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Aim: The aim of this study was to evaluate post-marketing label changes in dosing information of biologicals. Methods: Biologicals authorized between 2007 and 2014 by the European Medicines Agency (EMA) were included and followed up from marketing authorization until 31 December 2016 or date of withdrawal of the marketing authorization. The primary outcome of the study was defined as label change in dosing information for the initially approved indication. Incidence of changes, type of change and mean time to change were assessed. As a secondary outcome, label changes in dosing information for extended indications were assessed. Results: A total of 71 biologicals were included. Dosing information in the label changed for the initial indication during follow-up for eight products (11%). In one of the eight products the change concerned an increase in dose. Also, a change in dosing frequency was identified in three products, for one product a recommendation was added that therapy could be initiated with or without a loading dose, and for one product the minimum dose was removed and a maximum dose was added. For the remaining product the dose was decreased due to safety issues. For 30 products (42%) the indication was extended at least once. No changes in dosing information were observed for the extended indications (n = 59) during follow-up. Conclusions: This study showed that in 11% of the biologicals, the dosing for the initial indication in the label was changed. In contrast to small molecules, the dose was rarely reduced for safety reasons.

Background and aims Biosimilars have been available in the European Union (EU) since 2006. However, their uptake in routine care is heterogeneous across countries. The aim of the present study was to compare the safety information of biosimilars and their originators based on the information in the European risk management plan (RMP). Methods A cross-sectional analysis on publicly available regulatory documents (RMPs and Summaries of Product Characteristics) of biosimilars and corresponding originators up to 1 November 2015 was performed. The safety concerns were extracted and merged into general safety concerns, and clinical relevance was assessed. The frequency of safety concerns and the representation of these safety concerns per general safety concern were assessed by either comparing RMPs of biosimilars and originators (if available for both) or comparing RMPs with the Summary of Product Characteristics of the originator. Results Nineteen biosimilars and six originators were included. Overall, 55 general safety concerns (12 low, 21 medium and 22 highly clinically relevant) were identified. For all active substances, except for infliximab, no or only one difference was found in the listed general safety concerns. Comparison of regulatory documents for infliximab identified three medium clinically relevant general safety concerns more for infliximab biosimilars and two general safety concerns more for its originator. Conclusion Based on publicly available information filed for regulatory purposes, no substantial differences were observed in the reporting of safety information for biosimilars and related originators. A direct comparison between biosimilars and related originators through formal postmarketing studies is needed to evaluate specific safety issues emerging during the products’ life cycle.

Aim: The aim of the present study was to provide an insight into the characteristics and follow-up of postmarketing studies of medicines that were conditionally authorized in the European Union (EU). Methods: We compiled a list of all postmarketing studies attached as specific obligations to the licence of medicines that were granted conditional marketing authorization from January 2006 to April 2014. Studies were characterized based on their objective, design, status upon marketing authorization (MA) and due data set by authorities. They were linked to online study registrations (Clinicaltrials.gov, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines, and determined whether studies were completed on time. Results: A total of 59 postmarketing studies were requested for 21 conditionally authorized medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting postmarketing studies were ‘long-term follow-up’ and ‘increase data on subpopulations’. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed on time. Actual completion time took a median (interquartile range) of 274 (−121 to 556) days longer than expected. Conclusions: Our results indicated that most postmarketing studies attached to a conditional marketing authorization were eventually completed but that half were completed with a substantial delay. The observations suggest caution when broadening the use of postmarketing studies for resolving uncertainties about benefits and risks after MA.

textabstractAim The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. Methods A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. Results In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). Conclusions Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity.

The aim of the present study was to provide an insight into the characteristics and follow-up of postmarketing studies of medicines that were conditionally authorized in the European Union (EU).We compiled a list of all postmarketing studies attached as specific obligations to the licence of medicines that were granted conditional marketing authorization from January 2006 to April 2014. Studies were characterized based on their objective, design, status upon marketing authorization (MA) and due data set by authorities. They were linked to online study registrations (Clinicaltrials.gov, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines, and determined whether studies were completed on time.A total of 59 postmarketing studies were requested for 21 conditionally authorized medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting postmarketing studies were 'long-term follow-up' and 'increase data on subpopulations'. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed on time. Actual completion time took a median (interquartile range) of 274 (-121 to 556) days longer than expected.Our results indicated that most postmarketing studies attached to a conditional marketing authorization were eventually completed but that half were completed with a substantial delay. The observations suggest caution when broadening the use of postmarketing studies for resolving uncertainties about benefits and risks after MA.

