Oluwaseun Egunsola

A prospective study of adverse drug reactions to antiepileptic drugs in children

Objectives To prospectively determine the nature and rate of adverse drug reactions (ADRs) in children on antiepileptic drugs (AEDs) and to prospectively evaluate the effect of AEDs on behaviour. Setting A single centre prospective observational study. Participants Children (<18 years old) receiving one or more AEDs for epilepsy, at each clinically determined follow-up visit. Primary and secondary outcomes Primary outcome was adverse reactions of AEDs. Behavioural and cognitive functions were secondary outcomes. Results 180 children were recruited. Sodium valproate and carbamazepine were the most frequently used AEDs. A total of 114 ADRs were recorded in 56 of these children (31%). 135 children (75%) were on monotherapy. 27 of the 45 children (60%) on polytherapy had ADRs; while 29 (21%) of those on monotherapy had ADRs. The risk of ADRs was significantly lower in patients receiving monotherapy than polytherapy (RR: 0.61, 95% CI 0.47 to 0.79, p<0.0001). Behavioural problems and somnolence were the most common ADRs. 23 children had to discontinue their AED due to an ADR. Conclusions Behavioural problems and somnolence were the most common ADRs. Polytherapy significantly increases the likelihood of ADRs in children. Trail registration number EudraCT (2007-000565-37).

Safety of lamotrigine in paediatrics: a systematic review

Objectives To identify adverse drug reactions associated with lamotrigine in children and compare the safety profile with other antiepileptic drugs. Setting Databases EMBASE (1974–April 2015), MEDLINE (1946–April 2015), PubMed and the Cochrane library for randomised controlled trials were searched for studies on safety of lamotrigine. Participants All studies involving paediatric patients aged ≤18 years who have received at least a single dose of lamotrigine with safety as an outcome measure were included. Primary and secondary outcome measures The primary outcome measure was safety of lamotrigine. Drug interaction of lamotrigine was the secondary outcome. Results A total of 78 articles involving 3783 paediatric patients were identified. There were 2222 adverse events (AEs) reported. Rash was the most commonly reported AE, occurring in 7.3% of the patients. Stevens-Johnson syndrome was rarely reported, with a risk of 0.09 per 100 patients. Discontinuation due to an adverse drug reaction (ADR) was recorded in 72 children (1.9% of all treated patients). Fifty-eight per cent of treatment discontinuation was attributed to different forms of rash and 21% due to increased seizures. Children on lamotrigine monotherapy had lower incidences of AEs. Headache (p=0.02), somnolence (<0.001), nausea (p=0.01), vomiting (p<0.001), dizziness (p<0.001) and abdominal pain (p=0.01) were significantly lower among children on monotherapy. Conclusions Rash was the most common ADR of lamotrigine and the most common reason for treatment discontinuation. Children receiving polytherapy have a higher risk of AEs than monotherapy users. Trial registration number CRD42013006910.

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.

Use and safety of azithromycin in neonates: a systematic review

Objectives To identify the use and adverse drug reactions associated with azithromycin in neonates. Setting Databases MEDLINE (1948–August 2015), EMBASE (1980–August 2015) and Pubmed (August 2015) were searched for studies on azithromycin in neonates. Participants All studies involving neonates (<28 days old) who have received at least a single dose of azithromycin for which safety was evaluated. Primary and secondary outcome measures The primary outcome was adverse event (AE) associated with use of azithromycin. Use of azithromycin in neonates was the secondary outcome. Results A total of 11 articles involving 473 neonates were identified. 371 AEs were reported. Adverse events were mainly respiratory (358/1000 neonate), neurological (273/1000 neonates) and gastrointestinal (196/1000 neonates) in origin. Azithromycin significantly reduced the risk of bronchopulmonary dysplasia (BPD) in extremely premature neonates (RR=0.83, 95% CI 0.71 to 0.98, p=0.02). There was no significant difference in the incidence of elevated liver enzymes between the azithromycin and placebo group (p=0.76). There were four cases of infantile hypertrophic pyloric stenosis (IHPS). Conclusions Azithromycin significantly reduces the risk of BPD in preterm neonates. The relationship between azithromycin and IHPS requires further investigation.

