Long-term patterns of adherence to medication therapy among patients with type 2 diabetes mellitus in Denmark: The importance of initiation.

AIMS: Poor adherence to medication therapy among type 2 diabetes patients is a clinical challenge. We aimed to determine which factors are associated with the three phases of long-term adherence to medication: initiation, implementation and discontinuation in a register-based study. METHODS: Adherence to six medicine groups (metformin, sulfonylureas, acetylsalicylic acid, thiazide diuretics, renin angiotensin system inhibitors, and statins) were analysed among 5,232 patients with type 2 diabetes at a tertiary referral hospital during 1998-2009. Rate-ratios of initiation of treatment, recurrent gaps in supply of medication, and discontinuation of treatment were analysed using Poisson regression. RESULTS: Poor initiation rather than poor implementation or discontinuation was the main contributor to medication nonadherence. Polypharmacy was a risk factor for slower initiation of treatment for all six medicine groups (rate ratio ranging 0.79 95%CI [0.72-0.87] to 0.89 95%CI [0.82-0.96] per already prescribed medicine), but once patients were in treatment, polypharmacy was not associated with recurrence of gaps in supply of medication, and polypharmacy was associated with lower risk of discontinuation (rate ratio ranging 0.93 95%CI [0.86-1.00] to 0.96 95%CI [0.93-0.99] per prescribed medicine). Other identified risk factors for slow initiation, poor implementation, and discontinuation were diabetes duration, younger age, and Turkish/Pakistani origin. DISCUSSION: This study showed that a risk factor does not necessarily have the same association with all three elements of adherence (initiation, implementation and discontinuation), and that efforts supporting patients introduced to more complex drug combinations should be prioritized.

'Better medicines for children' within the Integrated Management of Childhood Illness framework: a qualitative inquiry in Uganda.

BACKGROUND: The Integrated Management of Childhood Illnesses is the main approach for treating children in more than 100 low income countries worldwide. In 2007, the World Health Assembly urged countries to integrate 'better medicines for children' into their essential medicines lists and treatment guidelines. WHO regularly provides generic algorithms for IMCI and publishes the Model Essential Medicines List with child-friendly medicines based on new evidence for member countries to adopt. However, the status of 'better medicines for children' within the Integrated Management of Childhood Illnesses approach in Uganda has not been studied. METHODS: Qualitative interviews were conducted with: two officials from the ministry of health; two district health officials and, 22 health workers from public health facilities. Interview transcripts were manually analyzed for manifest and latent content. RESULTS: Child-appropriate dosage formulations were not included in the package for the Integrated Management of Childhood Illnesses and ministry officials attributed this to resource constraints and lack of initial guidance from the World Health Organization. Underfunding reportedly undercut efforts to: orient health workers; do support supervision and update treatment guidelines to reflect 'better medicines for children'. Health workers reported difficulties in administering tablets and capsules to under-five children and that's why they preferred liquid oral dosage formulations, suppositories and injections. CONCLUSIONS: The IMCI strategy in Uganda was not revised to reflect child-appropriate dosage formulations - a missed opportunity for improving the quality of management of childhood illnesses. Funding was an obstacle to the integration of child-appropriate dosage formulations. Ministry of health should prioritize funding for the Integrated Management of Childhood Illnesses and revising the Essential Medicines and Health Supplies List of Uganda, the Uganda Clinical Guidelines and, the Treatment Charts for the Integrated Management of Childhood Illnesses to reflect child-appropriate dosage formulations.

Switch in Therapy from Methylphenidate to Atomoxetine in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: An Analysis of Patient Records.