Aim To assess dosing and determinants of the choice of statins among starters of statins. Methods Data were obtained from the PHARMO database comprising pharmacy and linked hospital discharge records of approximately 300 000 subjects in the Netherlands. All new users of statins in 1998 were selected. Patient characteristics and drug regimens were compared between starters of different statins. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression modelling, using the start of simvastatin therapy as reference category. Results In 1998, 1738 patients started using simvastatin (41.1%), pravastatin (23.1%), fluvastatin (11.9%), atorvastatin (22.8%) or cerivastatin (1.0%). Compared with starters with simvastatin [mean dose 1.02 ± 0.39 defined daily doses (DDDs)], starters with pravastatin (1.27 ± 0.56 DDDs) and atorvastatin (1.43 ± 0.59 DDDs) received higher doses (P

Aims To assess the level of undertreatment of hypercholesterolaemia in the general population, taking intra-person variability in serum cholesterol concentrations into account, and to identify determinants of undertreatment of hypercholesterolaemia. Methods In this cross-sectional study, data from two population-based surveys on cardiovascular disease risk factors conducted between 1987 and 1997 in the Netherlands were used. For all 64 757 respondents aged 20‐59 years, treatment eligibility for lipid-lowering drug use was established according to the Dutch Cholesterol Consensus. Multivariate logistic models were used to identify determinants of undertreatment. Results During the study period, 56.8% of the study population had undesirable cholesterol concentrations (serum total cholesterol > 5 mmol l - 1 ) and 5.5% of those were eligible for pharmacological treatment based on their absolute risk of coronary heart disease. Of those eligible for pharmacological treatment, 16.3% were treated, and 19.6% of those treated had their serum total cholesterol concentration controlled. Only 3.2% of those eligible for pharmacological treatment were both treated and controlled. We identified several determinants for undertreatment, e.g. male gender and younger age for primary prevention and female gender and older age for secondary prevention. Treatment has improved slightly in more recent years. Conclusions Over 95% of the population eligible for the pharmacological treatment of hypercholesterolaemia was either untreated or was uncontrolled. To decrease undertreatment, identification of high-risk patients should be increased. Those who are treated with lipid-lowering medication could further benefit from more aggressive treatment, especially with statins.

Aims To assess time trends in lipid lowering drug use in The Netherlands. Methods Data were obtained from the PHARMO-database, comprising pharmacy records of approximately 300 000 people in The Netherlands. In the period from 1991–98, we estimated prevalence of lipid lowering drug use on the first Wednesday of October. A patient was defined as incident user if (s)he filled a prescription for lipid lowering medication after a 360 days lipid lowering drug free interval. Both prevalence and incidence estimates were weighted for the sex and age distribution of the general Dutch population. Results From 1991 to 1998, the prevalence of lipid lowering drug use increased from 0.5% (95% confidence interval (CI): 0.5, 0.6) to 2.3% (95% CI: 2.2, 2.4) in women and from 0.6% (95% CI: 0.6, 0.6) to 2.9% (95% CI: 2.8, 3.0) in men. Prevalence increased with increasing age and was highest in the age category 60–69 years (in 1998: 9.9% (95% CI: 9.4, 10.4) in women and 11.6% (95% CI: 11.0, 12.1) in men). In 1992, the estimated incidence of lipid lowering drug use was 251(95% CI: 226, 277)/100 000 person years in women and 251(95% CI: 225, 276)/100 000 person years in men. The largest incidence estimates were observed in 1996 (685(95% CI: 644, 726)/100 000 person years in women and 881(95% CI: 834, 928)/100 000 person years in men). After 1996, incidence stabilized in 1997 and decreased in 1998 to 599(561, 637)/100 000 person years in women and 731(688, 773)/100 000 person years in men. Most of the patients (approximately 95%) were treated with one lipid lowering agent. Statins were used by over 90% of patients from 1996 onwards. In 1998, 35% of the patients started with a statin that was not a first choice drug (mainly atorvastatin). Conclusions In the period from 1991–98, prevalence of lipid lowering drug use significantly increased in The Netherlands. However, incidence stabilized and decreased after 1996 which may be explained by the fact that the number of patients eligible for treatment was reached. The question remains whether lipid lowering medication was targeted to the appropriate patients.

Aims To assess the potential annual savings due to generic and therapeutic substitution of statin therapy for the general Dutch population, taking the patients medical history into account. Methods We conducted a population-based costing study using the PHARMO Record Linkage System (RLS). PHARMO RLS contains drug dispensing records from a representative sample of pharmacies located in more than 50 regions in the Netherlands. We selected all statin users in the database since 2003. The cost-savings of generic substitution of statin therapy for all simvastatin and pravastatin users, and of therapeutic substitution of statin therapy for other statin users were calculated. Substituting current users and new users of statins were considered separately. Therapeutic substitution was based on the medical history of the individual patient. Patients were only substituted if there was an appropriate substitute available. The appropriateness of substitution was based on drug–drug interactions between statins and possible comedication and the availability of an equipotent alternative. Results Substituting (generic and therapeutic) statin therapy for all current users would lead to potential annual savings of approximately €87 million. Substituting (generic and therapeutic) all starters on statin therapy would lead to potential annual savings of around €51 million. In the case of generic substitution only, the potential annual savings for all current simvastatin and pravastatin users would be €2.4 million and for the new users about €1.8 million. Conclusions From an economic point of view, society could gain a lot from substituting statin therapy, especially from therapeutic substitution.

