Pharmacoepidemiology and Drug Safety

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Online ISSN: 1099-1557
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Article
To compare mortality and the incidence of hospitalization for myopathy, rhabdomyolysis, acute renal failure and acute liver injury in patients receiving rosuvastatin and those taking other statins. Patients prescribed a statin that they had not used before were selected from the Saskatchewan Health Databases (SHD) and followed up from 1 July 2003 until 31 March 2005. We studied 10,384 patients on rosuvastatin and 14,854 taking other statins. Two cases of myopathy were identified (one on rosuvastatin, one on another statin). The relative risk (RR) of myopathy in patients currently taking rosuvastatin compared with other statins was 1.31 (95% confidence interval [CI]: 0.13-13.41). Two cases of rhabdomyolysis were detected among current rosuvastatin users (incidence: 2.9 [95% CI: 0.8-10.7] per 10 000 person-years). No cases of acute liver injury occurred among rosuvastatin patients. Seventeen cases of acute renal failure were identified (five among rosuvastatin users, 12 taking other statins). The RR of acute renal failure in current rosuvastatin users compared with other statins was 0.49 (95% CI: 0.16-1.50). We identified 285 deaths during the study period (87 among rosuvastatin users, 198 taking other statins). The RR of death in current rosuvastatin users compared with other statins was 0.42 (95% CI: 0.32-0.57). We found no evidence that patients prescribed rosuvastatin were at greater risk of the study outcomes than patients prescribed other statins. There was no evidence of increased mortality among patients taking rosuvastatin, even after allowing for age, sex and prior statin use.
 
Article
Clinical benefits of statin therapy are accepted, but their safety profiles have been under scrutiny, particularly for the recently introduced statin, rosuvastatin, relating to serious adverse events involving muscle, kidney and liver. Therefore, a historical cohort study was performed to evaluate the association between rosuvastatin versus other statin use and the incidence of rhabdomyolysis, myopathy, acute renal failure and hepatic impairment. Incident users of rosuvastatin or other statins in 2003-2004 and a cohort of patients not prescribed statins were included from the PHARMO database of >2 million Dutch residents. Cases of hospitalisations for myopathy, rhabdomyolysis, acute renal failure or hepatic impairment were identified for these cohorts. Potential cases were validated through a multi-step process using data obtained from hospital records. Additionally, cases of all cause deaths were identified from certification alone. In 2003 and 2004, 10,147 incident rosuvastatin users, 37,396 incident other statin users and 99,935 patients without statin prescriptions were included. There were 26 validated outcome events in the three cohorts including one case each of myopathy (other statin group) and rhabdomyolysis (non-treated group). There were no significant differences in the incidence of outcome events between rosuvastatin and other statin users. This study indicated that the number of outcome events is less than 1 per 3000 person years. This study in more than 45,000 Dutch statin users suggests that rosuvastatin does not lead to an increased incidence of rhabdomyolysis, myopathy, acute renal failure or hepatic impairment compared to other statins.
 
Article
To compare mortality and the incidence of hospitalization for myopathy, rhabdomyolysis, acute renal failure and acute liver injury in patients receiving rosuvastatin and those taking other statins. Patients prescribed a statin that they had not used before were selected from the UK General Practice Research Database (GPRD) and followed up from 1 April 2003 to 31 December 2005. We studied 10 289 patients on rosuvastatin and 117 102 taking other statins. No cases of myopathy, rhabdomyolysis or acute liver injury occurred among rosuvastatin users. In those taking statins other than rosuvastatin, the incidence of myopathy was 0.4 (95% confidence interval (CI): 0.1-0.9), of rhabdomyolysis was 0.4 (95%CI: 0.1-0.9) and of acute liver injury was 0.4 (95%CI: 0.2-1.0), per 10 000 person-years. Fourteen cases of acute renal failure were identified (two among rosuvastatin users and 12 among other statin users). Among current users, the relative risk (RR) of acute renal failure in rosuvastatin users compared with other statin users was 1.16 (95%CI: 0.15-9.03).We identified 3232 deaths during the study period (173 in the rosuvastatin-treated group and 3059 in the other statin group). The RR of death associated with current use of rosuvastatin compared with other statins was 0.55 (95%CI: 0.44-0.68). We found no evidence that patients prescribed rosuvastatin were at greater risk of these outcomes than patients prescribed other statins. There was no evidence of increased mortality among patients taking rosuvastatin, even after allowing for age, sex and prior statin use.
 
Article
Diarrhoea is one of the most frequently reported adverse events during proton pump inhibitor use in any setting. Because of the limited available information, this study was set up with the aim of assessing the incidence and characteristics of diarrhoea and to investigate possible associated co-factors in proton pump inhibitor users in daily practice. Data were used from a prospective, observational study in which 10,008 lansprazole users were followed over time (1994-1998). The study was designed according to the SAMM guidelines. A nested case-control design was used to compare proton pump inhibitor users reporting diarrhoea with those reporting no diarrhoea. The frequency of diarrhoea was 3.7% and the incidence density 10.7 per 1000 patients months of proton pump inhibitor use. The diarrhoea was most commonly loose and occurred on average 4.4 times per day. The analysis of co-factors revealed that patients with concomitant use of oral antibiotics and patients reporting neurological and/or dermatological adverse events, were at risk of developing diarrhoea during proton pomp inhibitor use. In conclusion, diarrhoea was as frequently reported in our study as in clinical trials and observational data of lansoprazole users. We found the concomitant use of oral antibiotics and the reporting of certain other adverse events to be associated with the reporting of diarrhoea during lansoprazole use. Although a relationship with the proton pump inhibitor intake seemed very plausible, we recommend that use of concomitant medicines as a cause of diarrhoea must be taken into consideration in lansoprazole users.
 
Article
This study compared the effectiveness of rosuvastatin (RSV) to other statins prescribed in clinical practice in prevention of cardiovascular (CV) events. This longitudinal inception cohort study, using Thomson Healthcare's MarketScan databases, included patients aged > or = 18 starting statin therapy during August 2003-December 2005. Patients were followed until 90 days after index statin monotherapy exposure, start of another lipid-lowering therapy, an event, end of eligibility, or end of study. The primary endpoint was a composite of CV death (in-hospital only), myocardial infarction, unstable angina, coronary revascularization, stroke, and carotid revascularization. Adjusted time-to-event analyses incorporating a propensity score covariate were used, and analyses were stratified by duration of statin exposure. Among 395 039 patients who met inclusion/exclusion criteria, 12% initiated RSV, and 9622 (2.4%) of the total patient population experienced an outcome event. The median duration of statin treatment and follow-up was 100 days and 180 days, respectively. No statistically significant difference in CV event rates between RSV and other statins was observed after adjustment for demographics and medical/prescription history (HR = 0.99, 95%CI = 0.93-1.06). However, with longer exposure time, there was a suggestion of increased benefit with RSV compared to other statins. The primary analysis showed similar incidence rates of CV-related events between the statin cohorts over a median of 180 days of follow-up.
 
