Off-label In Children Research Articles

Anastrozole improves height outcomes in growing children with congenital adrenal hyperplasia due to 21-OHD.

Hyperandrogenemia resulting in estrogen-mediated accelerated bone maturation and early growth plate fusion contributes to short stature in children with congenital adrenal hyperplasia (CAH) due to 21OHD. Aromatase inhibitors block androgen conversion to estrogen and have been used off-label in children with short stature to improve adult height. There are no adequately powered studies examining the use of aromatase inhibitors in children with CAH with advanced bone age and reduced predicted adult height. Records of CAH patients treated with anastrozole were reviewed. Z-scores of bone age, predicted adult height and height corrected for bone age were examined over an 8-year period. Outcome changes were analyzed using weighted mixed-effects models, adjusting for sex, diagnosis, age at diagnosis, and average hydrocortisone dose before and during treatment with anastrozole. In 60 patients (26 females, 52 classic, 8 non-classic) started on anastrozole therapy, the mean bone age Z-score decreased from 4.2 to 2.0 at 4 years and 1.3 at 6 years (both p <0.001); predicted adult height Z-score improved from -2.1 to -0.45 at 4 years and 0.18 at 6 years (both p <0.001); corrected height Z-scores improved from -1.7 to -0.33 at 4 years and 0.18 at 6 years (p <0.001). There was no significant difference in the average total daily hydrocortisone dose used before or during treatment. Anastrozole decreased the rate of bone maturation and led to improved height outcomes, indicating that anastrozole could have a role as an adjunct therapy in children with CAH and advanced bone age.

LGG-19. SLIPPED CAPITAL FEMORAL EPIPHYSIS (SCFE): A RARE ADVERSE EVENT ASSOCIATED WITH FGFR TYROSINE KINASE INHIBITOR THERAPY IN A CHILD

Abstract BACKGROUND FGFR tyrosine kinase inhibitors (FGFR-TKIs) are being increasingly used off-label in children with hard-to-treat tumors harboring specific FGFR alterations. We report a case of Slipped Capital Femoral Epiphysis (SCFE), an on target skeletal toxicity of a pan-FGFR TKI inhibitor, erdafitinib. METHODS Data was extracted from chart review of the patient and literature search for the use of FGFR-TKIs in children and their side effects. RESULTS A 13-year-old boy was diagnosed to have a optic pathway/ hypothalamic glioma with signs of increased intracranial pressure and obstructive hydrocephalus requiring placement of ventriculo-peritoneal (VP) shunt. Sequencing of the tumor showed FGFR1-Tyrosine kinase domain internal tandem duplication (FGFR1-KD-ITD) and was negative for BRAF mutation/ fusion. Two weeks later, he was treated for a VP shunt infection (surgical revision and 6 weeks antibiotics). He developed hypothalamic obesity with rapid weight gain and BMI &amp;gt;30. After a four-month delay from the initial diagnosis, he was started on erdafitinib a pan-FGFR1-4 inhibitor, through a special access program. At 12 weeks of treatment, he developed persistent knee pain. X-ray of the hips showed slipped capital femoral epiphysis (SCFE) of the right hip. Erdafitinib was discontinued and he underwent surgery with in-situ pinning of the right hip and prophylactic pinning of the left hip. MRI at the time of stopping the medication showed a 30% decrease in the size of the tumor, which has remained stable at 6 months follow up. CONCLUSIONS Based on our experience and literature review of pediatric patients who are treated with pan-FGFR TKIs, we recommend: a) monitoring both rate of weight gain/ BMI for obesity and growth velocity while on therapy and b) update the drug toxicity profile of FGFR TKIs to include skeletal toxicities and inform parents/ patients of these toxicities at the time of consent for therapy.

Long-Term Effectiveness of Off-Label Risperidone Treatment in Children and Adolescents: A Randomized, Placebo-Controlled Discontinuation Study.

