Drug-induced progressive multifocal leukoencephalopathy: Lessons learned from contrasting natalizumab and rituximab.

Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were received sooner after occurrence. This study serves as an important reminder that spontaneous reports should only be used with great caution to quantify and compare safety profiles across products over time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety.

Dispensing of potentially teratogenic drugs before conception and during pregnancy: a population-based study.

OBJECTIVE: To study the dispensing of potentially teratogenic drugs in the 12-month period before as well as during pregnancy in the Netherlands. DESIGN: Population-based study. SETTING: A cohort was constructed using a linkage between the PHARMO Database Network and the Netherlands Perinatal Registry (PRN). POPULATION: A total of 203 962 Dutch pregnancies reported between 1999 and 2007 METHODS: Drug-dispensing information was identified from the PHARMO Database Network for the 12-month period before conception and during pregnancy. Drugs with either a Swedish FASS 'D' classification, an Australian ADEC or American FDA 'D' or 'X' classification were considered potentially teratogenic (n = 202). MEAN OUTCOME MEASURES: Proportion of pregnancies that received potentially teratogenic drugs in the 12-month period before and during pregnancy and specific for the risk category X drugs and newly initiated drugs. RESULTS: Sixteen percent of the pregnancies received a potentially teratogenic drug in the 12-month period before and 5.07% during pregnancy. Doxycycline and paroxetine were most frequently received during pregnancy by 1.01% and 0.85% of women, respectively; 0.66% of the women received a risk category X drug during pregnancy which most frequently consisted of triptorelin (0.25%), norethisterone (0.22%) and simvastatin (0.03%). Fifty-three percent of the women who received a potentially teratogenic drug during pregnancy received this for the first time during the study period. These percentages were heterogeneous between therapeutic drug classes. CONCLUSIONS: Five percent of the pregnancies received a potentially teratogenic drug during pregnancy and 0.66% received a drug from the risk category X. It may be possible to reduce these proportions when reasons for prescription have been explored.

Risk management plans as a tool for proactive pharmacovigilance: a cohort study of newly approved drugs in Europe.

Risk Management Plans (RMPs) have become a cornerstone in the pharmacovigilance of new drugs in Europe. The RMP was introduced in 2005 to support a proactive approach in gaining knowledge on safety concerns through early planning of pharmacovigilance activities. However, the rate at which uncertainties in the safety profile are resolved through this proactive approach is unknown. We therefore examined the evolution of safety concerns in the RMP after initial approval for a selected cohort of 48 drugs, to provide insight into the knowledge gain over time. We found that 20.7% of the uncertainties existing at approval had been resolved 5 years after approval. Because new uncertainties were included in the RMP at a similar rate, the overall number of uncertainties remained approximately equal. The relatively modest accrual of knowledge, as demonstrated in this study through resolution of uncertainties, suggests that opportunities for optimization exist while ensuring feasible and risk-proportionate pharmacovigilance planning.

When direct health-care professional communications have an impact on inappropriate and unsafe use of medicines.

Serious safety issues relating to drugs are communicated to health-care professionals via Direct Health-Care Professional Communications (DHPCs). We explored which characteristics determined the impact of DHPCs issued in the Netherlands for ambulatory-care drugs (2001-2008). With multiple linear regression, we examined the impact on the relative change in new drug use post-DHPC of the following: time to DHPC, trend in use, degree of innovation, specialist drug, first/repeated DHPC, DHPC template, and type of safety issue. DHPCs have less impact on use of specialist drugs than nonspecialist drugs (P < 0.05). The DHPCs' impact increased after availability of a template emphasizing the main problem (P < 0.05), and for safety issues with a risk of death and/or disability (both P < 0.05) (adjusted R² = 0.392). Risk communication can be effective, specifically in case of well-structured information, and very serious safety issues. Effectiveness may improve by tailoring DHPCs and adding other communication channels, for example for drugs that are increasingly being used.

Impact of safety-related regulatory action on drug use in ambulatory care in the Netherlands.

