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Background: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011. Objectives: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal. Methods: A cross‐sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months. Results: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment. Conclusion: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies acting on the calcitonin gene‐related peptide or its receptor (CGRP‐mabs) are novel drugs for resistant migraine prophylaxis. As CGRP‐mabs cause inhibition of vasodilatation, their use is reserved to patients with no recent history of cardiovascular diseases. We report a case of myocardial infarction associated with erenumab. Case: A 57‐year‐old woman with a familial history of coronaropathy was first treated with erenumab 70 mg for 6 months and then increased to 140 mg. Almost 5 months after, the patient presented chest pain, increased troponin, and abnormal electrocardiogram. A myocardial infarction without coronarography abnormality was diagnosed through MRI. Conclusion: Further evidence is needed to assess the risk of myocardial infarction in patients treated with a CGRP‐mab. In patients over 40 years of age, the risk of coronary or cardiovascular events should be assessed using risk tables or algorithms to take into account cardiovascular risk factors. This may be complemented by appropriate examinations to measure the burden of coronary atherosclerosis, if necessary. [ABSTRACT FROM AUTHOR]

Owing to a broad spectrum and low cost antimicrobial, cotrimoxazole is largely prescribed. However, its use is associated with various adverse drug reactions (ADRs) that warrant to ensure rational prescribing. This study aimed to describe spontaneous reports of cotrimoxazole ADRs and to evaluate the quality of prescription in patients who had ADRs. Suspected cotrimoxazole‐induced ADRs cases reported to the Bordeaux regional pharmacovigilance center (France) during a 5‐year period were described. Seriousness was assessed according to international criteria. Quality of prescription was assessed by compliance with the Summary of Product Characteristics (SPC) and relevance of cotrimoxazole indication. Then, an ADR was considered as preventable if the cotrimoxazole indication was not relevant, or potentially preventable if indication was relevant but the prescription was not compliant with the SPC. A total of 96 cases were analyzed: median age was 60.5 years (range: 4–94); 59.4% of patients were male. ADRs were mostly cutaneous disorders (n = 46) and hematological disorders (n = 25). A total of 60 serious ADRs occurred in 55 patients. Prescribers complied with all SPC recommendations in 21.9% of cases. Indication of cotrimoxazole was relevant or highly relevant in 41 cases. In 58% of cases, the occurrence of a cotrimoxazole‐induced ADR would have been preventable or potentially preventable. In a context of increasing interest for this antibiotic to treat infections due to resistant bacteria, physicians should be more aware of the potential consequences of inappropriate prescribing cotrimoxazole and reserve its use when there is no alternative and under suitable monitoring. [ABSTRACT FROM AUTHOR]

Aims: Analgesics are the most widely used medicines worldwide. In parallel, opioid abuse has increased and is of major concern. The accessibility of pharmacologically powerful medicines and the addictovigilance signals in France about the risk of opiates addiction call for an overview of analgesic use. The objective of this study was to investigate the use of analgesics reimbursed in France over a 10‐year period through its prevalence. Methods: A cross‐sectional study repeated yearly was conducted by using data from the French reimbursement database from 2006 to 2015. Analgesics were classified according to their pharmacological potency: prevalence of use for each category and sociodemographic characteristics of patients treated were analysed. Results: The annual prevalence of analgesic use was high and increased during the study period (59.8%, 253 976 users in 2015). In 2015, prevalence was always higher in women and increased with age, except for those older than 84 years. Peripheral analgesics were the most used (55.3%, 234 739 users). The prevalence of weak analgesic use decreased (21.3%, 90 257 users), mainly due to the definitive withdrawal of dextropropoxyphene in France in 2011, which was not offset by an increase in the consumption of other weak analgesics. For strong analgesics (1.2%, 5129 users), morphine was the most widely used, with a dramatic increase in oxycodone use, especially in the elderly. Conclusion: The prevalence of analgesic use is high: approximately 31 million adults had at least 1 analgesic reimbursed in 2015. The most widely used analgesics were peripheral analgesics, far ahead of opioid analgesics. [ABSTRACT FROM AUTHOR]

