Extent and risks of antidepressant off-label use in children and adolescents in Germany between 2004 and 2011.

PURPOSE: So far, only little is known about antidepressant off-label use in pediatric patients. This is the first study examining the prevalence and the risks of off-label antidepressant prescriptions in minors over time in Germany and analyzing patterns regarding age, sex, drug class, and type of off-label use. METHODS: We used claims data of about two million individuals (<18 y) to calculate the share of off-label antidepressant prescriptions for the years 2004 to 2011, stratified by age, sex, and drug class. Off-label prescriptions were analyzed regarding underlying diagnoses, the prescribing doctor's specialty, and the type of off-label use. Incidence rates of adverse events were calculated for off- and on-label use, and the risk of suicidal events associated with off- or on-label use was examined in a nested case-control study. RESULTS: The prevalence of off-label prescriptions decreased from 58.0% to 40.9%. Selective serotonin reuptake inhibitors were more frequently prescribed off-label than tricyclic antidepressants (37.7% vs 17.5% in 2011). The most common type of off-label use was off-label use by age, followed by off-label use by indication, and off-label use by contraindication. Adverse events were rare with no significant differences between on- and off-label use. CONCLUSIONS: Although off-label antidepressant use in minors decreased over time, it is still common. However, this rather indicates a lack of approved drugs for the treatment of depression in this population than inappropriate medical treatment. This is supported by the fact that off-label use was not associated with a higher risk of adverse events than on-label use.

Outpatient antidepressant drug use in children and adolescents in Germany between 2004 and 2011.

PURPOSE: Recent studies on the utilization of antidepressant drugs in minors are scarce, methodologically limited, and do not factor in off-label use sufficiently. Beyond that, little is known about the short treatment durations that have been observed for many young antidepressant users. The present study examined antidepressant use in pediatric patients aged 0 to 17 years over time, investigated changes regarding the prescribed drugs, analyzed underlying diagnoses, and assessed the rate of off-label use. METHODS: We used claims data of roughly two million individuals to calculate annual prevalence and incidence rates of antidepressant prescriptions for the years 2004 to 2011. Analyses were stratified by age, sex, and drug type. For antidepressant users, numbers of prescriptions, frequencies of disorders/diseases, and specialties of the prescribing physicians were examined. The share of off-label prescriptions was calculated for each year. RESULTS: The prescription prevalence of antidepressants ranged between 1.7 and 2.1 per 1000 minors. The use of tricyclic antidepressants decreased from 0.9 to 0.6 prescriptions per 1000 minors, while the use of selective serotonin reuptake inhibitors increased from 0.5 to 1.1. Of the patients with an antidepressant prescription, 46.4% only received one prescription. Depression was by far the most frequent diagnosis among all antidepressant users as well as among subjects with only one prescription. In 2011, 36.3% of all prescriptions were off-label. CONCLUSIONS: The high proportion of single prescriptions, even in patients with a diagnosed depression, and the high rate of off-label use are particularly noteworthy and should be further investigated in future studies. Copyright © 2016 John Wiley & Sons, Ltd.

Characterization of new users of cilostazol in the UK, Spain, Sweden, and Germany.

PURPOSE: To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. METHODS: New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off-label prescribing. RESULTS: We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. CONCLUSIONS: In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Outpatient antipsychotic drug use in children and adolescents in Germany between 2004 and 2011.

Studies from different countries showed increasing use of antipsychotics in pediatric patients. However, these studies were methodologically limited and could not assess underlying diagnoses and off-label use sufficiently. This is the first study to examine antipsychotic prescriptions in a representative sample of minors over a long period, looking at changes regarding substances and drug classes, underlying diagnoses, and the rate of off-label use. Claims data of about two million pediatric subjects were used to calculate annual prevalences and incidence rates of antipsychotic prescriptions for the years 2004-2011. Analyses were stratified by sex, age, and drug type. Numbers of prescriptions, frequencies of diseases/disorders, the prescribing physicians' specialties, and the share of off-label prescriptions were examined. During the study period, the prevalence of antipsychotic prescriptions ranged between 2.0 and 2.6 per 1000 minors. Antipsychotic prescriptions in children younger than 6 years decreased from 2.42 per 1000 subjects in 2004 to 0.48 in 2011. Among antipsychotic users, 47.0 % had only one prescription and hyperkinetic disorder was, by far, the most frequent diagnosis. The annual share of off-label prescriptions varied between 61.0 and 69.5 %. Antipsychotics were mainly prescribed to manage aggressive and impulsive behaviors in hyperkinetic disorder patients. This explains the high share of off-label prescriptions but raises concerns, since efficacy and safety of antipsychotics in this indication have not been sufficiently investigated. The decreasing antipsychotic use in younger children and the high proportion of antipsychotic users with one-time prescriptions are striking and should be further investigated in the future.