Article
Purpose—Soon after the introduction of the proton pump inhibitor, lansoprazole, a 4-year observational follow-up study was started to evaluate the safety of this drug in naturally-occurring groups of patients in The Netherlands. Results of this study were compared with clinical trial data and the limited published data from observational studies. Methods— prospective, observational study in which patients with a new episode of lansoprazole use were followed during the medication period for a maximum of 2 years. All (adverse) events during use were documented by the prescriber, irrespective of possible association with lansoprazole therapy. Results— total of 805 general practitioners (GPs) and 266 specialists provided a total of 10,008 lansoprazole users with a broad range of diagnoses. Of all patients, 17.4% reported one or more adverse events. The profile and frequency of reported adverse events was consistent with results from clinical trials and other observational studies. The most frequently reported adverse events were diarrhoea, headache, nausea, skin disorders, dizziness and generalized abdominal pain/cramps. There was no new evidence of rare adverse events. Furthermore, no lansoprazole-related unlabelled adverse events of clinical significance were recorded. Conclusions— Although the patterns of use of lansoprazole in daily practice deviated to some extent from the diagnoses in the information leaflet, lansoprazole was found to have a highly acceptable safety profile in this large naturally-occurring group of users. Reporting rates were higher soon after introduction of lansoprazole before falling to a lower stable level. Copyright
 
Article
The development of the risk management paradigm for the enhancement of post-marketing approval drug safety carries with it the need for external monitoring of the different approaches used by the sponsor. The concept of a Data Monitoring Committee (DMC), widely used in the management of randomized clinical trials, is adapted to provide this monitoring function. The rationale for the post-marketing approval DMC is considered in the context of the risk management paradigm, as well as in the more traditional post-marketing approval surveillance setting. The composition and operation of the post-marketing approval DMC are considered, as well as the process of implementing the committee. Although the adaptation proposed in this article is focused on the paradigm proposed by the United States Food and Drug Administration, it is likely that it will require modification as risk management is adopted (and adapted) by other health regulators.
 
Article
Herbal medicines are used in health care around the world and may increase in importance. There is much uncertainty, however, with regard to their composition, efficacy and safety. There is substantial evidence that herbal medicines can cause serious adverse reactions, but more data are needed as regard their nature, frequency and preventability. In this respect the Uppsala Monitoring Centre of the World Health Organization can play a crucial role. Better reporting of adverse reactions to herbal medicines is needed, in particular with regard to the precise identity and composition of these products. A consistent use by producers, regulators and reporters of the international Latin binomial nomenclature and the use of the new Herbal Anatomical Therapeutic Chemical (ATC) classification are recommended. Copyright (c) 2000 John Wiley & Sons, Ltd.
 
Article
This study describes the use of psychotropic drugs in a sample of eight Italian psychiatric hospitals. A cross-sectional approach was used to collect information about sociodemographic and clinical characteristics of the inpatient population, and about medications prescribed. Prescribing behaviour in the hospitals was compared using three indicators: the number of patients taking psychotropic drugs, the use of high doses of neuroleptics and the use of multiple neuroleptics. More than a thousand patients were resident in the eight hospitals on the census day, 56% of them males. Half the population had an ICD-X diagnosis of schizophrenia, one third of mental retardation. Sixty-nine percent of the sample was on neuroleptic therapy, nearly 47% on benzodiazepines and 4% on antidepressants. Twenty percent of the sample did not take any psychotropic drug on the census day. After adjustment for sociodemographic and clinical variables, setting-related variables resulted as determinants of psychotropic drug use. These data call for continuing education in psychopharmacology towards a more rational use of drugs; longitudinal audits of clinical practice should be implemented to guide clinicians toward a more rational use of psychotropic drugs.
 
Article
We examined the association between high doses of Epoetin alfa (EPO), which are used to raise and maintain hemoglobin (Hb) levels within target ranges for hemodialysis patients, and short-term mortality risk using multivariable regression and an instrumental variable (IV) analysis. We identified 32 734 patients receiving hemodialysis in 786 facilities from a large US dialysis provider between July 2000 and March 2002 who received care for >4 consecutive months, and had an Hb < 11 g/dL in the third month. We assessed dose titrations following the Hb < 11 g/dL and characterized facilities based on the percentage of patients with dose titrations >25% (instrument). We assessed deaths during the subsequent 90 days and evaluated the EPO dose-mortality association using conventional linear and IV regression. The study population had a mean (SD) age of 60.4 (15.0) years; 48% were white, 42% were black and 51% were male. In unadjusted analyses, high EPO doses were associated with 90-day mortality risk (Risk Difference, RD = 3.0 per 100 persons, 95%CI:2.3-3.6); mortality risk was attenuated after adjustment for confounding (RD = 1.5 per 100 persons, 95%CI:0.8-2.2) and not associated with high EPO dose in the pooled IV analysis, though confidence intervals (CI) were wide (RD = -0.4 per 100 persons, 95%CI:-3.2-2.4). The difference in risk estimates between the adjusted linear regression and the IV regression suggests that the short-term mortality related to EPO dosing may be largely attributable to confounding-by-indication for higher doses. The IV method, which was employed to address the possibility of residual confounding, yielded near null though imprecise effect estimates.
 
Article
Adverse drug events (ADEs) are a common complication of medical care resulting in high morbidity and medical expenditure. Population level estimates of outpatient ADEs are limited. Our objective was to provide national estimates and characterizations of outpatient ADEs and determine risk factors associated with these events. Data are from the National Center for Health Statistics which collects information on patient visits to outpatient clinics and emergency departments throughout the United States. We examined visits between 1995 and 2005 and measured the national annual estimates of and risk factors for outpatient ADEs requiring medical treatment. The national annual number of ADE-related visits was 4 335,990 (95%CI: 4 326 872-4 345 108). Visits for ADEs to outpatient clinics increased over the study period from 9.0 to 17.0 per 1000 persons (p-value for trend < 0.001). In multivariate analyses, factors associated with ADE visits included patient age (OR: 2.13; 95%CI: 1.63-2.79 for 65 years and older), number of medications taken by patient (OR: 1.88; 95%CI: 1.58-2.25 for five medications or more), and female gender (OR: 1.51; 95%CI: 1.34-1.71). Overall, outpatient ADEs resulted in 107,468 (95%CI: 89 011-125 925) hospital admissions annually, with older patients at highest risk for hospitalization (p-value for trend < 0.001). Both patient age and polypharmacy use are risk factors for ADE-related healthcare visits, which have substantially increased in outpatient clinics between 1995 and 2005. The incidence of ADEs has particularly increased among patients 65 years and older with as many as 1 in 20 persons seeking medical care for an ADE.
 
Article
Cigarette smoking is a common habit that is associated with many diseases. Smoking is often an important confounding variable in pharmacoepidemiological studies. The General Practice Research Database (GPRD) is widely used in pharmacoepidemiological research. In this study, we compare data recorded in the GPRD with the smoking history obtained from direct query of general practitioners (GPs) and from a population-based survey. We completed a mailed survey of GPs caring for a random sample of 150 patients with inflammatory bowel disease. The survey asked the GP to categorize the patients smoking status on a specified date. These results were then compared to the data recorded in the GPRD. Smoking status of 225,308 randomly selected GPRD patients without inflammatory bowel disease was compared to the results of a population-based household survey. Completed surveys with usable data were received from GPs on 136 of the 150 patients (91%). The sensitivity and positive predictive value of the database for current smoking were 78% (95% CI: 52-94) and 70% (95% CI: 46-88) respectively. The sensitivity and positive predictive value of former smoking were 53% (95% CI: 28-77) and 60% (95% CI: 32-84) respectively. Current and former smoking rates in the GPRD were 79% and 29% respectively of expected rates according to the population-based survey. Current smoking is more completely recorded in the GPRD than former smoking. These data need to be considered when planning GPRD studies where smoking is an important exposure variable.
 