OBJECTIVE: The purpose of this study was to investigate therapy switching from methylphenidate (MPH) to atomoxetine (ATX) in a clinical sample of Danish children and adolescents with attention-deficit/hyperactivity disorder (ADHD); specifically, to determine the duration of MPH treatment before switching to ATX, and the reasons leading to a switch in therapy. METHODS: We included 55 patients with ADHD who switched from first-line MPH to second-line ATX during January 01, 2012 and May 15, 2014. Patient and treatment characteristics along with clinical reasons for switching therapy were extracted from individual patients' records. RESULTS: Mean duration of MPH treatment until switch to ATX was 11.2 months (range = 0.3-28.5 months); 36% of the patients switched within the first 6 months, 56% within the first year, and 76% within 1.5 years of initiating MPH; 24% continued MPH treatment for up to 2.5 years prior to switching. Most common reasons for switching were "adverse events" (AEs) (78%), "wish for more optimal day coverage" (24%), and "lack of efficacy" (16%). Other reasons for switching included "patient/parental request" (13%) and "noncompliance" (2%). Most common AEs leading to switch were psychiatric disorders (insomnia, aggression, tic, depression, anxiety) and decreased appetite. CONCLUSIONS: Our findings highlight the importance of continuous evaluation of the need for prescription switch to ATX in children and adolescents treated with MPH, taking into consideration various factors including potential AEs, non-optimal day coverage, lack of efficacy, patient/parental preferences, and noncompliance. These factors should be considered, not only at the initial stage of MPH treatment but throughout the whole treatment course.

Socioeconomic Variations in Use of Prescription Medicines for COPD: A Register-Based Study.

BACKGROUND: The purpose of this study was to examine socioeconomic variations in the use of prescription medicines among elderly subjects with COPD. METHODS: Data from the Danish national administrative registers were used. The study population included 1,365 individuals >60 y old residing in the Municipality of Copenhagen and diagnosed with COPD in a hospital setting in 2007. Logistic regression analysis was applied to examine the associations between the use of all prescription medicines for obstructive pulmonary diseases and the use of long-acting bronchodilators, in subject groups of different socioeconomic position. RESULTS: The study demonstrated that approximately 90% of subjects with COPD purchased at least one prescription medicine for obstructive pulmonary diseases, whereas approximately 50% purchased a long-acting bronchodilator. Medicine use did not vary according to educational status or personal wealth. CONCLUSIONS: There were no systematic socioeconomic differences in the use of relevant prescription medicines in elderly subjects diagnosed with COPD in hospital settings in Copenhagen. However, our findings indicate a gap between guideline recommendations and observed use of long-acting bronchodilators and hence suboptimal quality of treatment in the elderly COPD population.

Medication overuse, healthy lifestyle behaviour and stress in chronic headache: Results from a population-based representative survey.

AIM: This cross-sectional study investigated associations between chronic headache (CH) with and without medication overuse, healthy lifestyle behaviour, and stress. METHODS: Questionnaires were sent to 129,150 adults. Those with headache ≥15 days per month for three months were classified as having CH then further described as having medication-overuse headache (MOH) or CH without medication overuse. Associations between headache and daily smoking, physical inactivity, obesity, excessive drinking, illicit drug use, and high stress were analysed by logistic regression. RESULTS: CH with and without medication overuse (prevalence 1.8% and 1.6%, respectively) had strong, graded associations with stress. Associations with daily smoking, physical inactivity, and obesity were significant only for MOH. Odds for MOH were highest among people who had all three factors compared to those who had none (OR 2.8 in women and 5.1 in men). High stress plus any of these three factors had synergistic effects in MOH but not clearly in those who had CH without overuse. Associations between CH subtypes and excessive drinking or illicit drug use were not statistically significant. CONCLUSION: Results suggest strong links between healthy lifestyle behaviour and stress in MOH. Stress reduction and promoting healthy behaviour are highly relevant in MOH management.

Empirical relations between sense of coherence and self-efficacy, National Danish Survey.