Increase in vertebral fracture risk in postmenopausal women using omeprazole.

Proton pump inhibitors are taken by millions of patients for prevention and treatment of gastroesophageal diseases. Case-control studies have suggested that use of omeprazole is associated with an increased risk of hip fractures. The aim of this prospective study was to assess the risk of vertebral fractures in postmenopausal women using omeprazole. We studied 1,211 postmenopausal women enrolled in the Osteoporosis and Ultrasound Study from the general population. Information on omeprazole and other risk factors for fractures including prevalent fractures and bone mineral density was obtained at baseline. Vertebral fractures were assessed on X-rays obtained at baseline and at the end of the 6-year follow-up and analyzed centrally. At baseline, 5% of this population was using omeprazole. Age-adjusted rates for vertebral fractures were 1.89 and 0.60 for 100 person-years for omeprazole users and nonusers, respectively (P = 0.009). In the multivariate analysis, omeprazole use was a significant and independent predictor of vertebral fractures (RR = 3.50, 95% CI 1.14-8.44). The other predictors were age higher than 65 years (RR = 2.34, 95% CI 1.02-5.34), prevalent vertebral fractures (RR = 3.62, 95% CI 1.63-8.08), and lumbar spine T score

Vertebral fracture diagnosis in the multinational BONE study of oral ibandronate: quality management in radiology.

A multicenter trial has established the antifracture efficacy of oral daily (2.5mg) as well as intermittent (20mg every other day for 12 doses every 3 mo) ibandronate in women with postmenopausal osteoporosis. As diagnostic spinal radiographs for this trial were read at 2 centers, the study protocol included rigorous procedures for diagnosis of morphometric vertebral fractures. These included standardized qualitative and morphometric assessment methods for diagnosing vertebral osteoporotic fractures and consensus cross-validation procedures for maximizing fracture diagnostic accuracy and consistency between the 2 radiographic reading centers. Using these stringent measures, the between-center discrepancy in the diagnosis of prevalent fractures was only 8%. Furthermore, after cross-validation, discrepancy in the final diagnosis of incident fractures between centers was found for only 4 patients, resulting in a net gain of only 2 fractures in the trial. This meticulous methodology provided a highly effective means of identifying vertebral fractures and recruiting the trial population in which to assess the efficacy of ibandronate in postmenopausal osteoporosis.

Extent and Risks of Antipsychotic Off-Label Use in Children and Adolescents in Germany Between 2004 and 2011.

OBJECTIVE: Only little is known about antipsychotic (AP) off-label use (OLU) in pediatric populations. It was the aim of this study to examine the frequency as well as the risks of off-label AP use in underaged patients. METHODS: To calculate the frequency of off-label AP prescriptions for the years 2004-2011, we used claims data of more than two million minors aged 0-17 years. Off-label prescriptions were analyzed with regard to type of OLU, physician specialty, and underlying diagnoses. Incidence rates of selected adverse events were calculated for on-label as well as for OLU. The risk of poisoning associated with on- or OLU was assessed in a nested case-control study. RESULTS: The annual share of pediatric AP users with off-label prescriptions varied between 52.3% and 71.1%. OLU by indication (42.8%-66.5%) was the most common type of OLU. Of the subjects with OLU by indication, 52.5% had a diagnosis of hyperkinetic disorder. Adverse events were scarce (incidence rates between 0.8 and 8.6 per 10,000 person-years), and no significant difference was observed between on- and OLU. CONCLUSION: Because of their frequent use in hyperkinetic disorder patients, APs are commonly prescribed off-label for minors. Since OLU by contraindication was rare and the risk of the adverse events under study was similarly small for on- and OLU, this is not necessarily an indication for inappropriate treatment. It rather indicates that further randomized studies are needed to examine efficacy and safety of pediatric AP use in this indication.

Greater association of peak neuromuscular performance with cortical bone geometry, bone mass and bone strength than bone density: A study in 417 older women.