Article
We surveyed the safety and effectiveness of 13 drug products under the reexamination system in Japan. Until the time of reexamination, a total of 106,328 case reporting forms were collected in the drug use investigations, while 1340 adverse drug reactions (ADRs) were reported in the spontaneous case reporting on ADRs. In the drug use investigations, the data were primarily obtained on the incidence of unexpected ADRs and the incidence of ADRs in special patient populations. The spontaneously reported ADR provided the data on serious and unexpected ADRs. We established proper use of the 13 products by examining the data for significant risk factors for serious ADRs, including agranulocytosis, jaundice, hypotension, and QT prolongation. We revised the package inserts of the 13 products with the new safety information a total of 50 times and passed on the revisions to health care professionals. We also assessed the safety and effectiveness of the 13 products compared with that before marketing. We summarized the data and submitted them to the Japanese Ministry of Health and Welfare (JMHW). For all 13 products, the same indications and dosage and administration as those approved previously were approved at the reexamination.
 
Article
To evaluate the effect of the consumption of benzodiazepines at age 40-42 years on prescription of opioids later in life. A cohort of 6707 men and 6683 women aged 40-42 years reported no use of analgesics in health surveys in 1985-1989. This cohort was linked to the Norwegian prescription database (NorPD) and their prescriptions of opioids during 2004-2006 were analysed. Low-high, moderate-high and high prescription frequency of opioids were defined as at least 6, 12 or 16 prescriptions during January 2004-December 2006. Non-steroid anti-inflammatory drugs (NSAIDs) were used as comparators. The unadjusted odds ratios (ORs) for low-high prescription frequency of opioids for men and women using benzodiazepines were 3.8 (95%CI 2.5-5.7) and 3.4 (2.6-4.4), respectively, as compared with non-users. After adjustment for alcohol, smoking habits and socio-economic variables, the ORs were lowered for both sexes: 2.6 (1.7-4.0) in men and 2.5 (1.9-3.3) in women. The adjusted OR for those with high prescription of opioids was higher for both sexes: 4.5 (2.4-8.5) in men and 3.7 (2.4-5.7) in women. A stratified analysis revealed no relationship between benzodiazepine use and later low and moderate prescription frequency of opioids among teetotallers. The adjusted ORs for low-high prescription frequency NSAID use for men and women using benzodiazepines were 1.6 (1.1-2.4) and 1.6 (1.3-2.0), respectively. In this study population, a history of benzodiazepine use raised the chance of being prescribed opioids later in life among those who also used alcohol.
 
Article
Iodine-131-labeled lipiodol is currently licensed for unresectable hepatocellular carcinoma with portal thrombosis. It is thought to be well tolerated. Cases of interstitial pneumonia have been reported, but their frequency (≈2%) has not been well estimated. Quantifying adverse drug event frequency requires an appropriate statistical approach because standard methods are biased. To estimate the frequency of interstitial pneumonia in patients with hepatocellular carcinoma receiving iodine-131-labeled lipiodol, we conducted a systematic review of English articles using MEDLINE and EMBASE. All types of articles were considered except case reports. Primary outcome measure was symptomatic interstitial pneumonia based on investigators' judgment. All pooled analyses were based on a random effects meta-analysis model using an exact likelihood approach based on the binomial within-study distribution. Ten studies, including 142 patients, used low activity per dose, ranging from 0.3 to 1.1 GBq. No respiratory adverse event was noticed in these studies. Eighteen studies, including 542 patients, evaluated higher activity per dose, around 2.2 GBq; 24 cases of interstitial pneumonia were reported in these studies. Estimated frequency of interstitial pneumonia was 1.6% (95%CI, 0.4-6.4%) after one high dose and 4.1% (95%CI, 1.0-16.0%) after two or more high doses. The frequency of interstitial pneumonia appears higher and more precise than previously estimated. The risk appears to be related to the number of injections and the dose level per injection. Generalized linear mixed models using the exact binomial within-study distribution initially described to summarize data on diagnostic evaluation could be relevant for drug-related adverse reaction frequency assessment.
 
Article
Retrospectively investigate potential associations between rosiglitazone and congestive heart failure (CHF) and, separately, events of myocardial ischemia. Data from 14 237 individuals in 42 short-term, double-blind, randomized studies of rosiglitazone versus placebo or active diabetes medications were analyzed across seven treatment comparisons using an exact logistic regression model, adjusted for number of major cardiovascular risk factors and duration of exposure. CHF incidence ranged 0-1.27% (SAEs) and 0.12-2.42% (all AEs) with rosiglitazone versus 0.07-0.75% (SAEs) and 0.25-1.36% (all AEs) with control. Higher odds ratios (95%CI) were observed for CHF SAEs with sulfonylurea- and insulin-containing combinations: rosiglitazone monotherapy versus placebo, 0.25 (<0.01-4.75); rosiglitazone monotherapy versus sulfonylurea/metformin monotherapy, 0.23 (<0.01-2.14); sulfonylurea + rosiglitazone versus sulfonylurea monotherapy, 0.95 (0.01-75.20); metformin + rosiglitazone versus metformin monotherapy, 0.60 (0.00-8.28); metformin + rosiglitazone versus metformin + sulfonylurea, 1.04 (0.39-2.86); sulfonylurea + metformin + rosiglitazone versus sulfonylurea + metformin, 3.15 (0.35-150.52); insulin + rosiglitazone versus insulin monotherapy, 1.63 (0.52-6.01). Myocardial ischemia incidence ranged 0.75-1.40% (SAEs) and 1.49-2.77% (all AEs) with rosiglitazone versus 0.21-2.04% (SAEs) and 0.56-2.38% (all AEs) with control. Each comparison had an OR >1, with wide confidence intervals generally including unity. With data pooling, more events of myocardial ischemia were observed with rosiglitazone (2.00%) versus control (1.53%) (HR 1.30, 95%CI 1.004-1.69). CHF incidence may be greater when rosiglitazone is combined with sulfonylureas or insulin. When data were pooled, more events of myocardial ischemia were observed with rosiglitazone versus control. Final results from RECORD will allow a more rigorous evaluation of the cardiovascular safety profile.
 
Article
(1) The scientific study of drug safety is a relatively new discipline. (2) The public may find it difficult to evaluate the risks and benefits of drug therapy. (3) Pursuit of drug safety must be a multidisciplinary exercise, and the International Society for Pharmacoepidemiology (ISPE) provides a valuable focal point. Copyright (c) 2000 John Wiley & Sons, Ltd.
 