To assess time trends in lipid lowering drug use in The Netherlands.Data were obtained from the PHARMO-database, comprising pharmacy records of approximately 300 000 people in The Netherlands. In the period from 1991-98, we estimated prevalence of lipid lowering drug use on the first Wednesday of October. A patient was defined as incident user if (s)he filled a prescription for lipid lowering medication after a 360 days lipid lowering drug free interval. Both prevalence and incidence estimates were weighted for the sex and age distribution of the general Dutch population.From 1991 to 1998, the prevalence of lipid lowering drug use increased from 0.5% (95% confidence interval (CI): 0.5, 0.6) to 2.3% (95% CI: 2.2, 2.4) in women and from 0.6% (95% CI: 0.6, 0.6) to 2.9% (95% CI: 2.8, 3.0) in men. Prevalence increased with increasing age and was highest in the age category 60-69 years (in 1998: 9.9% (95% CI: 9.4, 10.4) in women and 11.6% (95% CI: 11.0, 12.1) in men). In 1992, the estimated incidence of lipid lowering drug use was 251(95% CI: 226, 277)/100,000 person years in women and 251(95% CI: 225, 276)/100,000 person years in men. The largest incidence estimates were observed in 1996 (685(95% CI: 644, 726)/100,000 person years in women and 881(95% CI: 834, 928)/100,000 person years in men). After 1996, incidence stabilized in 1997 and decreased in 1998 to 599(561, 637)/100,000 person years in women and 731(688, 773)/100,000 person years in men. Most of the patients (approximately 95%) were treated with one lipid lowering agent. Statins were used by over 90% of patients from 1996 onwards. In 1998, 35% of the patients started with a statin that was not a first choice drug (mainly atorvastatin).In the period from 1991-98, prevalence of lipid lowering drug use significantly increased in The Netherlands. However, incidence stabilized and decreased after 1996 which may be explained by the fact that the number of patients eligible for treatment was reached. The question remains whether lipid lowering medication was targeted to the appropriate patients.

Drug effects are not solely determined by the pharmacological properties of the active substance, but also depend heavily on the way it is used in practice by health professionals and patients. Non-adherence to instructions for use seems to have contributed to the withdrawal of drugs such as troglitazon, mibefradil, and most recently cerivastatin [1–3]. Hepatotoxicity andmyopathy are two rare but serious side-effects of statins. Myopathy can lead to a life threatening rhabdomyolysis. Product labelling of statins advises to monitor hepatic function and creatinine kinase (CK) concentrations (especially in patients who are experiencing muscle pain), because this may prevent progress of these drug-induced complications. The objective of the present study was to estimate the incidence of CK and hepatic function measurements in a cohort of patients starting with a statin, and to evaluate whether this was influenced by the withdrawal of cerivastatin. From eight community pharmacies located in Tilburg, the Netherlands and surroundings, patients starting with a statin during the period December 2000–April 2001 (period 1), or during the period August 8, 2001–October 2001(period 2) were selected. Period 2 was chosen after the withdrawal of cerivastatin. Date of filling the prescription was the index date. Age, gender, statin, prescribed dosage, and relevant concomitant drug use were obtained for all patients. From the regional clinical chemistry laboratory, which performs measurements for in-as well as outpatients, the number of hepatic function and CK measurements was determined during a 3 month follow-up period after the index date. Five hundred and thirty patients were included. Any clinical chemistry measurement during follow-up was performed in54.2% (287) of all patients; CK levels were checked in 13.0% (69) of the patients while hepatic functiontests were performed in 22.3% (118) of all patients. There was no difference in these frequencies before, and after the withdrawal of cerivastatin (Table 1). Table 1 Incidence of CK, hepatic function or any clinical chemistry measurement during 3 months of follow-up Gender, age, standardized dosage, interacting concomitant drug use, and CK-inducing concomitant drug use did not cause significant deviations of these outcomes. Only 5.3% (1) of the patients starting with cerivastatin was checked for CK compared with 13.3% (68) of the patients using other statins (RR 0.40 (95% CI 0.06, 2.70)). In contrast, any clinical chemistry measurement and hepatic function were determined more frequently in cerivastatin starters compared with other statin starters: RR 1.48 (95% CI 1.16, 1.90) respectively RR 3.04 (95% CI 2.08, 4.47). This study shows that, in daily medical practice, adherence to drug prescribing guidelines to perform clinical chemistry measurements is limited. The withdrawal of cerivastatin has not led to an increase in hepatic function-and CK measurements. Cerivastatin was taken off the market because available evidence (mainly case reports) suggested a higher frequency of serious side-effects in comparison with other statins [4]. It is remarkable that CK was less frequently checked in patients using cerivastatin while hepatic function was more frequently measured in this study. It is important to recognize that the population was limited to 530 patients with only 19 starters of cerivastatin. The strength of this study was the conductance in daily practice. The risk of losing patients during follow-up was minimized because in The Netherlands outpatients usually visit the same pharmacy [5], and all clinical chemistry testing was concentrated in one laboratory. Overall it is important to realize that a drug is not a chemical entity alone but comes along with instructions for patients and prescribers in order to optimize the benefit-harm balance. Strategies for adherence to such instructions should be developed and implemented.