BACKGROUND: We evaluated which aspects of neuromuscular performance are associated with bone mass, density, strength and geometry. METHODS: 417 women aged 60-94years were examined. Countermovement jump, sit-to-stand test, grip strength, forearm and calf muscle cross-sectional area, areal bone mineral content and density (aBMC and aBMD) at the hip and lumbar spine via dual X-ray absorptiometry, and measures of volumetric vBMC and vBMD, bone geometry and section modulus at 4% and 66% of radius length and 4%, 38% and 66% of tibia length via peripheral quantitative computed tomography were performed. The first principal component of the neuromuscular variables was calculated to generate a summary neuromuscular variable. Percentage of total variance in bone parameters explained by the neuromuscular parameters was calculated. Step-wise regression was also performed. RESULTS: At all pQCT bone sites (radius, ulna, tibia, fibula), a greater percentage of total variance in measures of bone mass, cortical geometry and/or bone strength was explained by peak neuromuscular performance than for vBMD. Sit-to-stand performance did not relate strongly to bone parameters. No obvious differential in the explanatory power of neuromuscular performance was seen for DXA aBMC versus aBMD. In step-wise regression, bone mass, cortical morphology, and/or strength remained significant in relation to the first principal component of the neuromuscular variables. In no case was vBMD positively related to neuromuscular performance in the final step-wise regression models. CONCLUSION: Peak neuromuscular performance has a stronger relationship with leg and forearm bone mass and cortical geometry as well as proximal forearm section modulus than with vBMD.

Association of five quantitative ultrasound devices and bone densitometry with osteoporotic vertebral fractures in a population-based sample: the OPUS Study.

UNLABELLED: We compared the performance of five QUS devices with DXA in a population-based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA. INTRODUCTION: Quantitative ultrasound (QUS) methods have found widespread use for the assessment of bone status in osteoporosis, but their optimal use remains to be established. To determine QUS performance for current devices in direct comparison with central DXA, we initiated a large population-based investigation, the Osteoporosis and Ultrasound Study (OPUS). MATERIALS AND METHODS: A total of 463 women 20-39 years of age and 2374 women 55-79 years of age were measured on five different QUS devices along with DXA of the spine and the proximal femur. Their vertebral fracture status was evaluated radiographically. The association of QUS and DXA with vertebral fracture status was evaluated using logistic regression. RESULTS: All QUS approaches tested discriminated women with and without osteoporotic vertebral fractures (20% height reduction), with age-adjusted standardized odds ratios ranging 1.2-1.3 for amplitude-dependent speed of sound (AD-SOS) at the finger phalanges, 1.2-1.4 for broadband ultrasound attenuation (BUA) at the calcaneus, and 1.4-1.5 for speed of sound (SOS) at the calcaneus, 1.4-1.6 for DXA of the total femur, and 1.5-1.6 for DXA at the spine. For more severe fractures (40% height reduction), age-adjusted standardized odds ratios increased to up to 1.9 for DXA of the spine and 2.3 for SOS of the calcaneus. CONCLUSIONS: In conclusion, all five QUS devices tested showed significant age-adjusted differences between subjects with and without vertebral fracture. When selecting the strongest variable, QUS of the calcaneus worked as well as central DXA for identification of women at high risk for prevalent osteoporotic vertebral fractures. QUS-based case-finding strategies would allow halving the number of radiographs in high-risk populations, and this strategy works increasingly well for women with more severe vertebral fractures. It is likely that the good performance of QUS was in part achieved by rigorous quality assurance measures that should also be used in clinical practice.

Hormonal therapies and meningioma: is there a link?

BACKGROUND: The aetiology of meningiomas is largely unknown although hormones have been suggested to play a role. METHODS: A cohort study was performed to evaluate hormone-related factors associated with meningioma. Patients (12-89 years) with a first diagnosis of meningioma (January 1996-June 2008) were identified from The Health Improvement Network UK primary care database and age- and sex-matched to controls (n=10000) from the same cohort. Odds ratios (ORs) were calculated following a nested case control analysis using unconditional logistic regression. RESULTS: In total, 745 patients with meningioma were identified from a study population of 2171287. No significantly increased risk of meningioma was found among female users of oral contraceptives (OR: 1.15; CI: 0.67-1.98), hormone replacement therapy (OR: 0.99; CI: 0.73-1.35) or low-dose cyproterone acetate (CPA; OR: 1.51; CI: 0.33-6.86) compared with non-users. There was a significantly increased risk of meningioma among male users of androgen analogues (OR: 19.09; CI: 2.81-129.74) and among users of high-dose CPA (OR: 6.30; CI: 1.37-28.94) compared with non-users, however there were only three cases currently using these drugs. No significant association was found between meningioma and prostate, breast, or genital cancers. CONCLUSIONS: Our results do not support a role for exogenous hormone use by females in meningioma development. The risk in males was only observed with high-dose, short-term (<1 year) therapy. IMPACT: While hormonal cancers and therapies are not associated with meningioma in females, the risk in males requires further investigation.