Pediatric Drugs

Safety and Tolerability of Adjunctive Brivaracetam in Pediatric Patients < 16 Years with Epilepsy: An Open-Label Trial Abstract Objective This trial evaluated the short-term safety and tolerability, steady-state pharmacokinetics, and preliminary efficacy of brivaracetam oral solution in children aged 1 month to < 16 years with epilepsy. Methods This was a phase IIa, open-label, single-arm, fixed three-step dose escalation trial of 3-weeks duration (N01263; NCT00422422). Patients were taking one to three concomitant antiepileptic drugs. Brivaracetam oral solution dosage, in two divided daily doses, was increased each week: approximately 0.8, 1.6, and 3.2 mg/kg/day for patients aged ≥ 8 years, and 1.0, 2.0, and 4.0 mg/kg/day for patients aged < 8 years. Results Of the 100 patients enrolled, 90 (90.0%) completed the trial. The safety population comprised 99 patients. Treatment-emergent adverse events (TEAEs) considered drug related by the investigator were reported by 32/99 (32.3%) patients, most commonly (≥ 5%) somnolence (7.1%) and decreased appetite (6.1%). TEAEs were reported by 66/99 (66.7%) patients, most commonly (≥ 5%) convulsion, irritability, pyrexia, somnolence, and decreased appetite. In patients with a history of focal seizures with or without secondary generalization and no primary generalized seizures aged 4 to < 16 years (n = 34), drug-related TEAEs and TEAE incidences were 47.1% and 67.6%, respectively. Steady-state trough brivaracetam and brivaracetam metabolite plasma concentrations increased proportionally with dose. The ≥ 50% responder rates (all seizure types) were 21.3% (all patients, n = 80) and 36.4% (patients with focal seizures, aged 4 to < 16 years, n = 22). Conclusions This open-label trial in pediatric patients with epilepsy provides preliminary information that short-term, adjunctive brivaracetam treatment is well tolerated and effective. Plasma concentrations of brivaracetam and metabolites increased with increasing dose.

Vancomycin Use in a Paediatric Intensive Care Unit of a Tertiary Care Hospital Abstract Background Vancomycin is one of the commonly used anti-microbial drugs in intensive care units (ICUs). Guidelines recommend maintaining therapeutic trough levels of vancomycin (10–20 mg/L). The success of achieving the recommended therapeutic concentration of vancomycin is influenced by several factors, and this is even more complex in children, particularly those admitted in the ICU. Hence, we carried out the present study in children admitted in the ICU who were administered vancomycin. Methods We carried out a chart review of children admitted in the paediatric ICU unit of a tertiary care hospital over a period of 3 years. Information on their demographic factors, diagnoses, duration of hospital stay, vancomycin treatment (dose, frequency and time of administration) and concomitant drugs, and vancomycin trough levels were retrieved. Descriptive statistics were used for representing the demographic factors, and multivariable logistic regression analyses were carried out to assess the determining factors. Results One-hundred and two children were identified, of whom 13 had renal dysfunction. Two-hundred and fifty-two vancomycin trough levels were available, of which only 25% were observed in the recommended range (10–20 mg/L) amongst patients without any renal dysfunction and 22% amongst patients with renal dysfunction. Vancomycin was administered intravenously at an average [standard deviation (SD)] dose (mg/dose) of 13 (3.9) mostly either thrice or four times daily. Even in patients receiving vancomycin as a definitive therapy, only 40.9% achieved the recommended trough levels. Lower trough levels were associated with an increased risk of mortality. Nearly 4% of the levels were above 20 mg/L (toxic range). Seven children were suspected to have acute kidney injury (AKI) during the course of therapy where the cumulative vancomycin dose and mortality rate was higher. Only one serum vancomycin level during augmented renal clearance was observed in the recommended range. All the patients received at least one concomitant drug that either had nephrotoxic potential or predominant renal elimination, and use of a greater number of such drugs was associated with an increased risk of AKI. Conclusion The current vancomycin dosing strategy is ineffective in achieving therapeutic trough levels in children admitted to the ICU. Sub-therapeutic vancomycin trough levels significantly increase the risk of mortality.