Salutogenic orientation is a health promotion paradigm focusing on the resources of the individual. This study analyzed the relationship between sense of coherence (SOC) and self-efficacy (SE) based on population data. By conducting an empirical analysis of the two models, we wanted to see whether we could make a valid judgement as to whether both SOC and SE could be utilized in health promotion practice, or whether one is preferable to the other. The study population was randomly selected from the Danish Central Population Register and consisted of five birth-year cohorts (1920, 1930, 1940, 1965 and 1975). The study used the 13-item SOC scale and the general SE scale. The main findings were that SOC score increased by age cohort (p = 0.0004), and there is a positive and graded correlation between SOC and SE (r = 0.39; p < 0.0001) and adjusted OR = 10.3 (CI = 6.7-15.4). We found the strongest association at the lowest level of SOC. For health promotion practice, this finding signifies the importance of focusing on improving SOC in people with a low SOC score, as they are most in need and most likely to increase their SOC level. The finding of higher SOC scores in the older age cohorts indicates that SOC changes over lifetime. Public health work focusing on lifestyle change by increasing SOC can be effective throughout life, however early intervention is important. The finding of a positive correlation between SOC and SE indicates that health promotion altering one of the constructs is paralleled in the other.

Sociodemographic and diagnostic characteristics of prescribing a second-line lipid-lowering medication: ezetimibe used as initial medication, switch from statins, or add-on medication.

OBJECTIVE: Ezetimibe is used as a second-line lipid-lowering medication (LLM) if statin therapy is not tolerated or cholesterol targets are not reached by statins alone. We aimed to investigate the impact of sociodemographic factors on ezetimibe initiation as (a) incident LLM therapy, (b) add-on therapy, and (c) switch from statins. METHODS: All individuals aged 30+ who had filled at least one prescription for either statins (N = 581.074) or ezetimibe (N = 7.932) in 2011 were followed in the nationwide Danish registries to explore LLM prescribing patterns from 1 January 2011 to end 2012. Using logistic regression analyses, the odds ratio (OR) with 95% confidence intervals (CIs) was calculated for (a) incident ezetimibe use among LLM initiators (N = 77,472), (b) ezetimibe switching by discontinuing statin users (N = 37,509), and (c) ezetimibe as add-on by non-discontinuing statin users (N = 442,672). RESULTS: Women had higher odds for initiating ezetimibe than men (switch OR = 1.55; 95% CI = 1.32-1.82). While prior use of newer high-potency statins was the strongest predictor (add-on (5.56; 4.95-6.24), income was the strongest socioeconomic predictor for incident LLM use (1.33; 1.14-1.56) and switching (1.64; 1.27-2.13). Both income and education were predictors for add-on therapy, with the educational effect mediated by prior use of high-potency statins. Odds for ezetimibe prescribing were highest in myocardial infarction patients. CONCLUSION: While higher income is a predictor for switching to ezetimibe, both higher education and income are weak predictors for using ezetimibe as add-on therapy. Women and individuals with myocardial infarction are more likely to be prescribed ezetimibe than others, despite lack of evidence of ezetimibe lowering the risk of cardiovascular events.

Identification of possible adverse drug reactions in clinical notes: The case of glucose-lowering medicines.

OBJECTIVE: Through manual review of clinical notes for patients with type 2 diabetes mellitus attending a Danish diabetes center, the aim of the study was to identify adverse drug reactions (ADRs) associated with three classes of glucose-lowering medicines: "Combinations of oral blood-glucose lowering medicines" (A10BD), "dipeptidyl peptidase-4 (DDP-4) inhibitors" (A10BH), and "other blood glucose lowering medicines" (A10BX). Specifically, we aimed to describe the potential of clinical notes to identify new ADRs and to evaluate if sufficient information can be obtained for causality assessment. METHODS: For observed adverse events (AEs) we extracted time to onset, outcome, and suspected medicine(s). AEs were assessed according to World Health Organization-Uppsala Monitoring Centre causality criteria and analyzed with respect to suspected medicines, type of ADR (system organ class), seriousness and labeling status. FINDINGS: A total of 207 patients were included in the study leading to the identification of 163 AEs. 14% were categorized as certain, 60% as probable/likely, and 26% as possible. 15 (9%) ADRs were unlabeled of which two were serious: peripheral edema associated with sitagliptin and stomach ulcer associated with liraglutide. Of the unlabeled ADRs, 13 (87%) were associated with "other blood glucose lowering medications," the remaining 2 (13%) with "DDP-4 inhibitors." CONCLUSION: Clinical notes could potentially reveal unlabeled ADRs associated with prescribed medicines and sufficient information is generally available for causality assessment. However, manual review of clinical notes is too time-consuming for routine use and hence there is a need for developing information technology (IT) tools for automatic screening of patient records with the purpose to detect information about potentially serious and unlabeled ADRs.

