Population Exposure to Phthalate‐containing Drugs

Phthalates are known endocrine disruptors. Not commonly recognized, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate‐containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from medstat.dk. Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the ‘defined daily dose’ (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethyl phthalate (DEP) and dibutyl phthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate‐containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low‐molecular‐weight phthalates and three high‐molecular‐weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multi‐enzymes (24.6–32.8 mg per DDD) and mesalazine (12.5–26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate‐containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.     

Utilization of benzodiazepines in Chile during 1982–1986

Summary The consumption of benzodiazepine drugs (BDZ) in Chile in the period 1982–1986 has been studied by the DDD method. National use was assessed using drug import forms as a source of information, assuming that the total amount imported was manufactured and consumed in the same year.The utilization did not show a constant pattern, being 32.7, 33.6, 50.2, 34.9, and 31.3 DDD 1000 per inhabitants per day in 1982, 1983, 1984, 1985 and 1986, respectively. During the study period, diazepam was the most commonly used agent amongst anxiolytic BDZ, reaching a peak of 27.1 DDD per 1000 inhabitants per day in 1984, and flunitrazepam was the most popular hypnotic, attaining its maximum in 1986 (6.4 DDD per 1000 inhabitants per day). The use of BDZ at community pharmacy level was also evaluated, employing the International Marketing System (IMS) as the source of information. At that level the pattern of utilization showed a constant increase during the study period, being 14.9 and 25.8 DDD/1000 inhabitants/per day in 1982 and 1986, respectively.In community pharmacies the anxiolytic BDZ most often consumed was diazepam (maximum 9.1 DDD per 1000 inhabitants per day in 1985), and the commonest hypnotic was flunitrazepam (peak 6.0 DDD per 1000 inhabitants per day in 1986).National consumption of BDZ appeared higher and more variable than use at the community pharmacy level, but in both there was greater usage of anxiolytic than of hypnotic BDZ, and diazepam and flunitrazepam were the most popular agents.     

Differences in antidiabetic drug utilisation between three different health systems in the same national region

Summary The consumption of antidiabetic drugs in a Spanish region (Extremadura) in the period 1986–1987 has been investigated by the defined daily dose (DDD) method.The study was done in three health care systems in the region: civil servants (Mutualidad de Funcionarios Civiles del Estado: MUFACE) armed forces group (Instituto Social de las Fuerzas Armadas: ISFAS) and the national system (Instituto Nacional de la Salud: INSALUD). The total consumption of antidiabetic drugs varied three-fold, ranging from 5,73 DDD per 1000 inhabitants per day (3,71 DDD per 1000 inhabitants per day for oral antidiabetic drugs and 2,02 DDD per 1000 inhabitants per day for insulin) in the civil servant group to 15,82 DDD per 1000 inhabitants per day (12 DDD per 1000 inhabitants per day for oral antidiabetic drugs and 3,82 DDD per 1000 inhabitants per day for insulins) in the armed forces. The differences were more pronounced for oral antidiabetics than for insulins. The utilization of insulin among the civil servants was about half of that by the two other groups. Of oral antidiabetics, sulphonylureas were the most frequently used by the three groups, and within them glibenclamide accounted for more than half of the DDDs, while biguanides were scarcely used in any group. The differences are difficult to assess, since they could be due to several factors, such as age-differences in the population studied, different prescribing habits, and differences in sociocultural level. The results justify further comparative studies of drug utilization in different health systems within the same region.     

A Regional Drug and Therapeutics Committee‐led Intervention to Reduce the Hospital Costs of Expensive HIV Drugs

In 2009, the regional Drug and Therapeutics Committee (DTC) began a series of meetings with lead specialists in infectious diseases. The role of the DTC was to engage clinicians and ensure commitment to prescribing the least expensive drugs among the clinically equivalent HAARTs (highly active antiretroviral therapy). DTC also led implementation of a national guideline. This study analyses the impact of this process on HAART consumption and expenditure. The HAART consumption and expenditure (2009–2013) was compared to forecasts produced by exponential smoothing (2004–2009). Abrupt switches between drug regimens coincided with the DTC‐led meetings. Overall, HAART consumption rose 16%, while price per defined daily dose (DDD) fell 11% and the 2013 expenditure decreased 23%. The consumption of drugs addressed by the guideline rose 48%. Still, the 2013 expenditure was 41.5 million DKK (5.5 million €) (27%) lower than expected, reflecting a fall in price per DDD that coincided with the intervention. The consumption of drugs not addressed by the guideline rose 8.3%, while price per DDD fell 8.5% and the 2013 expenditure was 26.8 million DKK (3.6 million €) (19%) lower than expected. Despite a steadily increasing consumption, significant cost savings followed this DTC‐led intervention. This multifaceted approach might be applicable to changing the prescribing of other expensive drug classes.     