Risk windows defined for the analysis of pregnancy outcomes around vaccination
Percentage (95%CIs) of all women reporting all unsolicited adverse symptoms, medically significant conditions, potential immune-mediated diseases and serious adverse events after vaccination (Total vaccinated cohort): 30-day and entire study follow-up periods
Day to onset of 122 potential immune-mediated diseases by MedDRA System Organ Class with onset within 1 year or after any dose of HPV-16/18 vaccine (all study groups (HPV group N = 27 353, Coad group N = 2166, Controls N = 20 504 doses)
Pregnancy outcomes observed at birth that were classified with congenital anomalies
Article
Purpose: The purpose of this study is to further evaluate the safety of the human papillomavirus (HPV)-16/18-AS04-adjuvanted vaccine (HPV-16/18-vaccine Cervarix®, GlaxoSmithKline, Belgium) through a pooled analysis of data from 42 completed/ongoing clinical studies. Methods: Unsolicited adverse events (AEs) were reported for 30 days after each dose. Medically significant conditions, serious AEs (SAEs), potential immune-mediated diseases (pIMDs) and pregnancy outcomes were captured until study completion. Events leading to subject withdrawal were reviewed. Relative risks compared incidences of spontaneous abortion and pIMDs in controlled studies. Results: Thirty one thousand one hundred seventy-three adolescent girls/women received HPV-16/18-vaccine alone (HPV group), 2166 received HPV-16/18-vaccine coadministered with another vaccine and 24 241 were controls. Mean follow-up was 39 months (range 0-113.3). Incidences of unsolicited AEs reported within 30 days after any dose were similar between HPV and Control groups (30.8%/29.7%). During the entire study period, reports of medically significant conditions (25.0%/28.3%) and SAEs (7.9%/9.3%) were also similarly distributed between groups. Deaths were rare: HPV (alone/coadministered) n = 25, controls n = 20 (n = 18 in blinded groups). pIMDs within 1 year were reported by 0.2% of HPV-16/18 vaccinees and controls. For each pIMD event category, no increased relative risks were reported for HPV-16/18 vaccinees versus controls. Coadministration did not change the overall safety profile. Pregnancy outcomes and withdrawal rates were similar between groups. Conclusions: Analysis of safety data arising from 57 580 subjects and 96 704 HPV-16/18-vaccine doses shows that the incidences and distribution of AEs were similar among HPV-16/18-vaccine recipients and controls. No new safety signals were identified. The data confirm previous findings that HPV-16/18-vaccine has an acceptable benefit-risk profile in adolescent girls and adult women.
 
Time to onset of potential immune-mediated diseases after vaccination with any dose of HPV-16/18 vaccine (for 137 Preferred Terms in which time-to-onset data were available). Notes: Bubble size is the proportion to the number of reports in any given week (range 1 to 24 cases). Not shown: one case under the neuro-inflammatory system organ class that occurred 189 weeks after vaccination. Other = erythema multiforme; uveitis; Raynaud's phenomenon; Stevens–Johnson syndrome; antiphospholipid syndrome; idiopathic thrombocytopenic purpura; IgA nephropathy; glomerulonephritis rapidly progressive
Reporting rate of the 10 most frequently reported potential immune-mediated diseases reported since launch until 18 May 2007 to 17 November 2011
Observed versus expected* analysis for Guillain-Barré syndrome cases reported in the UK according to Brighton Collaboration Diagnostic Level 17
Article
To summarise post-licensure safety surveillance over more than 4 years of routine use of the human papillomavirus-16/18-AS04-adjuvanted vaccine (HPV-16/18 vaccine: Cervarix®, GlaxoSmithKline, Belgium). We describe global post-licensure passive surveillance data based on routine pharmacovigilance from 18 May 2007 until 17 November 2011 and enhanced surveillance implemented during the 2-year national immunisation programme in the UK (school years 2008-2010). Spontaneous reports from countries worldwide showed a similar pattern for the most frequently reported adverse events after HPV-16/18 vaccination. No patterns or trends were observed for potential immune-mediated diseases after vaccination. Observed incidences of Bell's palsy and confirmed Guillain-Barré syndrome were within the expected range in the general population. Outcomes of pregnancy in women who were inadvertently exposed to HPV-16/18 vaccine during pregnancy, were in line with published reports for similar populations. Enhanced surveillance of adverse events in the UK triggered a review of cases of anaphylaxis, angioedema and syncope reports, leading to an update to the prescribing information. Collaborative partnerships between industry and national regulatory agencies facilitated rapid notification and transfer of safety information, allowing for rapid responses in the event of a safety signal of adverse event of concern. More than 4 years of post-licensure experience may provide confidence to providers and the public about the safety profile of HPV-16/18 vaccine in routine use. The safety profile appears to be consistent with pre-licensure data reporting that HPV-16/18 vaccine has an acceptable benefit-risk profile in adolescent girls and women. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.
 
Article
Recent observational studies suggest that various drugs are remarkably effective at reducing morbidity and mortality. These cohort studies used a flawed approach to design and data analysis which can lead to immortal time bias. We describe the bias from 20 of these studies and illustrate it by showing that unrelated drugs can be made to appear effective at treating cardiovascular disease (CVD). The illustration used a cohort of 3315 patients, with chronic obstructive pulmonary disease (COPD), identified from the Saskatchewan Health databases, hospitalised for CVD and followed for up to a year. We used the biased approach to assess the effect of two medications, namely gastrointestinal drugs (GID) and inhaled beta-agonists (IBA), both unknown to be effective in CVD, on the risk of all-cause mortality. We also estimated these effects using the proper person-time approach. Using the inappropriate approach, the rates ratios of all-cause death were 0.73 (95%CI: 0.57-0.93), with IBA and 0.78 (95%CI: 0.61-0.99), with GID. These rate ratios became 0.98 (95%CI: 0.77-1.25) and 0.94 (95%CI: 0.73-1.20), respectively, with the proper person-time analysis. Several recent observational studies used a flawed approach to design and data analysis, leading to immortal time bias, which can generate an illusion of treatment effectiveness. Observational studies, with surprising beneficial drug effects should be re-assessed to account for this source of bias.
 
Article
Widespread use of and serious adverse effects associated with use of analgesics accentuates the need to consider factors related to analgesic use. The objective of this study was to describe continuous regular analgesics use and examine factors associated with a continuous regular analgesic use. The study was based on data from two surveys and included a random sample of women and men aged 18-45 years from the general Danish population. Information on analgesics use, self-rated health, demographic and lifestyle factors was collected using a self-administered questionnaire. A total of 28,000 women and 33 000 men were invited to participate and 22,199 women (response-rate 81.4%) and 23,080 men (response-rate 71.0%), respectively, were included in the study. Data were analyzed using multivariate logistic regression. We found that 27% of the women and 18% of the men reported a regular monthly use of at least seven analgesic tablets during the last year (continuous regular analgesics use). Besides poor self-rated health we found in both sexes that increasing age, poor self-rated fitness, and smoking were related to a continuous regular analgesics use. Nulliparity, low level of education, overweight/obesity, binge drinking, and abstinence were associated with a continuous regular analgesics use for women, while underweight and marital/cohabiting status were associated with a continuous regular analgesics use only for men. Regular monthly analgesic use during the last year was generally prevalent. Besides self-rated health, several socio-demographic and lifestyle factors were associated with a continuous regular analgesic use, although with some gender differences.
 
Article
A recent report linked methylphenidate (MPH) use in children to cytologic abnormalities in plasma lymphocytes, a possible cancer biomarker. The purpose of this study was to investigate the association of MPH use and childhood cancer risk. Using automated pharmacy databases and the SEER-affiliated cancer registry of the Kaiser Permanente Medical Care Program (KPMCP), we compared cancer rates at 18 sites among 35,400 MPH users who received it before age 20 to rates among KPMCP membership (age, sex, and calendar year standardized). Medical records of MPH exposed cancer cases were reviewed to identify the presence of established risk factors. There were 23 cancers among MPH users, versus 20.4 expected (standardized morbidity ratio, SMR = 1.13, 95% confidence interval (0.72, 1.70)). Given the small number of cancers, site-specific SMR estimates were imprecise. Only one SMR was statistically significant at the p < 0.05 level, which given the number of comparisons is consistent with the absence of a true association at any site. MPH use was associated with increased risk of lymphocytic leukemia (SMR = 2.64 (1.14, 5.20)), based on eight observed cases). The medical records of these exposed cases did not reveal any lymphocytic leukemia risk factors (prior cancer, radiotherapy or chemotherapy, or Down syndrome). Our results are consistent with no moderate or strong association between MPH use and cancer risk in children, although our ability to examine dose and duration of use or risk at specific sites was limited by small numbers. Further study of MPH use and lymphocytic leukemia risk is needed to determine whether our results are due to chance alone.
 