Objectives: Risperidone is commonly prescribed off-label in children and adolescents to manage disruptive behavior. This study aimed to investigate continued benefits of risperidone after at least 1 year of treatment and effects of discontinuation on physical health. Methods: Thirty-five youths (aged 6-18 years, intelligence quotient [IQ] >70) who were treated with risperidone for at least 1 year in regular clinical practice receiving outpatient care were randomly assigned to double-blind continuation of risperidone during 16 weeks or continuation for 2 weeks, gradual dose lowering over 6 weeks, and placebo for 8 weeks. Primary outcome was the total Disruptive Behavior (D-total) score of the parent-reported Nisonger Child Behavior Rating Form-Typical IQ (NCBRF-TIQ). Secondary outcome measures were the clinician-rated Clinical Global Impressions-Improvement scale (CGI-I), the parent, child, and teacher-rated Strengths and Difficulties Questionnaire (SDQ), the parent-rated Retrospective Modified Overt Aggression Scale (R-MOAS), and several health parameters (Udvalg for Kliniske Undersøgelser Side Effect Rating Scale [UKU-SERS], dyskinesia, akathisia, parkinsonism, body mass index (BMI), waist circumference, and laboratory outcomes). Mixed models for repeated measures were conducted for continuous outcomes and a chi-square test for the CGI-I. Results: Discontinuation of risperidone, as compared with continuation, was not associated with significant changes in parent-reported disruptive behaviors. However, discontinuation was related to significant deterioration in parent-rated verbal aggression, teacher-rated behavioral functioning, clinician-rated general functioning, and significant improvements in weight, BMI, waist circumference, and glucose, insulin, and prolactin levels. Although 56% of participants in the discontinuation group experienced relapse, causing premature withdrawal from the study, 44% was able to successfully discontinue risperidone. Conclusion: Discontinuation of risperidone was associated with deterioration on some, but not all behavioral measures according to this explorative study. Discontinuation was associated with important health gains. Despite long-term benefits of risperidone, attempts to withdraw risperidone should be undertaken in individual children. This is a crucial step in preventing harm and fostering health.

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants.

Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.

Intravenous iron therapy in pediatrics: who should get it and when is the right time?

Iron-deficiency anemia occurs most commonly in young children due to a low-iron diet and adolescent girls due to menstrual blood loss. However, children with gastrointestinal conditions such as intestinal failure, inflammatory bowel disease, celiac disease, and/or other chronic conditions, including chronic kidney disease and heart failure, also commonly have iron deficiency. Many patients with classic iron-deficiency anemia will improve with oral iron therapy. However, in children who have an incomplete response to oral iron, intravenous iron therapy is increasingly being used. Benefits of intravenous iron therapy include a rapid repletion of iron stores in addition to resolution of anemia, less gastrointestinal side effects, and relief for patients and families struggling with long-term iron supplementation. Indications for first-line therapy with intravenous iron in children with chronic conditions have also increased. Four intravenous iron formulations have approved indications in pediatrics, and many are increasingly used off-label in children as well. Here we discuss the indications and appropriate timing of intravenous iron therapy in children with a wide range of underlying etiologies.

National survey in Switzerland calls for improved diagnosis and treatment in children with scabies.