Purified Cannabidiol for Treatment of Refractory Epilepsies in Pediatric Patients with Developmental and Epileptic Encephalopathy Abstract Background A pharmaceutical grade formulation of cannabidiol (CBD) has been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome; however, this formulation is not yet available to patients outside the USA. In addition, CBD is thought to have broad anti-seizure properties that may be beneficial for other types of intractable epilepsy. Objective The aim of this study was to evaluate the efficacy, safety and tolerability of artisanal medical CBD oil in patients with developmental and epileptic encephalopathy (DEE) at the tertiary epilepsy center of Bambino Gesù Children’s Hospital in Rome, Italy. Methods This was a single-center, prospective, open-label study. Patients aged from 1 to 18 years with DEE and seizures refractory to appropriate antiepileptic drugs (AEDs) and other alternative treatments (i.e., vagal nerve stimulator and ketogenic diet) were included. Crystalline extract CBD powder (98–99% pure) in an oil artisanal formulation was added to the baseline AED regimen at a dosage of 2–5 mg/kg/day divided for twice-daily administration, then up-titrated until intolerance or a maximum dosage of 25 mg/kg/day was reached. Patients were treated for at least 6 months. Efficacy, safety and tolerability of CBD treatment were assessed through the evaluation of seizure frequency and reports of adverse effects. Results Twenty-nine patients were enrolled in this study (41.4% male). The mean duration of exposure to artisanal CBD was 11.2 months [range 6–25 months; standard deviation (SD) ± 4.4 months]. Mean age at study enrollment was 9.3 years (range 1.9–16.3 years; SD ± 4.7 years). Eleven out of 29 patients (37.9%) had a ≥ 50% improvement in seizure frequency; one patient became seizure free. None of the patients reported worsening seizure frequency; however, 18 patients (62.1%) experienced no beneficial effect regarding seizure frequency. Adverse effects were reported in seven patients (24.14%), most commonly somnolence, decreased appetite and diarrhea. Adverse events were mild and transient, and no dose modification of CBD or other AEDs was required. Conclusions These data suggest that CBD may have beneficial effects in patients with DEE and an acceptable safety profile. Placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in patients with DEE.

Correction to: Medical Options for the Adjuvant Treatment and Management of Pediatric Melanoma Study NCT01519323 (A study of vemurafenib in pediatric patients with stage IIIC or stage IV melanoma harbouring BRAFV600 mutations) was included in a table listing ongoing clinical trials of adjuvant therapies for pediatric melanoma (Table 1) in error. The study was in fact closed early due to low enrollment as correctly noted in section 4 of the article.

Off-Label Use of Sirolimus and Everolimus in a Pediatric Center: A Case Series and Review of the Literature Abstract Background It has been 15 years since sirolimus, an mTOR inhibitor, received Food and Drug Administration approval to prevent acute rejection in kidney transplantation, and 8 years since its analog everolimus acquired the same status. Since then, these drugs have become more and more utilized and their immunosuppressive and antiproliferative properties have been tested in a great variety of clinical conditions, often achieving excellent results. Despite such positive evidence, the on-label indications for these rapalogs are still very restrictive, especially in children. Aims The aims of this study were to describe our center’s experience with sirolimus and everolimus in managing rare pediatric conditions for which mTOR inhibitors have been reported as a therapeutic option, although without conclusive approval from regulatory agencies, and to evaluate safety and tolerability of the treatment at the prescribed doses. Methods All the subjects who received off-label sirolimus or everolimus at the Pediatric Department of the IRCCS Burlo Garofolo in the last 13 years were included. For each disease found in our case series, we reviewed the current scientific literature. Results Off-label treatment with rapalogs was prescribed in 16 children (11 males, 5 females, median age of 9.5 years, range 1–16 years). Seven had immunologic disorders: four autoimmune lymphoproliferative syndrome (ALPS), one multicentric Castleman disease (mCD), one activated PI3K delta kinase syndrome (APDS), and one immunodysregulation with polyendocrinopathy enteropathy X-linked (IPEX). Eight had proliferative disorders or vascular anomalies: one cystic lymphangioma, two Bannayan–Riley–Ruvalcaba syndrome (BRRS), one blue rubber bleb nevus syndrome (BRBNS), two tuberous sclerosis complex (TSC), and one low-flow mixed arterial and venous malformation. One case had congenital hyperinsulinism (CHI). The average dosage administered was 1 mg/m2 for sirolimus and 7 mg/m2 for everolimus. We experienced a good measurable clinical improvement in 14 patients. Nobody experienced serious adverse events (SAEs). The therapy was interrupted in two cases, for lack of efficacy and poor tolerance in one case and for occurrence of bacterial pneumonia in the other one. A review of the literature identified 101 published reports that met our inclusion criteria. Conclusions Although use of mTOR inhibitors has been considered to be complicated, our experience shows that, using low dosages, it is possible to obtain relevant clinical improvements, with a good profile of safety and tolerability.