Prescription pain medications and chronic headache in Denmark: implications for preventing medication overuse.

PURPOSE: The aim of the present paper is to study which prescription pain medications are most commonly dispensed to people with chronic headache (CH), particularly those with medication-overuse headache (MOH). METHODS: This cross-sectional study analysed prescription pain medications dispensed within 1 year to 68,518 respondents of a national health survey. Participants with headache ≥ 15 days per month for 3 months were classified as having CH. Those with CH and over-the-counter analgesic use ≥ 15 days per month or purchase of ≥ 20 or ≥ 30 defined daily doses (DDDs) of prescription pain medication per month (depending on the drug) were classified as having MOH. Associations between CH and other chronic pain conditions were analysed by logistic regression. RESULTS: Among those with CH (adjusted prevalence 3.3%, CI 3.2-3.5%), pain medications most commonly dispensed were paracetamol, tramadol, ibuprofen and codeine. CH was associated with osteoarthritis, back pain, and rheumatoid arthritis. Among those with MOH, 32.4% were dispensed an opioid at least once within 1 year. Only 5.1% of people with CH were dispensed triptans. CONCLUSIONS: High prevalence of opioid use among people with CH may be due to inappropriate headache treatment or development of MOH among those treated for other pain conditions. While there were cases of triptan overuse, triptans remain underutilized among those with CH, suggesting that migraine may be under-recognized and inappropriately treated, leading to overuse of other medications. Education of physicians on appropriate headache management is essential for MOH prevention. There is a need to increase universal awareness about MOH as an adverse effect of long-term analgesic use.

Availability and utilization of the WHO recommended priority lifesaving medicines for under five-year old children in public health facilities in Uganda: a cross-sectional survey.

OBJECTIVES: To explore the availability and utilization of the World Health Organization (WHO) recommended priority life-saving medicines for children under five in public health facilities in Uganda. METHODS: We conducted a cross sectional survey in 32 lower level public facilities in Jinja district of Uganda. A proportionate number of facilities were randomly selected in each stratum following a hierarchy of Health Centers (HC) defined according to the level of care they provide: 17 HC IIs, 10 HC IIIs and 5 HC IVs. In the facilities, we verified the availability of the WHO recommended priority medicines for diarrhea, sepsis, pneumonia and malaria. 81 health workers from the facilities reported what they prescribed for children with the above diseases. RESULTS: Oral rehydration salt (ORS) and zinc sulphate dispersible tablets for diarrhea were available in all HC IIs and IIIs and in only 60% of HC IVs. Procaine benzyl penicillin injection powder for treatment of sepsis was available in the majority of all HCs with: 100% of HC of IVs, 83% of HC IIIs and 82% of HC IIs. Medicines for pneumonia were limited across all the HCs with: Amoxicillin dispersible tablets in only 30% of the HC IIs and 40% of the HC IVs. The most uncommon were child-friendly priority medicines for malaria with: Artesunate injection in only 6% of HC IIs, 14% of HC IIIs and 20% of HC IVs; Artemether lumefantrine dispersible tablets and rectal artesunate were missing in all the 32 HCs. Less than a third of the health workers reported prescribing zinc sulphate and ORS for diarrhea, 86% reported procaine benzyl penicillin injection powder for sepsis, and 57% reported amoxicillin dispersible tablets for pneumonia. None reported prescribing Artemether lumefantrine dispersible tablets and rectal artesunate for malaria. CONCLUSIONS: There is low availability and utilization of life-saving priority medicines for pneumonia and malaria in public health facilities in Uganda. However, the priority medicines for diarrhea and sepsis are available and highly prescribed by the health workers.