Aims: Azacitidine (AZA), a pyrimidine analogue, is validated for high‐risk myelodysplastic syndrome or low‐blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure. Methods: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2‐sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. Results: In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re‐challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2). Conclusion: This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Aims: In 2017, concerns regarding adverse events (AEs) associated with the Mirena levonorgestrel intrauterine device were largely echoed in the media in France. This resulted in a tremendous reporting of AEs to pharmacovigilance centres. The aim of this study was to describe the reporting of AEs regarding Mirena in France and to study the impact of media coverage on this reporting. Methods: All cases reports involving Mirena recorded in the French national pharmacovigilance database from marketing (21 July 1995) until 04 August 2017 were extracted. To allow studying the influence of mediatisation, reports were described separately for the periods preceding and following the observed media coverage peak (15 May 2017). Results: Overall, 3224 reports were considered, 510 (15.8%) recorded before the media coverage peak, and 2714 (84.2%) after. Before the peak, 76.5% of reports originated from health professionals; median time‐to‐report was of 5.5 months (interquartile range: 1.7–18.6), and median number of AEs per report was 1 (range: 1–17). After the peak, 98.6% originated from patients; median time‐to‐report was 21 months (interquartile range: 8.1–45.5), and median number of AEs per report was 6 (range: 1–37). After the peak, most reports mentioned anxio‐depressive disorders (38.8 vs 10.6% before) or sexual disorders (47.3 vs 6.9%). Other emphasised AEs were weight increase (42.3 vs 10.2%) and pain (gastrointestinal, 19.1 vs 3.5%; musculoskeletal, 22.2 vs 4.5%). Conclusion: This study highlighted the importance of mediatisation impact on spontaneous reporting with changes concerning amounts of reports, type of reporter, and type of reported AEs. For Mirena, this led to generate signals regarding anxio‐depressive and sexual disorders. [ABSTRACT FROM AUTHOR]

The article presents case of 64-year-old man treated with Continuous Positive Airway Pressure for obstructive sleep apnoea syndrome for six years and a case of 68-year-old man, with a history of myocardial infarction six months before, complained of dyspnoea, significant fatigue, and frequent awakenings during night. It discusses the need for clinicians to be aware of side effect of ticagrelor and search for central apnoeas in patients complaining from dyspnoea and fatigue during treatment.

Following a severe case of rhabdomyolysis in our University Hospital after a co‐administration of atorvastatin and fusidic acid, we describe this interaction as this combination is not clearly contraindicated in some countries, particularly for long‐term treatment by fusidic acid. All cases of rhabdomyolysis during a co‐administration of a statin and fusidic acid were identified in the literature and in the World and Health Organization database, VigiBase®. In the literature, 29 cases of rhabdomyolysis were identified; mean age was 66 years, median duration of co‐administration before rhabdomyolysis occurrence was 21 days, 28% of cases were fatal. In the VigiBase®, 182 cases were retrieved; mean age was 68 years, median duration of co‐administration before rhabdomyolysis was 31 days and 24% of cases were fatal. Owing to the high fatality associated with this co‐administration and the long duration of treatment before rhabdomyolysis occurrence, fusidic acid should be used if there is no appropriate alternative, as long as statin therapy is interrupted for the duration of fusidic acid therapy, and perhaps a week longer. Rarely will interruption of this sort have adverse consequences for the patient. [ABSTRACT FROM AUTHOR]

Parachuting (also called bombing) is a method of drug delivery where illicit drugs or medicines are ingested after wrapping the substance. There are little data describing parachuting in the literature. To provide a description of this practice, all cases of parachuting reported to the national addictovigilance network up to 31 December 2014 were identified from spontaneous reports and specific surveillance programs. Cases were described according to the type of substance used, patient age and gender, type of complications, context of use and year of the event. Forty-five cases of parachute use were identified and most ( n = 43) occurred after 2011. Patients were mostly men (60%), and mean age was 28.9 years. The context of use, known in 19 cases, was mostly recreational. Complications were present in 24 cases, of which eight were serious. The substance was supposed to be 3,4-methylenedioxymethamphetamine ( MDMA) in the majority of cases (64.4%); research chemicals were more involved in the most recent years. The physical form was mainly granular (51.6%). The wrappers were a cigarette paper (nine cases) and in one case plastic package; in the other cases, the term of parachute was used without further details. The reason for use was not explained in the majority of cases; two patients indicated using a parachute for faster effect than with a methadone capsule. Clinicians should be aware of this delivery form as the results suggest that it is common and can involve a great variability of drugs. [ABSTRACT FROM AUTHOR]