Use of benzodiazepines and benzodiazepine-related drugs in the Nordic countries between 2000 and 2020

Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000–2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55–78% of BZ use in 2020, followed by BZ sedatives at 20–44%, BZ-hypnotics at <1–5%, and clonazepam at <1–2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups—despite warnings against their use in this population.     

Consumption of analgesics and anti-inflammatory drugs in the nordic countries between 1978–1988

Summary Comparative wholesale statistics from the five Nordic countries show an increase of 15–42% in the total consumption of analgesics and anti-inflammatory drugs (including antirheumatics) in the period 1978–1988. Denmark had the highest total consumption (112 DDD/1000 inhab/day in 1988) and Norway had the lowest (61 DDD/1000 inhab/day). Iceland and Finland, with the highest increases in total consumption (45% and 35%), overtook Norway in the early to mid 1980's. Division of total consumption into subgroups showed that Denmark had the highest consumption of analgesics (90 DDDs) and that Finland and Iceland had the lowest figure. The latter countries, however, had the highest consumption of non-steroidal anti-inflammatory drugs (NSAID), 35 and 30 DDDs, respectively, in 1988. The increase in NSAID consumption was 57% in Finland and 54% in Iceland, while Denmark had only an 18% increase. The new NSAIDs introduced in the 1970's appear to have increased the overall consumption of pain relievers in the Nordic countries, especially in Finland and Iceland.     

Non-antiarrhythmic drugs prolonging the QT interval: considerable use in seven countries

AIMS: Many drugs belonging to different therapeutic classes appear to share a potentially fatal side-effect: ventricular tachyarrhythmias associated with QT prolongation. The aim of this study was to assess the relevance and the magnitude of the problem in seven countries by grouping all nonantiarrhythmic drugs according to the type of evidence on QT prolongation and analysing their sales data. METHODS: We divided all nonantiarrhythmic QT-prolonging agents into the following categories (in increasing order of clinical relevance): group A, drugs with published clinical or preclinical evidence on QT prolongation or with relevant official warnings; group B, drugs with published clinical or preclinical evidence; group C, drugs with published clinical evidence; group D, drug with published clinical evidence on torsades de pointes or ventricular arrhythmias associated with QT prolongation; group E, drugs belonging to group D with official warnings. We retrieved 1998 sales data from community pharmacies in seven countries (Australia, Denmark, England, Germany, Greece, Italy and Sweden). Data for individual agents were expressed as defined daily doses per 1000 inhabitants per day (DDD/1000/day). Overall use in each country was calculated for each drug group. Groups D and E were considered as the most clinically relevant. RESULTS: Among the 102 nonantiarrhythmic agents meeting at least one of the inclusion criteria, 33 drugs had sales data > or =1 DDD/1000/day and 71 drugs had a use > or =0.1 DDD/1000/day in at least one country. Among the 37 nonantiarrhythmic agents with published reports of ventricular arrhythmias associated with QT prolongation, 12 compounds had sales data > or =1 DDD/1000/day. Total consumption in each country ranged: from 51.9 to 94.7 DDD/1000/day for group A; from 51.6 to 92.7 DDD/1000/day for group B; from 37.1 to 76.6 DDD/1000/day for group C; from 12.9 to 29.1 DDD/1000/day for group D; and from 5.8 to 15.3 DDD/1000/day for group E. CONCLUSIONS: In spite of wide variations in the sales of individual agents, the overall extent of use of nonantiarrhythmic QT-prolonging drugs was of the same order of magnitude in all countries. The significant use of drugs belonging to categories D and E should prompt careful risk/benefit assessment of each agent.     