Discrepancies in listed adverse drug reactions in pharmaceutical product information supplied by the regulatory authorities in Denmark and the USA.

Pharmaceutical product information (PI) supplied by the regulatory authorities serves as a source of information on safe and effective use of drugs. The objectives of this study were to qualitatively and quantitatively compare PIs for selected drugs marketed in both Denmark and the USA with respect to consistency and discrepancy of listed adverse drug reaction (ADR) information. We compared individual ADRs listed in PIs from Denmark and the USA with respect to type and frequency. Consistency was defined as match of ADRs and of ADR frequency or match could not be ruled out. Discrepancies were defined as ADRs listed only in one country or listed with different frequencies. We analyzed PIs for 40 separate drugs from ten therapeutic groups and assigned the 4003 identified ADRs to System Organ Classes (Medical Dictionary for Regulatory Activities [MedDRA] terminology). Less than half of listed ADRs (n = 1874; 47%) showed consistency. Discrepancies (n = 2129; 53%) were split into ADRs listed only in the USA (n = 1558; 39%), ADRs listed only in Denmark (n = 325; 8%) and ADRs listed with different frequencies (n = 246; 6%). The majority of listed ADRs were of the type "gastrointestinal disorders" and "nervous system disorders". Our results show great differences in PIs for drugs approved in both Denmark and the USA illuminating concerns about the credibility of the publicly available PIs. The results also represent an argument for further harmonization across borders to improve consistency between authority-supplied information.

Paediatric adverse drug reactions following use of asthma medications in Europe from 2007 to 2011.

BACKGROUND: Information about safety issues from use of asthma medications in children is limited. Spontaneous adverse drug reaction (ADR) reports can provide information about serious and rarely occurring ADRs in children. OBJECTIVE: To characterize paediatric ADRs reported for asthma medications licensed for paediatric use. SETTING: Spontaneous ADR reports located in the European ADR database, EudraVigilance. METHOD: ADRs reported for asthma medications licensed for paediatric use from 2007 to 2011 were analysed. The included substances were beclometasone, budesonide, fenoterol, fluticasone, formoterol, mometasone, montelukast, salbutamol and terbutaline and the combinations of budesonide/formoterol, fenoterol/ipratropium and fluticasone/salmeterol. MAIN OUTCOME MEASURES: Reported ADRs were categorized with respect to distribution on age, sex, type and seriousness of reported ADRs, medications and type of reporter. The unit of analysis was one ADR. RESULTS: We located 326 spontaneous reports corresponding to 774 ADRs for the included asthma medications. Approximately 85% of reported ADRs were serious including six fatal cases. In total, 57% of ADRs were reported for boys. One quarter of all ADRs occurred in children up to 1 year of age. Physicians reported the majority of ADRs. Across medicines, the majority of reported ADRs were of the type "psychiatric disorders" (13% of total ADRs), followed by "respiratory, thoracic and mediastinal disorders" (10% of total ADRs) and "skin and subcutaneous disorders" (9% of total ADRs). The largest number of ADRs was reported for budesonide (21% of total ADRs), followed by salbutamol (20% of total ADRs) and fluticasone (19% of total ADRs). For salbutamol, the largest numbers of serious ADRs were "tachycardia", "accidental exposure/incorrect dose administered" and "respiratory failure". CONCLUSION: Only a few ADRs from use of asthma medications in children were identified in the EudraVigilance ADR database, but a large majority of these were serious including fatal cases.