The effect of Direct Healthcare Professional Communications (DHPCs) informing health-care providers of serious drug safety issues has been questioned. The aim of this study was to evaluate the impact of DHPCs on drug use.Nationwide dispensing data for the period 2000­2008 for new users of 46 drugs with one or more DHPCs were assessed. Impact on short-term volume of use was evaluated with regression models, and the presence of long-term changes in use was evaluated with interrupted time series analyses incorporating preexisting trends. The short-term prescription level was lower post-DHPC in 28 (48.3%) of 58 cases. Twenty (34.5%) DHPCs resulted in long-term changes in use. A long-term mean reduction in use was observed in 26.7% of cases (95% confidence interval, −15.2 to −38.2%).Long-term changes in use were not significantly related to preexisting trends in use. Although short- and long-term decreases in use were observed after only half and a third of DHPCs, respectively, the decrease was substantial.

Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study.

AIMS/HYPOTHESIS: Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. METHODS: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. RESULTS: Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. CONCLUSION/INTERPRETATION: Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.

Sudden deaths following influenza vaccination: can this be expected?

BACKGROUND: In November 2006, four Dutch people, aged 53, 58, 80 and 88, died unexpectedly on the day they had received their influenza vaccination. A rapid epidemiological assessment was needed to quantify the risk of a causal association. METHODS: Using routinely available data on age-stratified population size, cardiovascular mortality, and vaccination coverage, a daily rate and daily risk of sudden death per 5-year age-group was calculated. A cumulative probability that at least one person in four specific age-groups would die on the day of vaccination was calculated using a binomial distribution. No assumptions on deaths in other age groups were included. RESULTS: The overall likelihood that at least one person in each of the four age categories 50-54, 55-59, 80-84 and 85-89 would die suddenly on the day of influenza vaccination in the Netherlands was calculated to be 0.016. This was 330 times more likely than nobody dying in each of these categories, and 45 times less likely than the most probable outcome. CONCLUSION: We concluded that there was a small but real chance of the four deaths occurring without a causal link to the vaccination. Policy decisions regarding unexpected deaths following vaccination can benefit from a rapid epidemiological evaluation.

[Adverse events following influenza vaccination: reaction to specific reports and the necessity of a central registration system]. / Bijwerkingen na influenzavaccinatie: reactie op enkele incidenten en het belang van centrale registratie.

The influenza vaccine is considered safe, but information on vaccine-related adverse events is limited and a nationwide overview of adverse events is lacking. In 2006, after deaths occurred in Israel and the Netherlands following influenza vaccination, the Dutch Ministry of Health, Welfare and Sport (VWS) asked the National Institute for Public Health and the Environment (RIVM) twice for a recommendation regarding the continuation of the national vaccination campaign. After 4 deaths were reported in Israel in October 2006 following administration of Vaxigrip, the Dutch vaccination campaign was suspended for one week. One month later, 4 additional deaths were reported after influenza vaccination in the Netherlands. The newly appointed outbreak management team concluded that a causal relationship between vaccination and the deaths was highly unlikely, based on data regarding the individual cases, background mortality rates and prior reports of adverse events. Further suspension of the vaccination campaign was deemed unnecessary this time. A centralised nationwide registry of adverse events has since been established to provide further insight into the incidence of adverse events following influenza vaccination. Physicians are advised to report potential adverse events following influenza vaccination to the Netherlands Pharmacovigilance Centre Lareb (www.lareb.nl).

The incidence of sudden cardiac death in the general population.

BACKGROUND AND OBJECTIVES: To determine the incidence of sudden cardiac death in a general (Dutch) population. METHODS: Cohort study in the Integrated Primary Care Information (IPCI) project, a database with all medical data from 150 general practices in The Netherlands. The study population comprised 249,126 subjects with a mean follow-up of 2.54 years. RESULTS: In this period 4,892 deaths were identified, 582 of which were classified as (probable) sudden cardiac death. The overall incidence of sudden cardiac death in this population was 0.92 cases per 1,000 person-years (95%CI: 0.85-0.99). The risk was 2.3-fold higher in men than in women, and increased with age. The incidence of sudden cardiac death peaked in October and was lowest in August. CONCLUSIONS: The incidence of sudden cardiac death in the general Dutch population was almost 1 per 1,000 person-years per year during the period 1 January, 1995 to 1 April, 2001. Most of the cases occurred at home.