Evaluation of Children with Psoriasis from the BiPe Cohort: Are Patients Using Biotherapies in Real Life Eligible for Phase III Clinical Studies? Abstract Background Phase III clinical trials of biotherapies for childhood psoriasis are designed for a selected population, which can differ from real-life patients. Objective Our objective was to assess the proportion of children with psoriasis that received biotherapy in the biological treatments for pediatric psoriasis (BiPe) cohort that would be excluded from phase III clinical trials of these treatments. Methods Data concerning initiation of the first biotherapy from all patients included in the BiPe cohort were analyzed. Ineligibility was assessed after applying the exclusion criteria used in the principal phase III trials of etanercept, adalimumab, and ustekinumab for childhood psoriasis. Results Of the 134 patients included, 73 (54.5%) were ineligible for at least one randomized controlled trial based on one or more exclusion criteria. Amongst the 63 children treated with etanercept, 35 (55.5%) were ineligible: 22 because of the type of psoriasis, 12 because of concomitant treatment, and six because of psoriasis severity based on psoriasis assessment severity index (PASI) and physician global assessment (PGA) scores (PASI < 12 and PGA < 3). Amongst the 44 children treated with adalimumab, 32 (72.7%) were ineligible: 17 because of the clinical type of psoriasis, 12 because of psoriasis severity (PASI < 20 and PGA < 4), and seven because of concomitant treatment. Amongst the 27 children patients treated with ustekinumab, 12 (44.4%) were ineligible: eight because of psoriasis severity (PASI < 12 and PGA < 3), five because of the clinical type of psoriasis, and one because of concomitant treatment. Drug survival and the frequency of serious adverse events did not differ between eligible and ineligible patients. Conclusion The majority of children treated with biotherapies in real-life practice differ from those in phase III trials, most commonly because of the clinical type of their psoriasis, the disease severity being lower than required and the use of prior or concomitant psoriasis treatment. Efficacy and safety results from phase III clinical trials in selected populations may not sufficiently reflect what is seen in real life, thus results from real-life cohort studies are necessary.

Safety and Tolerability of Antipsychotic Medication in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis Abstract Background Antipsychotic medication is a commonly prescribed drug class in individuals with autism spectrum disorder (ASD). However, the safety of these agents has not been fully assessed. Objective Our objective was to investigate the safety and tolerability profile of antipsychotics in individuals with ASD. Methods The Cochrane Library, MEDLINE, Embase and PsycINFO databases were searched up to January 2018. We included studies that reported adverse events (AEs) in participants with ASD taking first- or second-generation antipsychotic medication. The studies included in the analysis were randomized controlled trials (RCTs) and observational studies that were comparative or noncomparative and published as full text in the English language. The primary outcome of this review was AEs of any severity reported with antipsychotic use at any dose. Meta-analysis was performed on studies with child and adolescent participants to estimate the pooled prevalence of the overall AEs and the relative risk (RR) of AEs associated with antipsychotic use using a random-effects model. The Cochrane Collaboration tool and the modified Newcastle–Ottawa Scale (NOS) were used to assess the risk of bias of the included RCTs and observational studies, respectively. Results In total, 54 citations fulfilled the inclusion criteria, of which 40 were RCTs and 14 were observational studies; eight RCTs were included in the meta-analysis to estimate the RR of AEs associated with antipsychotic use and seven observational studies were included to estimate the pooled prevalence of AEs. The RR of AEs with antipsychotic treatment was 22% higher than with placebo (RR 1.22; 95% confidence interval [CI] 1.11–1.34; I2 = 30.6%; p = 0.184). The estimated pooled prevalence of AEs was 50.5% (95% CI 33–67). The most commonly reported AEs were increased appetite and weight gain, which were associated with discontinuation in many participants. Conclusion Antipsychotic-related AEs were common among patients with ASD. Further studies to investigate the implications of antipsychotic-related AEs on health and medication adherence are warranted. PROSPERO registration number: (CRD42018083632)