Trends in consumption of psychiatric drugs in Serbia and Montenegro 2000-2004

PURPOSE: To investigate the trends in psychiatric drugs utilization in Serbia and Montenegro over the 5-years period (2000-2004). MATERIALS AND METHODS: The wholesale data issued by the manufacturers or distributors were used. Also, the lists of drugs used from the Institute of Mental Health (institution which provides primary, secondary and tertiary psychiatric care) were used to corroborate the wholesale data. The utilization of drugs in general population was calculated using ATC/DDD methodology, and was expressed in Defined Daily Doses (DDD) per 1000 inhabitants per day. The utilization of drugs in the Institute of Mental Health was calculated from the hospital pharmacy records and was expressed as the number of DDDs per 100 bed-days. The statistics was performed using standard statistical methods. RESULTS: The general consumption of psychiatric drugs in Serbia and Montenegro significantly increased during the 2000-2004 period (from 45.1 DDD/1000 inhabitants/day in 2000 to 69.1 DDD/1000 inhour/day in 2004). The general utilization of anxiolytic/hypnotic drugs surged significantly, but the inhospital use remained rather stable. The most prominent changes were noted in the utilization of antidepressants, which doubled in that period, both in general and inhospital settings. Among antipsychotics in general population, there is a significant increase in the utilization of clozapine. In inhospital setting, there is a significant increase of total utilization of antipsychotic drugs, but this is also mainly on the account of atypicals. CONCLUSIONS: The total consumption of psychiatric drugs significantly increased. The utilization of anxiolytic/hypnotic drugs in 2004 reached 60 DDDs/1000 inhabitants/day, which is in collision with the trend in developed countries. It is necessary to form national guidelines for prescribing anxiolytic/hypnotic drugs, in order to rationalize their use. More favourable is the antidepressant (SSRIs in particular) and atypical antipsychotic drugs utilization increase.     

Antidiabetic Drug Utilization in Hungary

Objective: To evaluate the utilization trends of antidiabetics in Hungary.Method: The analysis includes the drugs of antidiabetic therapy which were registered between 1998 and 2002 in Hungary. The consumption of antidiabetic drugs was analyzed by the ATC/Defined Daily Dose (DDD) method. The data used in this study were derived from the National Health Insurance and from MIS Consulting Company.Results: Between 1998 and 2002, the total consumption of antidiabetics increased by 41.8%, and reached 47.59 DDD/1000 inhabitants/day in 2002. The consumption of oral antidiabetics (OAD) increased by 33.41% (33.86 DDD/1000 inhabitants/d ay in 2002), while in the case of insulin the increase was 67.8% (13.74 DDD/1000 inhabitants/day). Sulphonylureas were the most frequently used class (21.11 DDD/1000 inhabitants/day in 2002). Glibenclamide was the most frequently used antidiabetic drug (12.63 DDD/1000 inhabitants/day in 2002).Conclusion: The insulin class had greater emphasis in therapy. Among OAD, the consumption rate of sulphonylureas decreased and the consumption rate of Biguanides and acarbose increased. By 2002 metformin replaced 90% of the buformin in use. The limited effect of therapeutic recommendations could explain these changes, although the out-of-date buformin and the non-micronized glibenclamide were still in use in 2002.     

Treatment of Community‐Acquired Pneumonia in Adults: Analysis of the National Dispensing Database

Crude national ambulatory antibiotic dispensing data (2007–2011) of adult patients (aged between 20 and below 65 years) with CAP were obtained and expressed as DDD per 1000 inhabitants and per day (DID). European quality indicators of antibiotic prescribing were calculated and adherence rate to the national CAP guideline was assessed. Antibiotic use for CAP in adults ranged between 0.27 and 0.30 DID in various years. The most frequently used antibacterials were levofloxacin, co‐amoxiclav and clarithromycin. Antibiotic use in CAP was compliant with the European recommendations in 6.4% in 2007, which decreased to 4.9% by 2011, in contrast to the optimal compliant range of 80–100%. The consumption of fluoroquinolones mounted up to ~40% in both genders, which exceeded the recommended range (0–5%) substantially. National guideline also favoured the use of macrolides in the empiric therapy of CAP in otherwise healthy adults; hence, guideline‐concordant antibiotic use ranged between 24.0–32.3%. Agents that were contra‐indicated in the empiric therapy of CAP were also used in 6.5–9.0% in various years. These data reflect some worrisome figures and trends in the outpatient antibiotic treatment of adults with CAP. Clarified and updated national guidelines focusing on outpatients and incentives/regulations to increase guideline concordance are warranted.     

Age standardisation of drug utilisation: comparisons of different methods using cardiovascular drug data from Sweden and Spain

In drug utilisation studies, the units of defined daily doses (DDD) and DDD/1000 inhabitants per day standardise for differences in dosage and population size, but not for age-related differences in drug utilisation. There is no consensus as to how age standardisation of DDD data should be carried out. Using cardiovascular drug utilisation data from Sweden and Spain, the current study compared the outcome of different methods of age standardisation. Both indirect methods (based on a comparison of observed and expected drug usage) and direct methods (using different weighting for the age categories) were used.The largest impact of standardisation was seen for diuretics. The crude rate for men and women combined was 26 DDD/1000 inhabitants per day in Costa de Ponent and 98 DDD/1000 inhabitants per day in Värmland. The corresponding figures when standardising the Costa de Ponent population were 26 and 58, respectively. Using the equivalent average rate (EAR) method, the rate for Värmland was 129 DDD/1000 inhabitants per day. Lesser but still important differences were found for -adrenoceptor and antihypertensives.Thus, the results of standardisation differ depending on which method is used and which drugs are evaluated. EAR is recommended for direct standardisation because of its ease of use and because it does not require the choice of a standard population.     