To assess the incidence of hospital admissions related to adverse drug reactions ( ADRs) in France and the frequency of preventable ADRs in France, a prospective study was conducted among a representative randomly selected sample of medical wards in public hospitals between December 2006 and June 2007; all patients admitted during a 2-week period were included. An ADR-related hospitalization case was defined as a hospital admission because of an ADR, and an independent committee reviewed and validated all potential cases. Preventability was assessed using the French ADR preventability scale. Data were extrapolated to the population of France. Among 2692 admissions, 97 were related to an ADR (incidence 3.6%, 95% confidence interval, CI [2.8-4.4]). Patients admitted for an ADR were significantly older than those admitted for other reasons ( P < 0.001). A third (32.0%) of ADR-related hospitalizations were 'preventable', 16.5% 'potentially preventable'. Drug interactions accounted for 29.9% of ADR-related hospitalizations. The most frequent causes of ADR-related hospitalizations were vascular disorders (20.6%), mainly bleeding complications, central nervous system disorders (11.3%), gastrointestinal disorders, and general disorders (9.3%). Antithrombotic and antineoplastic agents were the most frequently involved (12.6% each), followed by diuretics and analgesics (9.0% each). Vitamin-K-antagonists ( VKAs) were the most common drugs associated with admission. The estimated annual number of ADR-related hospitalizations in France was 143 915 (95% CI [112 063-175 766]). ADRs were a significant cause of hospital admission in 2006-2007, in particular those due to VKAs. As new oral anticoagulants ( NOACs) have been marketed, more attention needs to be paid to ensure a safe use of antithrombotic agents. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose To test an automated method to decrease the number of false-positive (FP) signals of disproportionate reportings (SDRs) generated by co-prescription. Methods Automated backward stepwise removal of reports concerning the drug associated with the highest ranked SDR for an event was tested for gastric and oesophageal haemorrhages (GOH), central nervous system haemorrhages and cerebrovascular accidents (CNSH), ischaemic coronary artery disorders and muscle pains (MP) using the reporting odds ratio in the French spontaneous reporting research database. After ranking SDRs detected in the complete dataset on the lower limit of the reporting odds ratio 95% confidence interval, reports concerning the drug with the highest ranked SDR were removed. In the dataset thus generated, SDRs were again identified, ranked and reports related to the drug involved in the newly highest ranked SDR removed. The process was repeated until no signal was detected. Initially detected SDRs eliminated using this technique were assessed regarding the summary of products characteristics and the literature to determine their FP nature. Results Seventeen SDRs were successively eliminated for GOH, 37 for CNSH, 15 for ischaemic coronary artery disorders, and 36 for MP. Four were FP for GOH, 29 for CNSH, 7 for ACI and none were FP for MP. The positive predictive value of the backward stepwise removal procedure in identifying FP SDRs ranged from 0% (MP) to 78.4% (CNSH). Conclusions Although further adjustment is needed to improve the method presented herein, our results suggest that numerous FP signals because of co-prescription bias could be eliminated using an automated method. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimer's disease (AD) or other dementia in France. Methods A cross-sectional multicentre study was conducted by the French network of the 31 regional pharmacovigilance centres on a given day. The subjects were selected by random draw to be a representative sample of French patients with dementia: consultations of dementia clinics, nursing-homes, acute and long care geriatric units, rehabilitation care geriatric units. The staff of each medical structure together with that of the pharmacovigilance centre defined a day for including the patients. Socio-demographic data, history, ADR and drugs given were registered. Results There were 1332 subjects included, 51.1% living at home, 48.8% in institutions, aged 82.0 ± 8.0 years (46-108); 61.3% suffered from AD. Mean number of drugs was 6.3 ± 3.1. Anti-dementia drugs were given to 66.4% subjects. ADR prevalence was 5.0% (95% CI: 3.9-6.2) without a significant difference between at home and institutionalized patients. ADR consisted of gastro-intestinal (23.2%), central nervous system (17.4%) and psychiatric disorders (8.7%). Of the ADR, 31.9% were serious, and 47.8% preventable. The drugs most often involved were anti-dementia (28.9%), cardio-vascular (28.9%) and psychotropic drugs (26.4%, anxiolytics, hypnotics, antidepressants, neuroleptics). Conclusion This national scale study showed that iatrogenesis in patients with AD and related dementia can at times be serious and preventable. Therefore, special attention is required when prescribing psychotropic and anti-dementia drugs, as they are frequently used and induce half of the ADR in this population. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose To study whether reports related to known drug-event associations could hinder the detection of new signals by increasing the detection thresholds when using disporportionality analyses in spontaneous reporting (SR) databases. Methods The French SR database (2005-2006 data) was used to test this hypothesis for the following events: bleeding, headache, hepatitis, myalgia, myocardial infarction, stroke, and toxic epidermal necrolysis (TEN). For each of these, using the Proportional Reporting Ratio (PRR) and the Reporting Odds Ratio (ROR), the number of cases needed to trigger a signal out of 50, 100, and 200 reports for a hypothetical newly introduced drug were computed before and after removing from the database reports involving drugs known to be associated with the event. Results For bleeding and stroke, removing potentially competitive data resulted in a decrease of the number of cases needed to trigger a signal for a newly introduced drug for both PRR and ROR (e.g., from 9 to 4, and 5 to 3 cases out of 50 reports for bleeding and stroke, respectively using the PRR). They were not or only slightly modified for the other studied events. Conclusions Removing reports related to known drug-event associations could increase the sensitivity of signal detection in SR databases. This should be considered when using SR databases for signal detection as it could result in earlier identification of new drug-event associations. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Some pharmaceutical tablets have an appearance that resembles that of ecstasy (a logo and often a name referring to it, a given shape and/or a colour). These are sometimes sold in the street as ‘ecstasy’. In order to assess the knowledge of this phenomenon, surveys were conducted among designer drug users (DDUsers), pharmacists and pharmaceutical firms. Three surveys were conducted: the first one was conducted among DDUsers by means of an anonymous questionnaire; the second one consisted of a 1-month postal survey within a network of 155 community pharmacies in the Aquitaine region, Southwestern France and the third one consisted of a postal questionnaire sent to 71 pharmaceutical firms. Nineteen users, 77 pharmacists and 25 pharmaceutical firms participated in the surveys. All DDUsers knew the existence of what they call ecstasy ‘swindles’, but less than one quarter of the pharmacists and one third of pharmaceutical firms were aware of the potential recreational and involuntary misuse of medicines. The phenomenon of ‘swindle’ in the illicit market is not new. However, the sale of medicines because of their appearance or logo seems to be quite rare. In order to limit this diversion, prevention should be reinforced. In addition, recommendations on the appearance of medicine tablets should be set up by regulatory agencies in charge of medicine approval. [ABSTRACT FROM AUTHOR]

