Eosinophilic pneumonia induced by non-steroidal anti-inflammatory drugs: An underestimated risk.

INTRODUCTION: Eosinophilic pneumonia (EP) is a rare but serious adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: We describe the second published case of EP induced by oral diclofenac. We also reviewed the literature as well as French pharmacovigilance database. Case presentation A 63 year-old woman with polyarthralgia had taken diclofenac for three days for analgesic purposes. Progressively, the patient presented weakness, dyspnea and fever. Computed tomography (CT) scan revealed bilateral interstitial infiltration. Broncho-alveolar lavage (BAL) showed an elevated level of eosinophils. After ruling out all other possible etiologies, drug-induced EP was diagnosed and treatment by corticosteroid was initiated. The patient recovered in three months. RESULTS: In the French pharmacovigilance database, six cases of EP were recorded (3 with naproxen, 2 with ibuprofen, 1 with piroxicam). In the literature, twenty-six cases of EP with NSAIDs were published. The most commonly involved drug was naproxen (n=8), followed by fenbufen (n=4), ibuprofen (n=3) and diclofenac (n=2). A high level of eosinophils was systematically observed in the blood cell count or BAL. Corticosteroid therapy was started in eleven cases. All patients recovered. CONCLUSION: Complete history taking and examination should be done to rule out other etiological diagnoses. BAL is sufficient to diagnose EP. Corticosteroid therapy should be indicated for more severe or refractory cases. This adverse drug reaction is underestimated, healthcare professionals should be informed.

[Adverse drug reactions in pediatrics: Experience of a regional pharmacovigilance center]. / Les effets indésirables médicamenteux en pédiatrie : expérience d'un centre régional de pharmacovigilance.

AIM: To describe the adverse drug reactions (ADR) and the drugs involved in pediatrics. METHODS: An observational study on all ADR notifications recorded in the French pharmacovigilance database by the Regional Pharmacovigilance Center of Champagne-Ardenne between 1 January 1985 and 31 December 2014 involving children from 0 to 17 years inclusive was performed. For all notifications, we studied the patient and the ADR characteristics. RESULTS: During the study period, 632 notifications were collected. The most frequently reported ATC (anatomical, therapeutic and chemical) classes were vaccines (15.9%), antineoplastics (12%) and antibiotics (11.1%). Forty-six percent of the notifications were serious. For serious ADRs, the most involved drugs were paracetamol, asparaginase and ibuprofen. Skin reactions were the most often reported ADRs. The most common lowest level terms (LLT) were urticaria (4.9%), hypersensitivity (4.1%), fever (2.9%) and vomiting (2.8%). CONCLUSION: ADR reporting to the pharmacovigilance system, in particular pediatric ADRs, should be encouraged. Information on the use of medicinal products, especially on self-medication use, need to be improve.

[Serious Adverse Drug Reaction and Their Preventability in the Elderly Over 65 Years]. / Les effets indésirables médicamenteux graves et leur évitabilité chez des sujets âgés de plus de 65 ans.

AIM: To describe the serious adverse drug reactions (ADR) in elderly subjects aged over 65 years and assess their preventability. METHODS: A retrospective study was conducted at the Regional Pharmacovigilance Center of Champagne-Ardenne (northeast of France) between January and May 2013. Patients aged over 65 years who presented a serious ADR notified to the Regional Pharmacovigilance Center were included in the study. RESULTS: Over the study period, 100 subjects were included in the study. The sex ratio was 0.96. Twenty seven percent of serious ADR were preventable. Off-label use accounted for 20% and non-compliance for 5%. Bleeding events were the most common serious ADR (36%). The drugs most frequently involved in serious ADR were antithrombotic agents (31.4%). CONCLUSION: More than a quarter of serious ADR were preventable. Off-label use and non-compliance are the main causes identified in the occurrence of preventable serious ADR.

Notoriety bias in a database of spontaneous reports: the example of osteonecrosis of the jaw under bisphosphonate therapy in the French national pharmacovigilance database.

PURPOSE: The purpose of this study was to identify a notoriety bias in a database of spontaneous reports and its consequences on the calculation of the reporting odds ratio (ROR). METHODS: We used the case/noncase methodology to calculate the ROR for bisphosphonates and osteonecrosis of the jaw (ONJ) in the French national pharmacovigilance database (from 1985 to 2013). To evaluate notoriety bias, drug-related risk factors for ONJ [as specified in the summary of product characteristics (SPC) of bisphosphonates] were systematically scanned for notifications of reports of ONJ occurring under bisphosphonate therapy. When a risk factor was present, the ONJ was considered as not due to bisphosphonates, and a second ROR was calculated under the hypothesis of maximum bias. RESULTS: In total, 148 cases of ONJ were reported (143 with bisphosphonates and five without). The raw ROR was 3448 (95% confidence interval 1413-8417). After analysis of the reports, only 86 had no mention of a risk factor for ONJ. The ROR under the maximum bias hypothesis was 87 (95% confidence interval 63-121). Among ONJ where chemotherapy was being administered simultaneously to bisphosphonates, 27 reports did not consider the chemotherapy to be implicated, despite seven of these occurring in cases where ONJ was mentioned in the summary of product characteristics. CONCLUSIONS: The existence of a notoriety bias has an impact on measures of disproportionality. The detection of pharmacovigilance signals might be delayed. It is advisable to list all drugs being taken when an adverse drug reaction occurs, and not only those known to be associated with the observed reaction.