Article
To assess the long-term efficacy and safety of DPP-IV inhibitors therapy versus comparators in patients with T2DM. A comprehensive search for randomized controlled trials (RCTs; ≥24 weeks) was performed. RCTs had to compare DPP-IV inhibitors therapy with placebo, metformin and sulphonylureas + metformin. Inverse variance mean difference (IV-MD) with 95%CI was calculated for the mean HbA1c changes (%) from baseline to (imputed) endpoint. Mantel-Haenszel odds ratio (MH-OR) with 95%CI was calculated for side reactions. Twenty-three RCTs were included. The mean HbA1c changes (%) were as follows: IV-MD, 95%CI = -0.35 [-0.51, -0.19], p < 0.0001 for DPP-IV inhibitors therapy versus comparators, and IV-MD, 95%CI = 0.11 [0.04, 0.18], p = 0.002 for DPP-IV inhibitors + met versus su + met. For hypoglycaemia, MH-OR, 95%CI = 0.13 [0.09, 0.19], p < 0.00001(DPP-IV inhibitors + met vs. su + met). For diarrhoea, MH-OR, 95%CI = 0.77 [0.64, 0.93], p = 0.008 (DPP-IV inhibitors + met vs. met). By comparing DPP-IV inhibitors therapy with comparators, we found 95%CI = 0.00 [-0.01, 0.01], p = 0.49, for the upper respiratory tract infection MH-OR; 95%CI = 0.97 [0.70, 1.34], p = 0.83 for the urinary tract infection MH-OR; and 95%CI = 1.07 [0.94, 1.21], p = 0.30 for nasopharyngitis MH-OR. DPP-IV inhibitors could achieve a long-term effective and safe glycaemic control for use as monotherapy or in combination with metformin. They have low incidences of hypoglycaemia and gastrointestinal side effects. There is no evidence that DPP-IV inhibitors increase the risk of infections. Copyright © 2014 John Wiley & Sons, Ltd.
 
Article
In the 1960s, the Centers for Disease Control and Prevention (CDC) held the investigational new drug (IND) application for the anthrax vaccine and collected short-term safety data from approximately 16,000 doses administered to almost 7000 individuals. While some recent anthrax vaccine safety studies have suggested that women experience more injection site reactions (ISRs), to our knowledge the IND safety data were not previously examined for a gender-specific difference. We identified and analyzed a subset of the IND study data representing a total of 1749 persons who received 3592 doses from 1967 to 1972. Original data collection forms were located and information extracted, including: vaccine recipient's name, age at vaccination, gender, dose number, date of vaccination, lot number, grading of ISR, presence and type of systemic reactions. Overall and gender-specific rates for adverse reactions to anthrax vaccine were calculated and we performed a multivariable analysis. We found an ISR was associated with 28% of anthrax vaccine doses; however, 87% of these were considered mild. Systemic reactions were uncommon (<1%) and most (70%) accompanied an ISR. Our dose-specific analysis by gender found women had at least twice the risk of having a vaccine reaction compared to men. Our age-adjusted relative risk for ISR in women compared to men was 2.78 (95%CI: 2.29, 3.38). Our results for both overall and gender-specific reactogenicity are consistent with other anthrax safety studies. To date, possible implications of these gender differences observed for anthrax and other vaccines are unknown and deserve further study.
 
Article
Spontaneous reporting systems (SRS) have been established to monitor drug safety problems after marketing, especially rare, but serious adverse drug reactions (ADRs). Among these are the skin disorders erythema multiforme (EM), Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The purpose of this study has been to evaluate the data on these serious skin disorders available in a SRS. All reports concerning these diseases submitted to the Danish Committee on ADRs during the period 1968 to 1991 were reviewed according to predefined criteria. Information was often scarce,and the diagnosis of the reporter had to be accepted at face value in 28% of cases. Two hundred cases of EM, 74 of SJS and 29 of TEN were identified. More than 60% of cases were hospitalized. The diseases had fatal outcome in six patients with TEN, three with SJS and a single patient suffering from EM. One hundred and twenty-eight different drugs were reported as causal agents. Major drug groups involved were antibiotics (sulphonamides and penicillins), non-steroidal anti-inflammatory drugs, anti-epileptics and analgesics. Incidence estimates based on spontaneous reports were compared to the incidence according to the literature and data from a nationwide hospital discharge diagnosis register. The reporting fraction for EM and SJS is estimated to 10-30%, and for TEN to 25-50%, but the validity of reports is in some cases difficult to assess owing to lack of detail.
 
Article
The present paper deals with the classification of adverse drug reactions (ADRs) according to today's largely accepted pathomechanisms. The classification system applied, relies primarily on the proposals of Rawlins and Thomson with type A ('augmented') and B ('bizarre') reactions. In the database of the Comprehensive Hospital Drug Monitoring (CHDM) Bern/St. Gallen on 48,005 consecutively hospitalized patients, ADRs had been attributed to 10 different pathomechanisms. These permit a versatile new system, easily adaptable to expanding knowledge. If we look at the 12,785 ADRs registered in the CHDM Bern/St. Gallen from 1974 to 1993, 76% were of type A, 13% of type B, and 11% of a pathomechanism not yet defined (type X). The main subgroups were A1 'not specified' in type A, Ba allergic/immunological and Bpa pseudoallergic/anaphylactoid in type B. Dose-related (A2) and drug-related reactions (A4, intolerance in a restricted sense), drug-to-drug interactions (A5), rebound/withdrawal effects (A6) and secondary reactions (A7) represented smaller subgroups. Patient-related reactions (A3, 'idiosyncrasy' in the strict sense) were not assessed. Today's algorithms for ADRs mainly rely on pharmacological, i.e. type A reactions. For most of the type B reactions adaptations including the experience of allergists, clinical immunologists and infectious disease specialists should be respected.
 
Article
Purpose: Review all the individualized cases of adverse drug reaction (ADR) potentially related to buflomedil, a vasodilator with the indication for peripheral arterial disease (PAD), marketed in Europe since the 1970s but recently suspended by the European Medicines Agency. Methods: A review of all available individualised case safety data relating to oral buflomedil from the buflomedil global safety database (provided by the manufacturer of buflomedil), the worldwide published medical literature, toxicology/poison centres and regulatory authorities. Results: The main ADRs reported were in the cardiovascular (CVS) and nervous systems (NS), grouped under four (MedDRA) System Organ Classes (SOCs): (i) Cardiac disorders; (ii) Vascular disorders; (iii) Investigations; (iv) NS disorders. From an initial cumulative number of 1054 case reports, there were 401 cases of intentional overdose (IOD) of which 63 were fatal, and 137 cases of accidental overdose, with two fatalities, and 516 case reports of ADRs under normal conditions of use of the product at normal therapeutic dosage with 11 fatalities. Overdosage (intentional or accidental) represented 50.9% of cases, with 47.6% of patients <40 years of age. The indications for which these young patients were prescribed buflomedil were not reported in most cases. Conclusions: The main indication of buflomedil is PAD; however, because most cases of IOD occurred in people <40 years of age, where PAD is unlikely, it is possible that buflomedil was prescribed for other indications and/or that it was not directly prescribed to the end user, who rather gained access to the medication prescribed to family members or friends.
 