In August 2001, the lipid lowering drug cerivastatin was withdrawn from the market after its use was associated with the deaths of 52 patients due to rhabdomyolysis. Our aim was to assess the patterns of lipid lowering drug use after the withdrawal of cerivastatin. A total of 36 Dutch community pharmacies were invited to extract medication histories from all patients who were prevalent users of cerivastatin (index group) on August 10, 2001 (index date), and from two age and gender matched controls. The controls had to be a prevalent user of any other statin at the index date. Medication histories were complete for a follow up period of 3.5 months (November 26, 2001: last day of the study). Logistic regression models were used to assess the association between patient and medication characteristics and discontinuation of lipid lowering drug use, defined as no prescription refilled for any lipid lowering drug after the index date and before end of the study. Of the 36 community pharmacies, 31 participated in the study (response rate 86.1%). Medication histories were available for 234 index patients and 431 matched controls. On the last day of the study, 37 patients in the index group (15.8%) and 41 controls (9.5%) had not refilled a prescription for any lipid lowering drug, and were therefore assumed to have discontinued lipid lowering drug use (OR = 1.8; 95% CI 1.1, 3.0). In men, the risk of discontinuation was similar for both users of cerivastatin and users of any other statin (OR = 0.9; 95% CI 0.5, 1.9), whereas in women the risk of discontinuation was higher for those using cerivastatin (OR = 3.4; 95% CI 1.7, 6.8). Stratification by age showed that discontinuation was more pronounced in those younger than 50 years of age (OR = 3.8; 95% CI 0.7, 22.4) than in older age categories (ORs ranging from 1.6 to 1.8, none statistically significant). Stratification by prescribed daily dose at the index date (expressed as defined daily doses (DDD)) showed that discontinuation was also more prevalent in those with the lowest doses of statins, < 1.00 DDDs day−1 (OR = 5.3; 95% CI 1.8, 15.6), compared with 1.00–1.99 DDDs day−1 (OR = 1.1; 95% CI 0.5, 2.5) and 2.00 DDDs day−1 (OR = 1.8; 95% CI 0.8, 3.7). In the cerivastatin group, 130 patients (66.0%) filled a new prescription for a lipid lowering drug before the theoretical end date of the prevalent prescription at the index date compared with 139 (35.6%) controls (OR = 3.5; 95% CI 2.5,5.1). Most of the patients who were on cerivastatin therapy switched to other lipid lowering drugs before they ran out of tablets. However, discontinuation of lipid lowering drug use was more prevalent in these patients than in users of other statins, especially in women, younger patients and those with low doses of statin therapy.

Prevalence of undertreatment of patients with hypercholesterolaemia is high and it remains uncertain which patients receive treatment. The aim was to identify determinants of non-use of lipid lowering drugs among those eligible for pharmacological treatment. Data were obtained from two population-based surveys (n = 65,428) on cardiovascular disease risk factors conducted from 1987–1997 in The Netherlands. All respondents (age 20–59 years) completed a questionnaire which contained questions on demographic variables, cardiovascular disease (CVD) risk factors and medication use. Blood pressure, total-cholesterol and HDL-cholesterol levels were measured. Treatment eligibility was established for all respondents according to the Dutch Consensus Cholesterol 1998. This standard indicates pharmacological treatment in secondary prevention (unless Tc160 mmHg or diastolic blood pressure >95 mmHg) (OR = 13.4; 7.0–25.8) current smoking (OR = 11.7; 6.4–21.2) were most strongly associated with non-use of lipid lowering drugs, while non-use decreased with concomitant anticoagulant drug use (OR = 0.05; 0.01–0.19). For age, we found an increase in risk of 1.26 (1.21–1.32) per year of age. This study indicates that many subpopulations of respondents eligible for treatment with lipid lowering drugs but not receiving medication can be identified. Attention should be focused on the elderly, men (especially in primary prevention), patients with diabetes mellitus and untreated hypertensives.