Benzodiazepine Dependence in Singapore

The study, conducted in 2003–2005, was aimed at investigating the pattern of benzodiazepine (BZD) use and the attitudes and perceptions of doctors' prescribing practices by a hundred BZD-dependent patients in Singapore. Data on patients' demographic characteristics, psychiatric profiles, patterns of BZD use, and perceptions about doctors' prescribing practices were collected. A benzodiazepine dependence self-report questionnaire (Bendep-SRQ) was also administered. The mean age of the study participants was 39.4 years (SD = 9.7); 88% were Chinese, 58% were males, 46% were married, 48% had received secondary school education, and 48% were unemployed. BZD abuse in Singapore is contributed to by both doctor-shopping behavior and doctors' prescribing practices. Doctors need training on the assessment and management of BZD dependence. The study's limitations were noted. This project was supported by an institutional block grant received from the National Medical Research Council, Singapore.     

Use of desmopressin in elderly patients in Denmark

PURPOSE: Against the background of the approval of the use of desmopressin in the treatment of nocturia in adults, the aim of the present study was to describe patterns of its use in elderly patients in Denmark from 2000 to 2004. METHODS: Data were obtained from the Danish Register of Medicinal Product Statistics on nationwide sales of desmopressin and two commonly used measures of drug utilisation: 1-year prevalence (number of patients treated at least once during 1 year/1000 inhabitants) and therapeutic intensity (Daily Defined Doses (DDD)/1000 inhabitants/day). RESULTS: In 2002, the 1-year prevalence rose ranging from a 5-fold increase among men aged 60-69 years to a 14-fold increased prevalence in men >/=90 years. In women, relative increases of the same magnitude were noted. Similarly, marked increases of the therapeutic intensities were observed in both men and women in 2002, this was followed by steady growth in most age groups. By the end of the study period in 2004, the highest therapeutic intensities were observed in men (1.06 DDD/1000 inhabitants/day) and women (0.92 DDD/1000 inhabitants/day) aged 80-89 years. CONCLUSION: After approval in 2002 of the use of desmopressin in the management of nocturia in adults, a substantial increased utilisation was observed in patients >/=80 years. Given the high prevalence of risk factors for hyponatremia in these elderly patients, the pattern of utilisation is noteworthy and may need to be reviewed.     

Utilisation of antibiotics in young children: opposite relationships to adult educational levels in Danish and Swedish counties

Background Antibiotic utilisation varies profoundly among and within countries, and the extent of antibiotic utilisation correlates with the frequency of bacterial resistance, particularly among children. Hence, it is important to assess which factors may influence prescribing. In addition to variations in morbidity, health-care organisation, drug regulatory and supply systems, prescriber's attitudes, parents' behaviour, attitudes and socio-economic positions seem important. We compared socio-economic position (educational level of adults) and antibiotic utilisation in children in the municipalities within a Danish and a Swedish county which are geographically close, have similar social and economic development, and similar drug regulatory and supply systems.Methods Data on antibiotic utilisation (1998), expressed in defined daily doses per 1000 inhabitants per day (DDD/TID), were obtained from the Copenhagen County Health Insurance register and from the National Corporation of Swedish Pharmacies. Data on municipal educational levels were obtained from Statistics Denmark and Statistics Sweden.Results The utilisation of antibiotics in 0- to 6-year-old children was higher in the Swedish than in the Danish county but varied between the municipalities within both the Swedish (9.6–17.7 DDD/TID) and the Danish (8.0–12.9 DDD/TID) counties. Most notably, utilisation rates correlated negatively with the education levels in the Danish (r=–0.539, P=0.021) but positively in the Swedish (r=+0.390, P=0.025) municipalities.Conclusion The observed variations in antibiotic prescribing may reflect different parental and/or prescriber attitudes towards use of antibiotics and they emphasise that antibiotic prescribing is influenced by factors other than the prevalence of bacterial infections. Relationships between socio-economic position (educational level) and drug utilisation should not be generalised from one area to another.