Androgen types used as a proportion of all androgens used among adult men, Saskatchewan, 1976–2008*. Ever use of an androgen type by a unique man is counted once. Each colored section of a bar represents the proportion of a specific type of androgen used as a proportion of all androgen types used by unique men in each calendar year (thus depicting secular trends in androgen types).
Users of androgens per 1000 adult men per year in province of Saskatchewan,1976–2008*.
Article
Prescription testosterone (T) has limited approved medical indications and is a controlled substance in Canada. Utilization studies in other Westernized countries have revealed sharp increases in T use in recent years. We examined medical use of androgens, including T, over a ≥30-year period among adult (18+) men in a population-based study set in a Canadian juridisdiction of universal health care. Analyses were based on data from electronic records of dispensed prescriptions during 1976-2008 in Saskatchewan, Canada. All formulations of androgens listed in the provincial formulary (oral and injectable) were included. We examined demographics of users, androgen types used, switching patterns, and trends in the annual rate of use over time. There were 11 521 androgen users who were followed for an average of 11.8 years. Overall, 11 types of androgens were used, and there were 86 812 dispensing events. The mean age at first use was 56.4 years (median: 58). Men had 7.5 prescription dispensing events on average (median: 2). The most commonly used formulations were methyl-T (36.2% of users) followed by T-enanthate (32.5%), T-cypionate (22.3%), and T-undecanoate (20.0%). Most users (82%) did not switch among androgen types. The annual rate of use varied substantially over time, with a marked increase observed from 1994 to 1999 and a decrease from 2000 to 2008. Androgen users were largely middle aged and had relatively few dispensings. We hypothesize that observed secular trends in androgen use may align with drug treatment pattern changes for erectile dysfunction, including the advent of phosphodiesterase type 5 inhibitors. Copyright © 2014 John Wiley & Sons, Ltd.
 
Article
Risks and benefits of marketed drugs can be improved by changing their labels to optimize dosage regimens for indicated populations. Such postmarketing label changes may reflect the quality of pre-marketing development, regulatory review, and postmarketing surveillance. We documented dosage changes of FDA-approved new molecular entities (NMEs), and investigated trends over time and across therapeutic groups, on the premise that improved drug development methods have yielded fewer postmarketing label changes over time. We compiled a list of NMEs approved by FDA from 1 January 1980 to 31 December 1999 using FDA's website, Freedom of Information Act request, and PhRMA (Pharmaceutical Research and Manufacturers of America) database. Original labeled dosages and indicated patient populations were tracked in labels in the Physician's Desk Reference. Time and covariate-adjusted risks for dosage changes by 5-year epoch and therapeutic groups were estimated by survival analysis. Of 499 NMEs, 354 (71%) were evaluable. Dosage changes in indicated populations occurred in 73 NMEs (21%). A total of 58 (79%) were safety-motivated, net dosage decreases. Percentage of NMEs with changes by therapeutic group ranged from 27.3% for neuropharmacologic drugs to 13.6% for miscellaneous drugs. Median time to change following approval fell from 6.5 years (1980-1984) to 2.0 years (1995-1999). Contrary to our premise, 1995-1999 NMEs were 3.15 times more likely to change in comparison to 1980-1984 NMEs (p = 0.008, Cox analysis). Dosages of one in five NMEs changed, four in five changes were safety reductions. Increasing frequency of changes, independent of therapeutic group, may reflect intensified postmarketing surveillance and underscores the need to improve pre-marketing optimization of dosage and indicated population.
 
Article
Economic factors, market dynamics, and safety issues are largely responsible for decisions to withdraw pharmaceutical products from the market. In this study, new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) were examined in the USA from 1980 to 2009. Data were obtained from the FDA, Micromedex, Medline, and Lexis-Nexis. Descriptive analyses were used to classify product discontinuations by therapeutic category, time frame for discontinuation, and reason for withdrawal. There were 740 NMEs approved by the FDA during the study period. As of 1 December 2010, the number of drugs discontinued was 118 (15.9%). Discontinuations were the highest for antiparasitic products, insecticides, and repellents (6, 33.3% of approvals), systemic hormonal preparations excluding sex hormones and insulins (5, 33.3%), musculo-skeletal system (11, 32.4%), diagnostic agents (16, 28.1%), and anti-infectives for systemic use (27, 25.2%). Safety was the primary reason for withdrawing 26 drugs (3.5% of approvals). Approximately one in seven approved NMEs were discontinued from the market in the period of 1980-2009. Less than one-quarter (22%) of the total withdrawals were attributed to safety reasons. An ongoing evaluation of new drugs throughout their product life cycle is important to determine their efficacy, safety, and value to society.
 
Article
Non-insulin-dependent diabetes may become a public health problem in the next decade, given the increasing life expectancy of populations and because the baby-boom generation will reach the age at risk. Moreover a modification of the diagnostic criteria may increase the number of diabetic patients. We studied the evolution of diabetes prevalence. A non-specific household survey, performed every 10 years was used. Patients who bought an oral antidiabetic drug during these studies were classified as diabetics. In 1980-81 and 1991-92 the crude diabetes prevalences were not significantly different even if there was a trend to increase (1.27% and 1.41%, respectively). When the 1980-81 prevalence was standardized to the age distribution of the 1991-92 sample, the trend disappeared (prevalence 1980-81:1.35%). There was no increase in an individual's risk of diabetes. However the crude prevalence tended to increase because of the changing age structure of the population. On-going studies are needed to follow the prevalence of diabetes during the next decade.
 
Article
To examine drug-related deaths due to adverse drug reactions between 1984 and 1994. Voluntary reports of deaths due to adverse events as reported to the Adverse Drug Reaction Monitoring Program, Drugs Directorate, Health Protection Branch, Health Canada. Drugs were classified according to the Anatomical, Therapeutic, Chemical (ATC) coding system. Descriptive statistics were utilized. One thousand four hundred and seventeen drug-related deaths were reported (700 male, 685 female, 32 unknown). The mean+/-SD age of patients was 54.6+/-21.7 years (range 1 month-97 years). In total, 2131 medications were implicated as suspect drugs (1.5+/-1.0, range 1-7). The most commonly reported categories of suspect drugs were the nervous system agents (50.6%), followed by cardiovascular system agents (9.0%), general antiinfectives for systemic use (8.8%) and musculoskeletal system agents (8.3%). One thousand and eighty-six deaths were classified as non-suicides. For non-suicide deaths, the most commonly reported suspect drugs were classified as nervous system agents (37.9%), followed by general antiinfectives for systemic use (12.3%), musculoskeletal system (11.5%) and cardiovascular system agents (10.2%). Three hundred and thirty-one (23.3%) reports were identified as suicides. For suicides, the most commonly reported suspect drugs were the nervous system agents (81.1%), followed by the respiratory system agents (8.5%) and the cardiovascular system agents (6.0%). Nervous system agents, musculoskeletal medications and general antiinfectives for systemic use figured prominently in deaths reported to HPB between 1984 and 1994.
 