The global prevalence of scabies is estimated to be up to 200 million cases annually, with young children particularly affected. In Europe, most cases are thought to originate in migrant populations. Scabies management is challenging in children. To identify knowledge gaps and research needs, we aimed to descriptively evaluate the management of children with scabies by different Swiss healthcare providers. An invitation for an anonymous online survey (36 questions) was sent to members of Swiss societies of dermatologists, general practitioners, paediatricians, paediatric dermatologists, paediatric infectious diseases specialists, and tropical medicine specialists, inviting clinicians to participate from 25thMay to 8thAugust 2020. One reminder invitation was sent. Hospital pharmacies and the distributor of permethrin were contacted to report consumption trends of scabicides in 2018 and 2019. The survey was completed by 248 clinicians: 146 (59%) paediatricians, 47 (19%) dermatologists, 28 (11%) general practitioners, 6 (2%) paediatric dermatologists, 13 (5%) paediatric infectious diseases specialists, and 8 (3%) tropical medicine specialists. Most consulted up to 10 scabies cases within a 16-month period, with similar numbers in migrant and Swiss children. Dermoscopy was used by 24% of non-dermatologists. Non-dermatologists did not consider co-treatment of close contacts in up to 59% of cases. While permethrin was the first-line treatment, treatment failures were frequently reported in children aged <5 years. Up to 67% of paediatric dermatologists regularly used oral ivermectin off-label in children weighing <15 kg. None of the paediatric dermatologists, 15% of the dermatologists, and 9% of the non-dermatologists used only one treatment cycle.Scabicide consumption increased. Treatment studies on ivermectin use in children weighing <15 kg had the highest research priority. In Switzerland, scabies is a frequent dermatosis in migrant and Swiss children. While accessible, optimal diagnostics are underutilised, and treatment is suboptimal. Permethrin resistance appears to be an increasing problem. Dermatologists regularly use ivermectin off-label in children weighing <15 kg. Treatment studies on ivermectin use in children weighing <15 kg, user-friendly diagnostic tools, new treatment protocols, and child-friendly dosage forms are needed to improve the diagnosis and treatment of children with scabies.

Model Based Estimation of Posaconazole Tablet and Suspension Bioavailability in Hospitalized Children Using Real-World Therapeutic Drug Monitoring Data in Patients Receiving Intravenous and Oral Dosing.

Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included a priori. Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.

1802. Off-label Use of Antimicrobial Agents at the University Hospital for Infectious Diseases, Zagreb, Croatia

Abstract Background Antimicrobial agents' (AMAs) off-label use can be associated with the prescriber's education. Little is known about the AMAs' off-label use by infectious disease (ID) specialists. We have conducted research at the University Hospital for Infectious Diseases (UHID), Zagreb, Croatia, a 230-bed tertiary center where ID specialists primarily prescribe AMAs. Methods A retrospective cross-sectional analysis was conducted on the day with the highest hospitalization number, January 17, 2019. Any use of AMA not complying with the SmPC was considered off-label and evaluated regarding modality (indication, dose, regimen, route of administration, and age) and justification by institutional or/and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines. Results The study included 155 patients, 63 (40.6%) adults and 92 (59.4%) children. 61 (96.8%) adult patients had at least one AMA. There were 134 AMA prescriptions in adults, 42 (31.3%) off-label. AMAs were most frequently prescribed off-label regarding regimen (21), dose (17), and indication (14). Institutional guidelines justified off-label in 5 cases regarding dose, 4 regarding indication, and 2 regarding regimen. ESCMID guidelines justified off-label prescriptions in 5 cases regarding indication. The rest of the off-label was not supported by the existing guidelines. 60 (65.2%) pediatric patients had at least one AMA. There were 73 prescriptions, 31 (42.5%) off-label. AMAs were most frequently prescribed off-label regarding indication (19), dose (12), and age (2). Institutional guidelines justified 3 off-label cases regarding indication and 1 regarding dose. ESCMID guidelines justified no off-label in children. The lack of guidelines was the leading cause of the off-label AMAs use in children. Conclusion One-third of AMAs are prescribed off-label regarding SmPC by ID specialists. However, institutional and international guidelines can justify part of this use. Disclosures All Authors: No reported disclosures.

Right-Sided Heart Failure and Cor Pulmonale in the Pediatric Patient.

Right-Sided Heart Failure and Cor Pulmonale in the Pediatric Patient.

Systemic Treatments in Pediatric Psoriasis: A Retrospective Single-Center Study.