Comparison of pregnancy and lactation labeling for attention-deficit hyperactivity disorder drugs marketed in Australia, the USA, Denmark, and the UK.

BACKGROUND: Pregnancy and lactation labeling is presented in the officially recognized product information (PI) accompanying prescription drugs to ensure appropriate prescribing in pregnant and breastfeeding women. OBJECTIVE: The aim of this study was to analyze pregnancy and lactation labeling in PI for attention-deficit hyperactivity disorder drugs marketed across countries and to compare this information with respect to consistency and discrepancy. METHODS: We manually surveyed PI for atomoxetine, methylphenidate, and modafinil marketed by the same pharmaceutical companies in Australia, the USA, Denmark, and the UK. We extracted information regarding data sources (animal and human data), risk to the fetus or breastfed child, excretion in breast milk, and recommendations for use. The extracted information was then analyzed and compared with respect to consistency and discrepancy. RESULTS: Inter-country discrepancies were identified with respect to both animal and human data sources presented, types of risks listed in association with exposure during pregnancy and lactation, information regarding excretion of the drug in breast milk, and recommendations for use. Consistency was identified between PI for drugs marketed in the EU. CONCLUSION: The study suggests that pregnancy and lactation labeling in PI for drugs marketed by the same pharmaceutical companies depend on the country of marketing; this raises concern about the reliability of PI documents as a useful source of information for appropriate prescribing during pregnancy and lactation. Discrepancies in this information can potentially lead to inappropriate prescribing in pregnant and breastfeeding women, who may expose their fetuses and breastfed children to unnecessary risks. At the same time, unjustified warnings against breastfeeding may result in children being unnecessarily weaned from being breastfed.

Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status.

Near-daily intake of acute symptomatic medication for frequent headache increases the risk for medication-overuse headache (MOH). Chronic headache (CH) and MOH prevalences are inversely related to socioeconomic position (SEP). It is not known how SEP influences the health status of people with these headaches. This cross-sectional study examined the prevalence of CH in Denmark; possible associations between CH and education, work status, and income; and the health status of people with CH across socioeconomic strata. A total of 129,150 individuals aged ⩾ 16 years were invited to the 2010 Danish National Health Survey. Data on SEP indicators and purchases of prescription drugs in 2009 were retrieved from national registers. Respondents with headache ⩾ 15 days per month over 3 months were classified as having CH. Those with concurrent over-the-counter analgesic intake of ⩾ 15 days per month or prescription medication overuse (⩾ 20 or ⩾ 30 defined daily doses per month depending on the drug or drugs) were classified as having MOH. Associations between headache and SEP were analyzed by logistic regression, and associations between headache and health status scores, by linear regression. Physical and mental health composite scores (SF-12) were summarized per headache group, stratified by SEP, and compared to the sample mean. Analyses were adjusted for stratified sampling and nonresponse. The response rate was 53.1%. CH prevalence was 3.3% with 53.0% of cases having concurrent medication overuse (MOH prevalence 1.8%). CH was more prevalent among those individuals with low SEP. Health status scores were significantly lower among persons with CH in all SEP categories. The burden of CH can be reduced by preventing and treating MOH.

A multistate model and an algorithm for measuring long-term adherence to medication: a case of diabetes mellitus type 2.

OBJECTIVES: To develop a multistate model and an algorithm for calculating long-term adherence to medication among patients with a chronic disease. METHODS: We propose definitions of the different states of waiting, persistence, with sufficient supply to implement the prescribed dosing regimen, gaps, nonpersistence, and nonacceptance and an algorithm for transitions between states to describe long-term adherence to medication treatment. The model and algorithm are operationalized for use in a case with a retrospective cohort of patients with type 2 diabetes mellitus, with access to records of prescribed drugs from a Danish diabetes research hospital and records of filled prescriptions at Danish pharmacies from the Danish Health and Medicines Authority. RESULTS: Calculations of long-term adherence to medication are shown for patients with type 2 diabetes mellitus on metformin and/or simvastatin. The study shows how the prevalence of patients waiting to initiate treatment, patients with supply to implement the prescribed dosing regimen, patients not accepting treatment, and patients discontinuing treatment varies over time. CONCLUSIONS: The proposed multistate model and algorithm can easily be translated and used for the calculation of adherence to medication in any chronic disease. The model and algorithm take time into account, and thus, changes in incidence rates and prevalence of the different states over time can be estimated on several time scales (calendar time, age of the patient, and time since indication for medication).