Improving Outcomes in Pediatric Multiple Sclerosis: Current and Emerging Treatments Abstract Pediatric-onset multiple sclerosis (MS) comprises 2–5% of MS cases, and is known to be associated with high disease activity and the accumulation of disability at an earlier age than their adult-onset counterparts. Appropriate therapy leading to disease control has the potential to alter the known trajectory of adverse long-term physical, cognitive, and psychosocial outcomes in this population. Thus, optimizing treatment for children and adolescents with MS is of paramount importance. The last decade has seen a growing number of disease-modifying therapies approved for relapsing MS in adults, and available agents now include oral, injectable, and infusion therapies. Recently, the development of randomized controlled MS trials in youth has led to the first agent approved by the US FDA for the treatment of pediatric MS—fingolimod. With this, we have entered a new era of knowledge and treatment in this population and ongoing pediatric trials are expected to further inform clinical management. With the emergence of highly effective therapies targeting the inflammatory component of the disease, there has been increased interest in identifying treatment strategies that instead target mechanisms such as remyelination/repair, neuroprotection, or rehabilitation. The potential role for such emerging therapies in the treatment of pediatric MS remains an important area of study. In this review, we discuss current evidence for MS therapies in children including the treatment of acute relapses, disease-modifying therapies, and symptomatic management. We will also discuss evidence for emerging therapies, including remyelinating and neuroprotective agents.

Comparison of Quality of Life, Depression, Anxiety, Suicide, Social Anxiety and Obsessive–Compulsive Symptoms Between Adolescents with Acne Receiving Isotretinoin and Antibiotics: A Prospective, Non-randomised, Open-Label Study Abstract Background The effects of isotretinoin on suicide, social anxiety and obsessive–compulsive symptoms in adolescents with acne have not been sufficiently investigated. Objective This study aimed to evaluate the quality of life, depression, anxiety, suicide, social anxiety, and obsessive–compulsive symptoms of adolescents receiving systemic isotretinoin and antibiotic treatments at baseline and at 3 months. Methods The study included a total of 102 adolescents using isotretinoin (n = 60) and antibiotics (n = 42). The Acne Quality of Life Scale (AQLS), Hospital Anxiety and Depression Scale (HADS), Suicide Probability Scale (SPS), Liebowitz Social Anxiety Scale (LSAS), and Maudsley Obsessive–Compulsive Question List (MOCQL) were administered to both groups at baseline and at 3 months. In order to exclude patients with comorbid psychiatric disorders, the patients were evaluated at the beginning of the study with the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL). Results There were no significant differences in the mean age, gender distribution, educational level, and family history of mental illness between the two groups. There were significant decreases in the Global Acne Grading System scores, visual analogue scale scores, AQLS scores, total and subscale scores of LSAS, and total and subscale scores of MOCQL at 3 months compared with baseline in both groups. However, there were no significant changes in the total and subscale scores of HADS and total and subscale scores of SPS at 3 months compared with baseline in both groups. Conclusion We found that neither isotretinoin nor antibiotic treatment affected the levels of depression, anxiety, and suicide in acne patients. Moreover, both isotretinoin and antibiotic treatment were shown to improve the quality of life, social anxiety, and obsessive–compulsive symptoms in acne patients. However, clinicians should be careful about psychiatric side effects in patients using isotretinoin. Further studies with a larger number of cases and with a longer follow-up period are needed to investigate the complex effects of isotretinoin on the central nervous system.

The Hemodynamic Effect of Intravenous Paracetamol in Children: A Retrospective Chart Review Abstract Aim Studies in adults have reported frequent episodes of blood pressure drops following intravenous paracetamol administration. We aimed to investigate the hemodynamic effects of intravenous paracetamol in critically ill children. Methods The charts of 100 pediatric intensive care patients (age range 0.1–18 years) who were treated with intravenous paracetamol between March and September 2017 were retrospectively reviewed. A hemodynamic event was defined as a drop of > 15% in systolic or mean arterial blood pressure within 120 min after drug administration. Hypotension was defined as either a drop in systolic blood pressure (SBP) below the 5th percentile for age or a hemodynamic event associated with tachycardia, increased lactate level, or treatment with a fluid bolus or vasopressors. Results A hemodynamic event was observed in 39 patients (39%). In these patients, SBP was in the pre-hypertension or hypertension values in 36/39 patients before paracetamol administration, median (IQR) SBP decreased from the 99th (95–99) percentile for age before to the 50th (50–95) percentile after paracetamol (p < 0.001) and mean heart rate was 137 bpm before treatment and 115 bpm after (p = 0.002). SBP values did not drop below the 5th percentile in any patient. In 15 patients diagnosed with shock on admission, paracetamol treatment did not cause an increase in vasopressor treatment after drug administration. Conclusions In the present study of critically ill pediatric patients, intravenous paracetamol administration was associated with a drop in SBP from high to normal values for age, possibly due to pain relief, with no evidence for a negative hemodynamic event.