Article
France is known to have a relatively high prescription rate for medicines. Few studies have investigated drug use among a healthy worker population. The aim of this study was to describe the changing patterns of drug use in French workers since 1986 and to evaluate the impact of programs developed to reduce drug consumption. A cross-sectional survey has been performed every 10 years since 1986 among workers from the Toulouse metropolitan area (Southwestern, France) using an anonymous questionnaire given to workers during their compulsory annual medical visit. Results of the 2006 survey (2213 workers) were compared to those obtained in 1986 and 1996. A multivariate analysis was performed to investigate factors associated to the modification of drug use with time. During the last ten years, prevalence of overall drug consumption decreased (40.7% in 2006 vs. 46.7% in 1996, p < 0.001) in contrast to the increase observed between 1986 and 1996. Since 1986, patterns of drug use have been modified with a decrease in anti-infectious (OR = 0.24) digestive (OR = 0.54), psychotropic (OR = 0.54), endocrine (OR = 0.57) and cardiotropic (OR = 0.68) drug use. In contrast, there was a significant increase in musculosqueletic (OR = 2.16) drug use. Whatever the period, overall drug consumption was related to age, gender or extraprofessional problems. This study illustrates the changing patterns of drug use in a population of workers during the last 20 years and underlines the importance of awareness raising campaigns on prescription patterns.
 
Article
Research using dispensing claims is used increasingly to study post-market medicines use and outcomes. The purpose of this review is to catalogue more than 25 years of published literature using Australia's Pharmaceutical Benefits Scheme (PBS) dispensing records. We searched MEDLINE, PreMEDLINE and Embase and conducted author searches for studies published from 1987 to 2013. Independent reviewers screened abstracts of 3209 articles and reviewed 264 full-text manuscripts. Included studies used PBS dispensing data to measure patterns and/or outcomes of prescribed medicines use or dispensing claims to derive a proxy for a specific disease cohort or health outcome. Of the 228 studies identified, 106 used PBS claims only (56 using claims-level data and 50 using individual-level data) and 63 studies linked individual-level PBS claims to other health data. Most commonly, studies examined trends in drug utilisation (33%), clinician and patient practices (26%), drug use and outcomes (18%) and evaluations of intervention impacts (17%). Sixty-two percent of studies using individual-level data were based on a subset of elderly Australians. Most studies focused on drug classes acting on the nervous system (36%), cardiovascular system (15%) and alimentary tract (11%). Few studies examined prescribed medicines use in children and pregnant women. Pharmaceutical Benefits Scheme claims represent a significant resource to examine Australia's billion-dollar annual investment in prescribed medicines. The body of research is growing and has increased in complexity over time. Australia has great potential to undertake world-class, whole-of-population pharmacoepidemiological studies. Recent investment in data linkage infrastructure will significantly enhance these opportunities. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
 
Article
To describe frequency, seriousness and recovery of the patient in reported suspected paediatric adverse drug reactions (ADRs) in Sweden using data from a nation-wide ADR reporting system. Data from ADR reports submitted to the Swedish Medical Products Agency (MPA) were collected from the database SWEDIS and analysed for the period from 1987 to 2001. All reports with certain, probable or possible causality assessments referring to paediatric patients < 16 years of age were included. In 5771 children an ADR report was documented during the whole 15-year period in a paediatric population of about 1.7 million individuals. The annual reporting frequency was about 385 reports per year. The most frequently reported reactions were application site reaction (24%) followed by fever (12%) and exanthema (6.7%). The clearly most frequently reported group of drugs were the vaccines (63.8%) followed by antibiotics for systemic use (10.1%). The proportion of children that suffered from a serious ADR was 13.0% and that for drug related deaths 0.14%. Nine per cent of the children had not recovered at the time of reporting and 1% recovered with sequelae. A male overrepresentation was observed regarding the total number of reports. About two-third of the reports concerned outpatients less than 4 years of age. In respect of the limited number of paediatric drug safety studies or availability of record-linkage databases, nation-wide reporting systems of ADRs represent a valuable hypothesis generating tool in evaluating the characteristics of ADRs occurring in the orphan paediatric population.
 
Article
Brazilian consumption of psychostimulant anorexigenic drugs--diethylpropion, fenproporex, and mazindol--and of 3,1-fenfluramine was studied, and results are presented in terms of DDDs/1000 inhabitants/day. As of 1988, consumption of these drugs in Brazil was equal to 4.59 DDDs/1000 inhabitants/day; in the following year it had risen by 43.8%. However, if only the population that can afford to buy medicines is considered, actual consumption figures are at least three times higher. Such numbers point to a very high rate of anorexigenic consumption in Brazil, in contrast with other countries where use of these drugs is smaller. It was also found that 68.6% of total consumption in 1988--and 39.4% in 1989--corresponded to prescription formulas prepared by specialized pharmacies, while the remainder was consumed in the form of ready-made medicines produced by pharmaceutical industries. The most used drugs were mazindol in 1988, and fenproporex in 1989; d,1-fenfluramine was the least used of these substances in both years. These reasons are discussed for this increased consumption in Brazil and the absence of an adequate controlling attitude on the part of public health authorities.
 
Article
To present and interpret drug prescription patterns, related to various groups of the population in a Swedish county, in order to estimate the prevalence of drug use in different age groups. Data on prescriptions, dispensed March-May 1988-2002, were combined with population statistics of Halland, a county in the south of Sweden, and analysed. Number of defined daily doses (DDD) per 100 inhabitants and day and prescriptions per 100 inhabitants and 3 months were used as indicators of drug prevalence. The total drug exposure in the population of Halland nearly doubled during the 15-year period. The most frequently used drugs overall, in 2002, were psycholeptics (N05), analgesics (N02), antibacterials (J01) and sex hormones (G03). Nearly 30% of the women of 15-69 years were exposed to sex hormones. Multiplied drug prevalence among people above 60 was found for antithrombotic drugs (B01), agents acting on the renin-angiotensin system (C09), sex hormones (G03), serum lipid reducing agents (C10), antidepressants (N06) and drugs for peptic ulcer and GORD (A02B). The increase in drug prescribing over the 15 years concerned both symptom-related treatments, like hormone replacement therapy, analgesics, antidepressants and drugs for acid-related disorders, as well as preventive treatments, like antithrombotics, lipid-lowering drugs and antihypertensives. The unit DDD/100 inhabitants and day gives a fairly correct measure of the percentage treated for chronic disorders. However, for short-term treatment courses and especially for drug use in children, number of prescriptions/100 inhabitants and adequate period of time, is easier to interpret.
 
Article
Adverse drug reaction surveillance conducted by the US Federal Food and Drug Administration (FDA) is important for detecting new safety information about pharmaceuticals. FDA has sought to stimulate reporting of reactions by practitioners and manufacturers. Over the five years from 1989 to 1993, reporting more than doubled and a total of 421,491 reports were received. This trend continued in 1994. The origin, type of reaction and drug are presented. Most reports are made by health professionals through pharmaceutical manufacturers. About 5% of such reports involve serious reactions to new drugs. Uses and limitations of ADR surveillance are briefly discussed.
 
Article
To update United States steroidal contraceptive use data for the period 1989 to 1994. Pharmaceutical marketing data were used to examine trends in the utilization and distribution of oral contraceptives, Norplant, and Depo-Provera. There were 56.8 million prescriptions for oral contraceptives dispensed through retail pharmacies in 1994. Estrogen and progestin doses remained fairly stable over time. The average ethinyl estradiol dose of formulations was approximately 34 microg per pill. Mentions for oral contraceptives among 35- to 44-year-old women increased. Approximately 169,000 Norplant systems were distributed from 1991 through 1994. More than 1.5 million milliliters of Depo-Provera were distributed from 1993 to 1994. Oral contraceptives remain a popular form of contraception. Parenteral formulations have been rapidly accepted.
 