The French pharmacovigilance surveys: A French distinctiveness, a real input.

INTRODUCTION: According to French guidelines on good pharmacovigilance practices, a pharmacovigilance survey is an assessment of the available drug safety data. It is requested by the French national agency for medicines and health products safety (ANSM). The objective is to validate a signal, to characterize it, or to provide strengthened monitoring of a drug. MATERIAL AND METHODS: All the available data were retrieved by ANSM/Regional Pharmacovigilance Centers (RPC) and assessed by a nominate RPC which provides a report for discussion during the monthly Committee between ANSM and the Regional Pharmacovigilance Network (RPN). A descriptive analysis of the minutes available on the ANSM website between 2016 and 2018 has been done: objective, data sources, duration of the survey, number of suspected adverse drug reactions, nature of the drugs and of the signals and recommendations for actions. RESULTS: Between 2016 and 2018, a total of 115 surveys were discussed concerning 135 drugs, mainly from the nervous system according to the anatomic therapeutic chemical classification (n=31, 27%). They involved a whole pharmacological class for 18 ones. The main objective of the 115 surveys was to provide a strenghtened monitoring for some drugs (72%) or to validate one or more than one signal (28%). Result from surveys allowed to detect one or several new potential safety signals in 63 ones (55%), an off-label-use in 12 (10%) or to characterize some others signals in all the studies. The Committee recommended one or several actions by survey: 67 prolongations (58%) of the survey and regulatory or investigatory actions which included 43 European actions (37%), 37 label changes (32%), 30 national communications (26%) and 29 additional monitoring (25%). DISCUSSION/CONCLUSION: The current process allows a collegiate, clinical and pharmacological discussion with integration of the regulatory framework. A significant number of new signals are detected and/or validated. This efficient tool which is unique in Europe and is allowed by the decentralized pharmacovigilance which leads to a great reactivity of decision-making. It has to be reassessed and to be adapted continuously to the new challenges of the growing multiplication of signals.

Interest of pharmacoepidemiology in pharmacovigilance: Post-authorization safety studies in regulatory pharmacovigilance activity.

During the past few decades, it has been stated that a paradigm shift has occurred in the assessment and management of patient related drug safety. Some of these changes have resulted in a significant increase in the importance of pharmacoepidemiology and its use in pharmacovigilance. For European member states, the Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing the protocols and results of imposed and non-imposed post-authorization safety studies (PASS). Between 2013 and 2017, the total number of PASS during this 5-years period of the different products, including protocols and results, was 1062. The number of protocols of PASS is increasing over time, except in 2017 where a 25% decrease has been observed. Whereas, PASS results steadily increased over the 5years period. Between 2014 and 2017, about 29% (n=137) of PRAC reviewed protocols were imposed. The number of imposed PASS was almost constant over time with a mean of 34.3±7.6 imposed protocols per year and 3.5±1.74 imposed results per year. The need for the implementation of PASS for pharmacovigilance regulatory activities is increasing. Nevertheless, conducting such studies remains difficult.

Psoriasis during angiotensin receptor blocker exposure: an underestimated adverse drug reaction.

BACKGROUND: Angiotensin receptor blockers (ARBs) can induce or exacerbate psoriasis. Psoriasis is unlisted in the Summary of Product Characteristics (SmPC) of ARBs. We aimed to investigate the association between psoriasis and ARB exposure. METHODS: We reviewed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD). The association between psoriasis and ARB exposure was assessed using the case/non-case method. We also analyzed literature reports. RESULTS: We identified 89 reports of psoriasis during ARB exposure in the FPVD. Time to onset was most often less than 1 year. Outcome was favorable in 67% of reports after ARB discontinuation. Almost all ARBs were concerned. The reporting odds ratio (ROR) for psoriasis with this therapeutic class was 4.86 (95%CI 3.92-6.03). In the literature, we found 14 published reports of psoriasis with ARB exposure. Time to onset ranged from 6 weeks to 9 months. Outcome was also favorable after ARB discontinuation in the literature. CONCLUSIONS: This underestimated adverse drug reaction is a class effect, time to onset is most often less than 1 year and outcome seems favorable after ARB discontinuation. The case/non-case approach highlights a potential safety signal. The SmPC of ARBs should be updated, increased awareness among healthcare professionals is warranted.