Systemic therapies commonly used in adult psoriasis are mostly used only off-label in children and little is known about the efficacy and tolerability of these drugs in this population. In this study, we aimed to evaluate the efficacy and safety of systemic treatments in pediatric patients with psoriasis. Data were obtained retrospectively from the Department of Dermatology, Ondokuz Mayis University, School of Medicine between 2010-2019. Our study consisted of 742 pediatric patients (age ≤18 years) with psoriasis. Demographic data, adverse events of systemic treatments and healing periods were considered. A total of 195 patients received systemic treatment. The mean age of onset of disease and the initiation of systemic therapy were 9.68±4.62 and 11.33±4.38 years, respectively. Patients received methotrexate (n=52, 26.67%), cyclosporine (n=18, 9.24%), acitretin (n=106, 54.35%) and others (biologics and/or one of conventional treatments) (n=19, 9.74%) as systemic therapy. Adverse events occurred in 12 patients (incidence of 6.15%, and its related 95% confidence interval of 2.75%, 9.56%) and nine of them had to discontinue the medication due to those adverse events. Healing periods calculated in the remaining 186 patients were 13.25±5.87, 10.85±5.67, 11.05±7.00, and 9.41±4.16 (mean±SD) weeks for acitretin, methotrexate, cyclosporine, and others, respectively. No statistically significant differences were noted between the treatments regarding the healing periods. All treatments were effective and none of them was superior in terms of the healing period. Systemic treatments used in adults can also be used in pediatric patients with psoriasis with similar efficacy and safety rates as long as routine monitoring is provided.

Clinical Pharmacokinetics of Enalapril and Enalaprilat in Pediatric Patients—A Systematic Review

Purpose: Enalapril has an established safety and efficacy in adults and is used in hypertension, heart failure, and renal failure. In pediatric patients, enalapril is labeled for children with hypertension and used off label in children with heart failure. The systematic literature search aims to assess the current knowledge about enalapril and its active metabolite enalaprilat pharmacokinetics in children as a basis for dose delineation for pediatric patients with heart failure.Methods: A systematic literature review was performed in the PubMed database using relevant keywords. Dose normalization of relevant pharmacokinetic parameters of the identified studies was done for comparison between different diseases and pediatric age groups.Results: The literature search has resulted in three pediatric pharmacokinetic studies of enalapril out of which Wells et al. reported about children with hypertension and Nakamura et al., and Llyod et al. presented data for pediatric heart failure patients. The area under the curve values of enalaprilat in hypertensive pediatric patients increased with respect to the age groups and showed maturation of body functions with increasing age. Dose normalized comparison with the heart failure studies revealed that although the pediatric heart failure patients of > 20 days of age showed the area under the curve a similar to that of hypertensive patients, two pediatric patients of very early age (<20 days) were presented with 5–6-fold higher area under the curve values.Conclusion: Data related to the pharmacokinetics of enalapril and enalaprilat in hypertensive patients and few data for young heart failure children are available. Comparison of dose normalized exposition of the active metabolite enalaprilat indicated similarities between heart failure and hypertensive patients and a potentially high exposition of premature patients but substantially more pharmacokinetic studies are required to have reliable and robust enalapril as well as enalaprilat exposures especially in pediatric patients with heart failure as a basis for any dose delineation.

Paroxetine-Overview of the Molecular Mechanisms of Action.

In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It mainly affects patients in the age category 15–44 years, regardless of gender. Anxiety disorders are often diagnosed in children and adolescents. Social phobias can account for up to 13% of these diagnoses. Social anxiety manifests itself in fear of negative social assessment and humiliation, which disrupts the quality of social functioning. Treatment of the above-mentioned disorders is based on psychotherapy and pharmacotherapy. Serious side effects or mortality from antidepressant drug overdose are currently rare. Recent studies indicate that paroxetine (ATC code: N06AB), belonging to the selective serotonin reuptake inhibitors, has promising therapeutic effects and is used off-label in children and adolescents. The purpose of this review is to describe the interaction of paroxetine with several molecular targets in various points of view including the basic chemical and pharmaceutical properties. The central point of the review is focused on the pharmacodynamic analysis based on the molecular mechanism of binding paroxetine to various therapeutic targets.

