety profile have not been explored sufficiently in pharmacovigilance studies. As reported in chapter 2, prospective cohort studies are the most common pharmacovigilance study methods, with adverse drug reactions (ADRs) often elicited with questionnaires or checklists. A systematic review to identify all published AED side effects rating scales, reported in chapter 3, identified nine AED ADR rating scales. Two of these, The Hague Side Effect Scale (HASES) and the Paediatric Side Effect Questionnaire (PESQ), are paediatric specific. A systematic review of AED utilisation rate reported in chapter 4, shows an increasing utilisation of levetiracetam and lamotrigine reported as the most frequently utilised new generation AED in paediatrics. Systematic reviews of the safety of both drugs in children, reported in chapters 5 and 6, identified rash (7.3%) and behavioural problems (10.9%) as the most common ADRs associated with lamotrigine and levetiracetam respectively. They were also the most common reasons for the discontinuation of treatment. In chapter 7, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) risks are reported to be significantly higher when lamotrigine was co-prescribed with sodium valproate (43%) than when either carbamazepine (8%) or phenobarbital (8%) were co-prescribed with sodium valproate. SJS/TEN also occurred more frequently with sodium valproate and lamotrigine co-medication than other non-cutaneous ADRs (19%). Being the more recent paediatric AED ADR rating scale, the PESQ was selected for the elicitation of ADRs in a prospective cohort study of AED safety in children reported in chapter 8. Half of the 124 participants in the study received levetiracetam, either as monotherapy or polytherapy. There were significantly fewer ADRs with levetiracetam than either carbamazepine or sodium valproate monotherapy. The risks of drowsiness, fatigue and weight gain were significantly higher with levetiracetam polytherapy than monotherapy (p<0.05). Attention difficulties, aggression and decreased concentration were significantly lower with valproate polytherapy (p<0.05). The common ADRs associated with AEDs are discussed in chapter 9. In conclusion, lamotrigine and levetiracetam are increasingly being used for the treatment of epilepsy in children. Lamotrigine may cause severe rash, especially when co-administered with valproate; while levetiracetam is a common cause of behavioural problems. In order to compare the safety profile of AEDs adequately, large multicentre paediatric safety studies are required

Safety of fluconazole in paediatrics: a systematic review

Purpose: To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment. Methods: A search of EMBASE (1950–January 2012), MEDLINE (1946–January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982–2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients’ exposure to fluconazole were included. Results: We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87–2.14, P = 0.175 and RR 1.43, 95 % CI 0.67–3.03, P = 0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12–5.60, P = 0.831 and RR 1.23, 95 %CI 0.87–1.71, P = 0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children. Conclusion: Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity

Discontinuities and disruptions in drug dosage guidelines for the paediatric population

AIMSThis study investigates paediatric drug dosage guidelines withthe aim of investigating their agreement with body surface area(BSA) scaling principles.METHODSA total of 454 drug dosage guidelines listed in the AMH-CDC 2015 were examined. Data extracted included the administration,frequency and dose per age bracket from 0 to 18 years. Drug treatments were categorized as follows: (1) The same dose rec-ommendation in milligrams per kilogram (mg kg 1) for all age/weights; (2) Change in the mg kg 1dosing according toage/weight; (3) Change in dose in mg according to age/weight; (4) Change from mg kg 1dosing to a dose in mg according toage/weight; (5) The same recommendation for all age/weight groups in mg; or (6) BSA dosing. Example drugs were selected toillustrate dose progression across ages.RESULTSMost drug treatments (63%) have the same mg kg 1dose for all age/weight groups, 14% are dosed in mg kg 1across all ageswith dose changes according to age/weight, 13% were dosed in mg across all ages with dose changes, 10% switched frommg kg 1to a set dose in mg, 4.2% have the same dose in mg for all age and weight groups and 2.2% are dosed according to BSA.CONCLUSIONSPaediatric dosage guidelines are based on weight-based formulas, available dosing formulations and prior patterns of use. Sub-stantial variation from doses predicted by BSA scaling are common, as are large shifts in recommended doses at age thresholds.Further research is required to determine if better outcomes could be achieved by adopting biologically based scaling of paedi-atric doses.NHMR

Safety of antiepileptic drugs in children and young people: a prospective cohort study