Tumor necrosis factor inhibitors added to nonbiological immunosuppressants vs. nonbiological immunosuppressants alone: a different signal of cancer risk according to the condition. A disproportionality analysis in a nationwide pharmacovigilance database.

We aimed at detecting a signal of an increased risk of cancer in patients treated with TNF inhibitor (TNFi) and nonbiological immunosuppressant (NBIS), compared with NBIS alone for autoimmune diseases. Secondly, we aimed at comparing this risk between the different TNFis. We conducted a disproportionality analysis (case/noncase study) from the French National PharmacoVigilance Database. We selected all the reports of serious adverse drug reactions from 2000 to 2010 in patients treated with NBIS for labeled indications of TNFi. Cases were all the reports of cancer that occurred after a minimal 3-month exposure to NBIS. Noncases were all the other reports. We searched for exposure to TNFi and calculated reporting odds ratios (RORs), stratified by condition and type of cancer and adjusted by age, gender, history of cancer, type of NBIS and year of reporting. Of the 1918 reports included in the study population, 217 were cases (135 solid and 82 blood cancers). A safety signal was found in rheumatoid arthritis (RA) (ROR: 5.43, 95% CI[3.52-8.38]) particularly for nonmelanoma skin cancer (NMSC) (20.17[2.49-163.36]), and in psoriasis/psoriatic arthritis (3.45[1.09-10.92]). No signal was found in inflammatory bowel diseases (IBD) and ankylosing spondylitis, whatever the type of cancer. There was no difference between TNFis. This study puts the argument of an increased risk of cancer (particularly NMSC) in patients with rheumatoid arthritis exposed to TNFi and NBIS compared with NBIS alone, but not in IBD and ankylosing spondylitis patients. No signal was detected for melanoma potentially related to the lack of power. The signal seems similar whatever the TNFi.

Methylphenidate off-label use and safety.

INTRODUCTION: Methylphenidate is a piperidine derivative structurally and pharmacologically similar to amphetamine. Methylphenidate is indicated for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. In adults, its indication, except in narcolepsy, is not defined. Methylphenidate received regulatory approval almost sixty years ago with a first registration in Switzerland in October 1954. OBJECTIVE: To evaluate the off-label use of methylphenidate and its characteristics from a database of spontaneous reports. METHODS: This study analysed data from the French Pharmacovigilance Database of adverse drug reactions spontaneously reported by health professionals from 1985 to December 2011. Off-label use was evaluated according to age. RESULTS: In the French Pharmacovigilance database, 181 cases of adverse drug reactions were reported with methylphenidate. Neuropsychiatric effects were the most frequent adverse event reported (41%) followed by cardiovascular and cutaneous side effects (14%). 143 reports concerned children (113 boys, 30 girls, mean age 10.6 ± 3.3 years) of which 46 (30%) were off-label uses. There were 38 adults (20 men, 18 women), of which 32 (88%) off-label use. In adults, methylphenidate was prescribed for depression, and this practice was associated with serious adverse events of drug dependence, overdose and suicide attempt. Overall, off-label use was detected in 43% (78/181) of all cases reported. CONCLUSION: More than 40% of the patients with drug reactions received methylphenidate for off-label indications. Additional long-term exposures and independent clinical studies are necessary to establish the long-term profile safety of methylphenidate.

Drug-induced hallucination: a case/non case study in the french pharmacovigilance database

Background and Objectives: Hallucinations are sensory perceptions which occur without external stimuli. There are associated with psychiatric disease but also can be related to organic disease and drug or toxic exposure. The purpose of our study was to investigate the association between exposure to medications and the reporting of hallucinations using data from the spontaneous-reporting French Pharmacovigilance Database (FPVD). Methods: We used the case/noncase method in the FPVD. Cases were all the observations of hallucination with the LLT term "perception disturbances", registered into the FPVD from January 1985 to Jan 2013. Data were expressed as odds ratio (OR) with their 95% confidence intervals. Results: Among the 469,181 reports of adverse effects recorded between 1985 and 2013, 4, 086 are hallucinations. For about 50% of these hallucinations were experimented by patient older than 65 years old. A statistically significant OR was found with several medications included rasagiline (OR 17.6 [ 95% CI 10.4-29.8] zolpidem (OR 12.9 [95% CI 11.3 - 14.8]), methylphenidate (OR 9.3 [95% CI 5.9-14.6]) and baclofene (OR 5.4 [95% CI 3.7-7.8]). An increased risk of hallucinations was also observing with non central nervous system drugs, including ertapenem (OR 24.0 [95% CI 14.2-40.5]), voriconazole (OR 12.9 [95% CI 10.2-16.5] and valacyclovir (OR 9.1 [95% CI 6.9-11.9]). Conclusions: This pharmacoepidermiological study describes and association between drugs and hallucinations. This relationship involves not only some already suspected drugs but also other drugs less known to induce such an adverse reaction. Despite the mandatory limits of this kind of study, these data should lead to special precautions in patient at risk (AU)

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