Article
Information on general practitioners' choices of initial and second-line antihypertensive treatment, and reasons for stopping therapy, are limited. We analysed data on the use of the four main classes of antihypertensive drugs (diuretics, beta-blockers, calcium antagonists and angiotensin-converting enzyme inhibitors) between 1990 and 1995 from an ongoing cross-sectional postal survey of general practitioners' prescribing activity (the New and Change Therapy Enquiry). There were 18,092 new courses and 9424 discontinuations between 1990 and 1995. Diuretics were the commonest first-line choice. Use of beta-blockers first-line decreased significantly in comparison with diuretics during the study period. Switches to calcium antagonists and angiotensin-converting enzyme inhibitors increased. The increased use of newer agents was not explained by increased use for concomitant conditions (diabetes or cardiovascular disease). Diuretics were most often discontinued because of poor efficacy (44% of diuretic stops). In contrast, most beta-blockers (55%), calcium antagonists (64%) and angiotensin-converting enzyme inhibitors (60%) were stopped because of side-effects. In conclusion, use of beta-blockers first-line decreased. Switches to calcium antagonists and angiotensin-converting enzyme inhibitors increased. The reasons may be due to greater perceived efficacy of newer agents rather than increased use for concomitant conditions.
 
Article
In an attempt to curb the rapidly rising costs of primary care prescribing in Ireland, the government introduced a financial incentive scheme in 1993, to encourage general practitioners to restrain their prescribing. To investigate the effects of a financial incentive scheme on GP prescribing in Ireland on prescribing costs and volume, and on some specific therapeutic areas. Prescribing for 3 years before (1990-1992) and 3 years (1993-1995) after the introduction of incentives, based on a defined cohort of 233 general practitioners in the area of one health board. GPs were divided into tertiles based on their performance against their prescribing budgets into 'savers' (generally underspent and received incentive payments), modest overspenders and large overspenders. Savers were always lower cost prescribers than the other groups. They contained their rate and costs of prescribing in contrast to the other groups, e.g. percentage rise in prescribing costs in the year after the introduction of the scheme -7.9%, +1.2% and +7.3% respectively, (P < 0.05) for savers, modest overspenders and large overspenders respectively. This effect was short lived however and was gone by the third year of the study. The financial incentives had a marked effect on prescribing volume and cost on some practices who could achieve targets and hence incentive payments. The incentives had little effect on high spending practices. Such incentive schemes need careful evaluation if they are not to become perverse to the good health of patients.
 
Deaths reported to VAERS by date of death
Article
To examine the fatalities reported to the federally administered Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, in its first 7 years. The working data set included variables such as demographic information, dates of vaccination, adverse event onset and death, vaccines administered, and vaccination facility data. Frequencies for these data and state reporting rates were calculated. A total of 1266 fatalities were reported to VAERS during July 1990 through June 1997. The number of death reports peaked in 1992-1993 and then declined. The overall median age of cases was 0.4 years, with a range of 1 day to 104 years. Nearly half of the deaths were attributed to sudden infant death syndrome (SIDS). The trend of decreasing numbers of deaths reported to VAERS since 1992-1993 follows that observed for SIDS overall for the US general population following implementation of the 'Back to Sleep' program. These data may support findings of past controlled studies showing that the association between infant vaccination and SIDS is coincidental and not causal. VAERS reports of death after vaccination may be stimulated by the temporal association, rather than by any causal relationship.
 
Article
Parkinson's disease (PD) is considerably underdiagnosed in Spain and its treatment relies mainly on levodopa (LD), a drug enjoying good access country-wide. In order to identify regions with the highest potential for improvement in the quality of life of PD patients, we evaluated total sales of levodopa in Spanish provinces during the period 1990-1995, using a reported method. Total annual crude sales in the country were medium-low and increased with time. When adjusted for age and infant mortality rates (IMRs), taken as an index of socio-sanitary development, annual LD sales become stable and similar to those in the reference population, Sweden 1994. Provincial LD use (LDU) showed a wide variation in annual levels and time trends, with a north-south gradient in evidence. Statistically significant clustering was seen, with the lowest crude age-adjusted and age- and IMR-adjusted LD sales in the south-west and moderately high levels in north-central and north-west provinces. The results show that LDU in Spain is medium-low, and that demographic and social factors may underlie geographical differences in LD sales. The remarkably low LDU in selected provinces in the south-west of the country might reflect deficient PD detection and/or treatment amenable to control.
 
Article
Post-licensure experience with a new intranasal inactivated influenza vaccine in Switzerland recently identified an increased risk for Bell's palsy. We reviewed reports in the Vaccine Adverse Event Reporting System (VAERS) to assess if parenteral inactivated influenza vaccines (influenza vaccines) may also increase the risk for Bell's palsy. Reports of Bell's palsy after influenza vaccines in VAERS from 1/1/1991 to 12/31/2001 were identified by searching the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) for 'paralysis facial' and by text string search in the automated database. The text descriptions on each report were reviewed to verify the diagnosis. The proportional reporting ratio (PRR) was calculated to aid signal detection. We found a total of 197 reports of Bell's palsy after receipt of influenza vaccines. The diagnosis was verified for 154 (78.2%), of which 145 (94.2%) had received influenza vaccines alone. The verified reports were submitted from 35 states; 58% of the reports involved persons living in states where the risk of Lyme disease, which can also cause facial paralysis, was low, minimal or none. The PRRs in all age groups exceeded the criteria for a signal of possible association. The highest PRR was 3.91 in the > or = 65 years age group. Our findings revealed a signal of possible association between influenza vaccines and an increased risk of Bell's palsy. A population-based controlled study is needed to determine whether this association could be causal and to quantify the risk.
 
Article
The Women's Health Initiative (WHI) study that documented an unfavorable benefit to risk ratio of Prempro and subsequently an increased risk of stroke with menopausal estrogen prompted us to investigate the use during 1992 through June 2003 of menopausal hormones in the United States. Two pharmaceutical research databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index, were accessed and analyzed. The number of dispensed outpatient prescriptions for oral menopausal estrogens and oral combination estrogen-progestins increased 2.5-fold (153%) from 34.5 million dispensed in 1992 to a high of 87.3 million in 2000. For July 2002 through June 2003, the year following the publication of the results of the WHI trial, prescriptions for these products declined to 59.6 million, a 32% decrease from their peak in 2000. Prescriptions for transdermal estrogen and transdermal combination estrogen-progestin products increased from 5.2 million dispensed in 1992 to their peak of 8.3 million in 2000, and declined 10% to 7.5 million during July 2002 through June 2003. By contrast, prescriptions for oral menopausal progestins rose to 17.5 million in 1995 and then steadily declined. In the year after the WHI, prescriptions for oral progestins decreased 49% to 8.9 million from their peak in 1995. The earlier decline in oral progestin prescriptions was primarily due to the marketing in 1995 of the popular oral combination estrogen-progestin drugs. Prescriptions dispensed for menopausal hormones increased substantially between 1992 and peaked in 2000. By June 2003, prescriptions for oral menopausal estrogens and oral combination estrogen-progestins had declined by about one-third from their peak year.
 
Top-cited authors
Sebastian Schneeweiss
  • Brigham and Women's Hospital, Harvard Medical School
Susan E Andrade
  • University of Massachusetts Medical School
Marsha A Raebel
  • Kaiser Permanente
Sean Hennessy
  • University of Pennsylvania
Nicholas D Moore
  • Université de Bordeaux