Combination oral minoxidil and spironolactone for the treatment of androgenetic alopecia in adolescent girls

Combination oral minoxidil and spironolactone for the treatment of androgenetic alopecia in adolescent girls

Pharmacokinetics of an intravenous bolus dose of clonidine in children undergoing surgery

Clonidine is used off-label in children but only limited pediatric pharmacokinetic data are available for intravenously administered clonidine. To determine pharmacokinetic parameter estimates of clonidine in healthy children undergoing surgery and to investigate age-related differences. Furthermore, to investigate possible pharmacokinetic differences of clonidine between this group of children and a cohort with cardiac diseases. In a randomized placebo-controlled trial (The PREVENT AGITATION trial), blood samples for clonidine pharmacokinetic analysis were collected in a proportion of the enrolled patients. Healthy children with ASA score 1-2 in the age-groups 1 to <2years and 2-5years were randomized for blood sampling. Clonidine was administered as a single intravenous bolus of 3µg/kg intraoperatively. Blood samples were drawn at baseline, 5, 10, 15, 30, 60minutes after dosing and additionally every hour until discharge from the PACU. Clonidine analysis was performed on liquid chromatography-mass spectrometry. Data form eighteen children were available for pharmacokinetic analysis (ASA I; male/female: 17/1; age: 1-5years; weight 8.7-24kg). Population parameter estimates for the 2-compartment model were similar to previous published data for children who underwent cardiac surgery. A pooled analysis including data from 59 children indicated clearance of 14.4Lh-1 70kg-1 and volume of distribution of 192.6L70kg-1 . No age-related pharmacokinetic differences and no difference in time from administration of study medication to awakening were found. Children 1 to <2years had a shorter PACU stay than children 2-5years (mean difference 17% 95% CI:3%-34%, P=.02). Pharmacokinetic parameter estimates were similar for children undergoing general surgery and cardiac surgery given a single dose of intravenous clonidine. These results indicated that no dose reduction is needed in children aged 1 to <2years compared with those 2-5years, which was supported by pharmacodynamic observations.

Assessment of Provider Practices Regarding Management of VTE in Pediatric Leukemia