Purpose Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high-priority events. Methods Scientific literature, medical textbooks, and websites of regulatory agencies were reviewed to create a preliminary list of events that are deemed important in pharmacovigilance. Two teams of pharmacovigilance experts independently rated each event on five criteria: 'trigger for drug withdrawal', 'trigger for black box warning', 'leading to emergency department visit or hospital admission', 'probability of event to be drug-related', and 'likelihood of death'. In case of disagreement, a consensus score was obtained. Ordinal scales between 0 and 3 were used for rating the criteria, and an overall score was computed to rank the events. Results An initial list comprising 23 adverse events was identified. After rating all the events and calculation of overall scores, a ranked list was established. The top-ranking events were: cutaneous bullous eruptions, acute renal failure, anaphylactic shock, acute myocardial infarction, and rhabdomyolysis. Conclusions A ranked list of 23 adverse drug events judged as important in pharmacovigilance was created to permit focused data mining. The list will need to be updated periodically as knowledge on drug safety evolves and new issues in drug safety arise. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Pharmacovigilance spontaneous reporting systems are primarily devoted to early detection of the adverse reactions of marketed drugs. They maintain large spontaneous reporting databases (SRD) for which several automatic signalling methods have been developed. A common limitation of these methods lies in the fact that they do not provide an auto-evaluation of the generated signals so that thresholds of alerts are arbitrarily chosen. In this paper, we propose to revisit the Gamma Poisson Shrinkage (GPS) model and the Bayesian Confidence Propagation Neural Network (BCPNN) model in the Bayesian general decision framework. This results in a new signal ranking procedure based on the posterior probability of null hypothesis of interest and makes it possible to derive with a non-mixture modelling approach Bayesian estimators of the false discovery rate (FDR), false negative rate, sensitivity and specificity. An original data generation process that can be suited to the features of the SRD under scrutiny is proposed and applied to the French SRD to perform a large simulation study. Results indicate better performances according to the FDR for the proposed ranking procedure in comparison with the current ones for the GPS model. They also reveal identical performances according to the four operating characteristics for the proposed ranking procedure with the BCPNN and GPS models but better estimates when using the GPS model. Finally, the proposed procedure is applied to the French data. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose (i) To monitor the potential clinical neurotoxic symptoms in patients treated with leflunomide in daily practice and (ii) to describe the characteristics of patients presenting with this peripheral nervous system symptoms. Method All patients treated with leflunomide between May 2000 and April 2003 and followed in the rheumatology department of the University Hospital participated in the study. Data concerning treatment patterns with leflunomide, demographic and disease characteristics were obtained from clinical charts. Neuropathy was diagnosed with nerve conduction study (NCS). Cases of neuropathy were described and then compared to other patients using univariate analyses. Results One hundred and thirteen patients were included in the study. M/F sex ratio was 0.45. Mean age at start of treatment was 55.6 years (range = 27-81). During the study period, eight incident cases of peripheral neuropathy and two cases of worsening of preexisting neuropathy were reported (incidence: 9.8%). Compared with other patients, neuropathy cases were older (69 vs. 54 years, p = 0.0006), more often diabetic (30% vs. 2.9%, p = 0.009) and more often treated with potentially neurotoxic drugs (20% vs. 1.9%, p = 0.039). At least one risk factor (potentially neurotoxic drug or diabetes) was found in 50% of patients with neuropathy versus 4% of patients without neuropathy (56% PPV, 96% NPV). Conclusion Cases of toxic neuropathy have been observed during treatment of rheumatoid arthritis with leflunomide. Their occurrence seems to be associated with known risk factors. Careful monitoring of the patient's neurological status during leflunomide treatment is therefore mandatory. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Clinical trials constitute the gold standard to assess the efficacy and safety of new medicines. However, because they are conducted in standardized conditions far from the real world of prescription and use, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks. On the basis of three examples, our objectives were to study the differences between the characteristics of treated populations and treatment patterns in clinical trials and in postmarketing settings and to discuss the potential consequences on actual efficacy and safety. Treated populations were compared with patients included in premarketing clinical trials. Comparisons were made on the basis of demographic characteristics and treatment patterns. Whatever the indicator and the drug studied, differences were observed: from 0.04% to 63% for tacrine, from 0% to 37% for celecoxib and from 6% to 52% for simvastatin, with possible consequences on the effectiveness and safety of the drug concerned. Our results confirm the under-representation of women and elderly patients in premarketing clinical trials, e.g. an M : F ratio of 4.6 in clinical trails of simvastatin vs 1.0 in the joint population. Moreover, the concomitant use of medicines was made extremely restrictive by the protocols of these trials while this was not the case in the postmarketing phase. This has possible consequences on the effectiveness and safety of the drug concerned. These results plead for systematic ad hoc observational postmarketing studies for any novel and/or expensive medicine to assess the relevance of premarketing data. [ABSTRACT FROM AUTHOR]

Aims: To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation., Methods: A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (0-0.05), unlikely (0.06-0.25), doubtful (0.26-0.45), indeterminate (0.46-0.55), plausible (0.56-0.75), likely (0.76-0.95), and certain (0.96-1); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used., Results: The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only 'doubtful' showed a significant rate of agreement (kappa = 0.32, P < 0.001). For all criteria, the kappa index was significant except for the item 'risk(s) factor(s)' (kappa = 0.09). Agreement between experts was good (0.64, P < 0.001) only for the criterion 'reaction at site of application or toxic plasma concentration of the drug or validated test'. However, the rate of agreement with kappa indices of the causality criteria ranged from 0.12 to 0.38., Conclusions: This study confirms that in the absence of an operational procedure, agreement between experts is low. This should be considered when designing a causality assessment method. In particular, criteria inducing a low level of agreement should have their weight reduced.