Purpose: This study aims to describe the incidence of adverse drug reactions (ADRs) in children receiving antiepileptic drugs (AEDs) and compare ADRs to the individual drugs when given as monotherapy. Method: Paediatric patients (≤18 years old) were enrolled for this prospective observational study over a 6-month period, between September 2015 and March 2016. Adverse reactions to antiepileptic drugs (AEDs) were elicited at the time of enrolment and after 3 months using the Paediatric Epilepsy Side Effects Questionnaire. Results: A total of 1139 suspected ADRs were reported in 124 participants. Eighteen different AEDs were prescribed. Sixty-six children (53%) were receiving AED monotherapy at the time of recruitment; 34/66 (52%) of whom received new generation AEDs. Levetiracetam was the most frequently prescribed AED (62/124, 50%). When only children receiving AED monotherapy were considered, fatigue, drowsiness, weight gain, dizziness were less likely with levetiracetam (p < .01). Slow thinking and decreased concentration were less likely with levetiracetam or carbamazepine than valproic acid (p < .05). Five patients (four on polytherapy) discontinued AED treatment due to ADRs and 2 had a dose reduction. Conclusions: Levetiracetam and carbamazepine were better tolerated than sodium valproate

Protocol for a prospective observational study of adverse drug reactions of antiepileptic drugs in children in the UK

Background Epilepsy is a common chronic disease of children that can be treated with anti-epileptic drugs (AEDs). AEDs, however, have significant side effects. Newer AEDs are thought to have fewer side effects. There have, however, been few comparative studies of AED toxicity. The aim is to compare the safety profile of the most frequently used AEDs by performing a multicentre prospective cohort study. This protocol describes the planned study. Design A multicentre prospective cohort study of children on AED treatment in hospitals across the UK. Ethical approval will be obtained. Sample size Three thousand children on treatment for epilepsy will be recruited from paediatric clinics. It is expected that this sample size will have the potential to compare toxicity between the most frequently used AEDs. Duration of study 24 months. Outcome measure Adverse drug reactions (ADRs) to AEDs. These will be identified by the use of a validated questionnaire, the Paediatric Epilepsy Side Effect Questionnaire. They will be evaluated using the Naranjo algorithm. Preventability will be assessed using the Schumock and Thornton scale. Discussion Toxicity of individual AEDs when given as monotherapy and polytherapy will be determined. Additionally, discontinuation rates due to ADRs will be determined. The data will assist clinicians in choosing AEDs with the least toxicity

Safety of Levetiracetam in paediatrics: a systematic review

Objective To identify adverse events (AEs) associated with Levetiracetam (LEV) in children. Methods Databases EMBASE (1974-February 2015) and Medline (1946-February 2015) were searched for articles in which paediatric patients (≤18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis. Results Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems. Conclusion Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy

Pharmacovigilance of antiepileptic drug toxicity in children

Several of the available antiepileptic drugs (AEDs) were approved in the last 25 years. These new generation AEDs have not been shown to be more effective than the old ones and their safety profile have not been explored sufficiently in pharmacovigilance studies. As reported in chapter 2, prospective cohort studies are the most common pharmacovigilance study methods, with adverse drug reactions (ADRs) often elicited with questionnaires or checklists. A systematic review to identify all published AED side effects rating scales, reported in chapter 3, identified nine AED ADR rating scales. Two of these, The Hague Side Effect Scale (HASES) and the Paediatric Side Effect Questionnaire (PESQ), are paediatric specific. A systematic review of AED utilisation rate reported in chapter 4, shows an increasing utilisation of levetiracetam and lamotrigine reported as the most frequently utilised new generation AED in paediatrics. Systematic reviews of the safety of both drugs in children, reported in chapters 5 and 6, identified rash (7.3%) and behavioural problems (10.9%) as the most common ADRs associated with lamotrigine and levetiracetam respectively. They were also the most common reasons for the discontinuation of treatment. In chapter 7, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) risks are reported to be significantly higher when lamotrigine was co-prescribed with sodium valproate (43%) than when either carbamazepine (8%) or phenobarbital (8%) were co-prescribed with sodium valproate. SJS/TEN also occurred more frequently with sodium valproate and lamotrigine co-medication than other non-cutaneous ADRs (19%). Being the more recent paediatric AED ADR rating scale, the PESQ was selected for the elicitation of ADRs in a prospective cohort study of AED safety in children reported in chapter 8. Half of the 124 participants in the study received levetiracetam, either as monotherapy or polytherapy. There were significantly fewer ADRs with levetiracetam than either carbamazepine or sodium valproate monotherapy. The risks of drowsiness, fatigue and weight gain were significantly higher with levetiracetam polytherapy than monotherapy (p<0.05). Attention difficulties, aggression and decreased concentration were significantly lower with valproate polytherapy (p<0.05). The common ADRs associated with AEDs are discussed in chapter 9. In conclusion, lamotrigine and levetiracetam are increasingly being used for the treatment of epilepsy in children. Lamotrigine may cause severe rash, especially when co-administered with valproate; while levetiracetam is a common cause of behavioural problems. In order to compare the safety profile of AEDs adequately, large multicentre paediatric safety studies are required

Prospective cohort studies.

<p>Prospective cohort studies.</p

Flow chart of included studies.

<p>Flow chart of included studies.</p