The development of venous thromboembolism (VTE) is a known complication occurring in children with leukemia with a reported incidence ranging from 1 to 37% (Ghanem, et al, Pediatric Blood &amp; Cancer, 2017) and can be a source of significant morbidity. Known risk factors for VTE include central venous catheter (CVC) use, thrombophilia, and certain medications, such as asparaginase (Caruso, et al, Blood, 2006.) Despite the known occurrence of VTE in this population, there are no leukemia-specific guidelines for VTE management. Anticoagulant use in children with frequent periods of thrombocytopenia and coagulopathy is not risk free. Various elements of management lack standardization and consensus among practitioners. Given that the majority of pediatric leukemia patients are treated according to standardized protocols, it may be beneficial to standardize anticoagulation care guidelines. Therefore, the primary objective of this study was to assess current practices regarding the management of VTE in the pediatric leukemia population. We performed a cross sectional, anonymous, electronic survey of members of the American Society of Hematology (ASH) who self-identified as focusing in pediatric hematology or pediatric hematology/oncology, and the pediatric subcommittee of VENUS (VTE Network of the Hemostasis and Thrombosis Research Society) using Qualtrics, a secure online survey tool. Survey items included questions on demographics and clinical practice. Respondents were excluded if they were not board certified/eligible, if they did not participate in patient care, or if they did not answer survey research questions. A $25 gift card incentive was offered anonymously. This study was approved by both the Weill Cornell Medicine and Northwell Health IRBs. Of 870 surveys distributed, 154 were submitted, giving a 17.7% response rate. Twelve surveys were excluded, leaving 142 surveys for final analysis. There was even distribution of years in practice and size of clinical program among respondents (Figure 1A). Most respondents identified as being in hematology or combined practice. 50% of responding physicians (n=136) reported treating CVC-associated VTE for 3 months. 92% of respondents (n=138) report repeating imaging of the VTE with 58% (n=124) repeating at 6 weeks, and 31% at 3 months. 40% of respondents (n=131) treat cerebral venous sinus thrombosis (CVST) for 3 months, followed by 24% treating for 6 months. 95% of respondents (n=131) repeat imaging for CVST and of these individuals, 40% repeat imaging at 6 weeks followed by 50% at 3 months. The most frequently utilized anticoagulant class was heparins (n=140); respondents also reported using the direct Xa inhibitors Rivaroxaban (21%) and Apixaban (14%). Within the group utilizing direct Xa inhibitors, those in practice the longest (≥16 years) had the highest percentage of use (Figure 1B.) When asked at what platelet counts they hold therapeutic anticoagulation (n=140), 39% of respondents chose 50 x 109/L, 33% chose 30 x 109/L, and 16% chose 20 x 109/L. One person chose 100, x 109/L, 11% said they did not hold anticoagulation for thrombocytopenia, and 2 respondents gave platelet transfusions rather than hold anticoagulation (one at a cutoff below 30 x 109/L and one below 50 x 109/L). While no significant associations were seen, the highest percentage among individual groups using a platelet cutoff of less than 50 x 109/L were among those in practice longest, and those in the largest centers (Figure 1C). The results of this survey revealed variation in practice among practitioners regarding VTE management and prevention. Despite the lack of data in this population, a number of physicians are using direct Xa inhibitors in children with leukemia for anticoagulation. Imaging is being done earlier than treatment is being discontinued, potentially implying it is being used to monitor for progression, rather than help guide duration of therapy. Our survey had some limitations, including the low response rate and missing data for questions, which may be due to electronic data collection errors or respondent choice. Recent ASH guidelines endorsed by the Children's Oncology Group propose limited general guidelines and do not consider a cancer patient's unique VTE risk profile. Given the variation seen, multi-center, prospective clinical trials are urgently needed for developing consensus guidelines for the management of VTE in children with leukemia. Figure 1 Disclosures Cooley: off-label: Other: drug use. Acharya:Takeda: Membership on an entity's Board of Directors or advisory committees; BioProducts Laboratory: Membership on an entity's Board of Directors or advisory committees; Bayer Pharmaceuticals, LLC: Research Funding; Novonordisk: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Anticoagulations that will be discussed are off-label in children.

Trends in Off-Label Drug Use in Ambulatory Settings: 2006-2015.

Off-label drug use in children is common and potentially harmful. In most previous off-label use research, authors studied hospitalized children, specific drug classes, or non-US settings. We characterized frequencies, trends, and reasons for off-label systemic drug orders for children in ambulatory US settings. Using nationally representative surveys of office-based physicians (National Ambulatory Medical Care Surveys, 2006-2015), we studied off-label orders of systemic drugs for children age <18 based on US Food and Drug Administration-approved labeling for age, weight, and indication. We characterized the top classes and diagnoses with off-label orders and analyzed factors and trends of off-label orders using logistic regression. Physicians ordered ≥1 off-label systemic drug at 18.5% (95% confidence interval: 17.7%-19.3%) of visits, usually (74.6%) because of unapproved conditions. Off-label ordering was most common proportionally in neonates (83%) and in absolute terms among adolescents (322 orders out of 1000 visits). Off-label ordering was associated with female sex, subspecialists, polypharmacy, and chronic conditions. Rates and reasons for off-label orders varied considerably by age. Relative and absolute rates of off-label orders rose over time. Among common classes, off-label orders for antihistamines and several psychotropics increased over time, whereas off-label orders for several classes of antibiotics were stable or declined. US office-based physicians have ordered systemic drugs off label for children at increasing rates, most often for unapproved conditions, despite recent efforts to increase evidence and drug approvals for children. These findings can help inform education, research, and policies around effective, safe use of medications in children.