Validation of the Danish translation of the Medicine Knowledge Questionnaire among elementary school children.

BACKGROUND: There is a lack of instruments which can be used to quantitatively assess school children's knowledge about medicine in different countries. OBJECTIVES: The aim of this study was to validate the Danish translation of a school children's medicine knowledge questionnaire developed in Finland. METHODS: A total of 685 children from 37 Danish elementary schools, aged 10-14 years, participated in a validation study. Test-retest and inter-rater reliability, as well as known-group-validity of the translated instrument were investigated. Significance level was set at P ≤ 0.05. RESULTS: For test-retest reliability, Spearman r correlation coefficients for correct knowledge score between the two rounds was 0.433, P < 0.001. For inter-rater reliability, kappa for agreement in correct knowledge score ratings between the two raters was 0.202. For known-group validity, a multivariate linear regression model was run for correct knowledge scores, and it significantly explained 9.2% of variance (R square 0.092, P < 0.001). Gender, school grade and use of medicine for asthma were significant predictors in the model. CONCLUSIONS: The translated questionnaire showed a fair test-retest and inter-rater reliability, as well as acceptable known-group validity. In order to be reliably used in further studies to evaluate school children's knowledge about medicine in Denmark, the methodic of knowledge scoring in the instrument is warranted.

Adverse drug reactions associated with asthma medications in children: systematic review of clinical trials.

BACKGROUND: Respiratory medications are frequently prescribed for use in children. Several studies have reported information on the safety of asthma medications in clinical studies in adults, but information about safety in children is scarce. OBJECTIVE: To review published clinical trials on the occurrence and characteristics of adverse drug reactions (ADRs) in children, reported for asthma medications licensed for paediatric use. METHODS: We systematically reviewed the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. PubMed, Embase, Cochrane Library, PsycINFO, IPA, and CINAHLs databases were searched from origin until July 2013 for studies reporting ADRs for beta2-receptor agonists, inhaled corticosteroids, leukotriene receptor antagonists and combination products in children from birth to age 17. Information on ADR reporting rates, age and gender, type and seriousness of ADRs, design, setting, observation period, type of assessors, and funding sources was extracted from the articles. RESULTS: Literature searches resulted in 162 potential relevant articles. However only 12 of these studies were included in this review as they reported information about ADR rates from use of salmeterol, formoterol, fluticasone, montelukast, zafirlukast and budesonide/formoterol in children. The total population was approximately 3,000 children; the majority was 6- to 11-year-olds and two thirds of these were boys. The observation period varied from 1 to 22 months. The most frequently reported ADRs were exacerbation of asthma, respiratory tract infection, cough, fever and headache. Only few ADRs were rated as being serious, however a number of children dropped out of the clinical trials due to serious ADRs, and, therefore, the real number of serious ADRs is probably higher. CONCLUSIONS: Few clinical trials reporting ADRs from use of asthma medications in children were identified in the literature. These studies reported only a few types of ADRs, the majority being non-serious.

Ethnic and migrant differences in the use of anti-asthmatic medication for children: the effect of place of residence.