Monotherapy or polytherapy for childhood epilepsies

Antiepileptic drugs (AEDs) were frequently used as polytherapy until evidence from a series of studies in the late 1970s and early 1980s suggested that patients derive as much benefit from monotherapy as polytherapy.1–3 AED polytherapy is increasingly becoming popular again and as much as 30–40% of prescriptions to children are polytherapy.4 ,5 The availability of new-generation AEDs in the last two decades has encouraged polytherapy. AEDs such as lamotrigine, topiramate, levetiracetam, oxcarbazepine and zonisamide have been approved for paediatric use and are recommended mostly as adjuncts or as second-line agents.6 Despite the availability of more AEDs, the prevalence of poorly controlled epilepsies still remains the same. About 30% of epilepsies are resistant to treatment.7 Drug-resistant epilepsies almost always require polytherapy, but the question of the best treatment approach when an initial monotherapy fails is still debatable. Rational polytherapy has been suggested for the treatment of epilepsies. It refers to the use of two or more drug combinations with different mechanisms of action. The goal is to achieve synergistic or supra-additive efficacy. A combination regimen is supra-additive when it produces a total effect that is higher than the effects of the sum of individual drugs. Rational polytherapy sometimes aims to attain infra-additive toxicity such that the component drugs in the polytherapy regimen produce a total toxicity less than the sum of the individual toxicities.8 Clinical evidence in support of rational polytherapy for epilepsy is sparse. A 1997 multicentre European study, involving 347 adults, reported synergism between sodium valproate and lamotrigine.9 Patients given sodium valproate with lamotrigine add-on had better response rate than those given carbamazepine or phenobarbital with add-on lamotrigine. Another multicentre cohort study in Spain showed that lacosamide, a sodium channel blocker, was more effective (with a higher seizure freedom rate and clinical …

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.

Is tenofovir/emtricitabine teratogenic?

The Truvada® (tenofovir/emtricitabine) and nevirapine combination is increasingly being prescribed for prevention of mother-to-child HIV transmission. There is presently no documented evidence of teratogenicity of either tenofovir/emtricitabine or nevirapine. We report two cases of spina bifida in infants of mothers on this drug combination.

Anti-epileptic drug utilisation in paediatrics: a systematic review

Objectives This study aims to determine global anti-epileptic drug (AED) utilisation prevalence and describe utilisation trends in different countries. Methods Databases Embase (1980–May 2017), Medline (1946–May 2017) and PubMed were searched for original research on AED utilisation. All paediatric national or regional database studies and surveys were included. Results Twenty-one studies were identified. Five were excluded from the analysis as the data were collected before 2005, leaving 16 studies. Monotherapy regimen varied between 58% and 94% in different countries. In several of the studies, sodium valproate was the most frequently prescribed AED. However, there is a trend towards increasing utilisation of new-generation AEDs, particularly levetiracetam, in some countries. Conclusion Monotherapy was used in 58%–94%of patients. There is increasing utilisation of the new-generation AEDs, in particular lamotrigine, levetiracetam and topiramate. Old-generation AEDs are still used in the majority of patients. There is a need for up-to-date studies to determine the prevalence of AEDs in children.

Retrospective review of paediatric case reports of Stevens-Johnson syndrome and toxic epidermal necrolysis with lamotrigine from an international pharmacovigilance database

Objectives This study aims to characterise paediatric reports with lamotrigine (LTG) and Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN), and to explore whether potential risk factors can be identified. Design This is a retrospective review of suspected adverse drug reaction (ADR) reports. Reported time from LTG start to SJS/TEN onset, indication for use and dose was explored. To identify potential risk groups, report features (eg, ages, patient sex, co-reported drugs) for LTG and SJS/TEN were contrasted with two reference groups in the same database, using shrinkage logOR. Setting Reports were retrieved from VigiBase, the WHO global database of individual case safety reports, in January 2015. Patients Data for patients aged ≤17 years old were extracted. Results There were 486 reports of SJS/TEN in LTG-treated paediatric patients. Ninety-seven per cent of the cases with complete information on time to onset of SJS/TEN occurred within 8 weeks of initiation of LTG therapy. The median time to onset was 15 days (IQR: 10–22 days). The proportion of SJS/TEN with LTG and valproic acid (VPA) co-reporting was significantly more than non-cutaneous ADRs (43% vs 19%, (logOR: 1.60 (99% CI: 1.33 to 1.84)). Conclusions The results suggest that VPA co-medication with LTG therapy is a risk factor for SJS/TEN in the paediatric population. Although this relationship has been identified from individual case reports, this is the first supportive study from a large compilation of cases. SJS/TEN risk is highest in first 8 weeks of treatment with LTG in children and clinicians should be aware of this risk during this period.

Protocol for a prospective observational study of adverse drug reactions of anti-epileptic 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.