Mechanical circulatory support in children: past, present and future.

Rapid advances in the field of mechanical circulatory support (MCS) have dramatically changed the management of pediatric patients with heart failure. There is now emphasis on timely implantation of ventricular assist devices (VADs) to preserve or recover end-organ function, and increased focus on post-implant management to improve the stroke rate. Transplant waitlist mortality has significantly decreased in the era of VAD use. Devices approved for adults are being used off-label in children with excellent outcomes, allowing chronic therapy and discharge home to become part of pediatric VAD therapy.

Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study

IntroductionTreatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. Methods and AnalysisPhase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. Ethics and disseminationClinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. Trial registration numbersEudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

Pharmacokinetics of Enoxaparin After Renal Transplantation in Pediatric Patients.

Enoxaparin is commonly used in the prevention of renal allograft vascular thrombosis but off-label in children, and no consensus exists regarding the optimal dosing and dose adjustment. In this retrospective study, 444 anti-Xa levels were obtained from 30 pediatric renal transplant recipients in order to investigate enoxaparin population pharmacokinetics. The main results were (1) 25% of children achieved the target anti-Xa activity 36hours after initiation of treatment, (2) anti-Xa time courses were best described by a 1-compartment open model with first-order absorption, (3) body weight but not renal function was the sole covariate influencing clearance and volume of distribution, and (4) large between-subject and between-occasion variabilities in anti-Xa activity were observed. However, creatinine-based estimated glomerular filtration rate in the first post-renal transplantation hours may not reliably reflect the actual renal function of the children. Based on the final population model, a Bayesian-based program was developed in order to estimate the individual pharmacokinetic parameters on a single anti-Xa measurement, allowing determination of the next enoxaparin dose that will quickly achieve an appropriate anti-Xa activity (targeting 0.3-0.5IU/mL) and anticoagulation. Finally, these results should help standardize practices that remain to date largely heterogeneous in pediatric intensive care units.

Labeling Changes and Costs for Clinical Trials Performed Under the US Food and Drug Administration Pediatric Exclusivity Extension, 2007 to 2012

Pharmaceutical manufacturers can receive 6 additional months of market exclusivity for performing pediatric clinical trials of brand-name drugs widely used in adults. Congress created this incentive in 1997 because these drugs were being used off-label in children without such trials. To review updates to drug labeling and the cost to consumers of extending market exclusivity related to the pediatric exclusivity program. From government records, we identified 54 drugs that earned the pediatric exclusivity incentive between 2007 and 2012. We evaluated labeling changes from the pediatric studies. We then extracted trial details from clinical review documents and used industry estimates of trial costs on a per-patient basis to estimate cost of investment for trials (with a 10% cost of capital). To calculate the net return and cost to consumers during the 6-month exclusivity period, we estimated additional revenue for the 48 drugs with available information. For each drug, we evaluated labeling changes and costs associated with pediatric trials under the Best Pharmaceuticals for Children Act and the cost to consumers of 6-month market exclusivity extensions. The 141 trials in our sample enrolled 20 240 children (interquartile range [IQR], 2-3 trials and 127-556 patients per drug). These trials led to 29 extended indications and 3 new indications, as well as new safety information for 16 drugs. Median cost of investment for trials was $36.4 million (IQR, $16.6 to $100.6 million). Among 48 drugs with available financial information, median net return was $176.0 million (IQR, $47.0 million to $404.1 million), with a median ratio of net return to cost of investment of 680% (IQR, 80% to 1270%). Clinical trials conducted under the US Food and Drug Administration's pediatric exclusivity program have provided important information about the effectiveness and safety of drugs used in children. The costs to consumers have been high, exceeding the estimated costs of investment for conducting the trials. As an alternative, policymakers should consider direct funding of such studies.