BACKGROUND: Ethnic differences in the use of anti-asthmatic medication have been reported, with ethnic minorities being at a higher risk of suboptimal asthma control. As contextual socioeconomic characteristics may play a role, we analysed whether ethnic differences in the use of anti-asthmatic medication among children residing in the Capital Region of Denmark varied by place of residence. METHODS: Data were obtained from the Danish Civil Registration System, the Central Taxpayers' Register and the Danish National Prescription Register and were linked at the individual level. Population used was the entire child population in the Capital Region from 0 to 17 years old in 2008 (n = 342,403). Use of anti-asthma medicine was defined as at least one prescription having been filled in 2008. The analyses included multiple multilevel logistic regression models. RESULTS: Children living in low-income places of residence had lower odds of being prescribed preventive anti-asthmatics compared with children living in higher-income places of residence [odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.84-0.91]. Immigrant children had the lowest OR of being prescribed anti-asthmatics medication, both relief (OR = 0.50, 95% CI 0.20-0.77) and preventive (OR = 0.47, 95% CI 0.24-0.82) compared with ethnic Danes. Similar associations were found among descendants of immigrant children (OR for preventive medication = 0.70, 95% CI 0.62-0.78). Place of residence contributed to but did not account for the ethnic differences in the use of anti-asthmatic medication. CONCLUSIONS: Ethnic differences in the use of anti-asthmatic medication were documented, and they cannot be explained by socioeconomic characteristics of place of residence. The lower prevalence of anti-asthmatic medication among ethnic minority children suggests poor asthma management control.

Adverse drug reactions in children reported by European consumers from 2007 to 2011.

BACKGROUND: Information about medicines safety in children is very limited. Consumer adverse drug reaction (ADR) reports can provide information about serious and unknown ADRs from medicine use in children. OBJECTIVE: To characterize ADRs in children reported by consumers in Europe from 2007 to 2011. METHODS: We analysed ADRs reported to the European ADR database, EudraVigilance (EV) for individuals from birth to 17 years. Data were characterized with respect to age and sex of the child, type of ADR (system organ class and preferred term), seriousness and suspected medicines (anatomical therapeutic chemical classification system level 1 and 5). RESULTS: In total, 240 ADR reports corresponding to 670 ADRs were identified. The relatively largest share of ADRs were reported for infants below 1 year followed by teenagers, and 60 % of all ADRs were reported for girls. The majority of ADRs reported were of the general type (20 %) and nervous system disorders (15 %). The largest share of serious ADRs was of the type nervous system disorders (17 % of all serious). Three cases of death were reported. Vaccines and anti-infectives for systemic use contributed to 30 % of ADRs, antineoplastic and immunomodulating agents for 23 % and sex hormones for 13 %. CONCLUSION: Only few paediatric ADR consumer reports were found in EudraVigilance. Many of these ADRs were serious, and fatal cases were reported, however also nonserious reports were present. The findings indicate that consumer reports may be of value in paediatric ADR signal detection.

Definitions of medication-overuse headache in population-based studies and their implications on prevalence estimates: a systematic review.

BACKGROUND: Case definitions of medication-overuse headache (MOH) in population-based research have changed over time. This study aims to review MOH prevalence reports with respect to these changes, and to propose a practical case definition for future studies based on the ICHD-3 beta. METHODS: A systematic literature search was conducted to identify MOH prevalence studies. Findings were summarized according to diagnostic criteria. RESULTS: Twenty-seven studies were included. The commonly used case definition for MOH was headache ≥15 days/month with concurrent medication overuse ≥3 months. There were varying definitions for what was considered as overuse. Studies that all used ICHD-2 criteria showed a wide range of prevalence among adults: 0.5%-7.2%. CONCLUSIONS: There are limits to comparing prevalence of MOH across studies and over time. The wide range of reported prevalence might not only be due to changing criteria, but also the diversity of countries now publishing data. The criterion "headache occurring on ≥15 days per month" with concurrent medication overuse can be applied in population-based studies. However, the new requirement that a respondent must have "a preexisting headache disorder" has not been previously validated. Exclusion of other headache diagnoses by expert evaluation and ancillary examinations is not feasible in large population-based studies.