Informativeness of patient initial reports of adverse drug reactions. Can it be improved by a pharmacovigilance centre?

PURPOSE: Little is known about the informativeness of initial patient reports before they are reviewed by a pharmacovigilance centre (PVC). We aim to describe the patterns of patient adverse drug reaction (ADR) reporting in France and estimate the contribution of a review by a PVC assessor on the informativeness of these reports. METHODS: A retrospective study was conducted on patient reports between July 2011 and July 2015. Informativeness of 16 key elements of information (including drug start and end date, duration of treatment, time to onset and duration of the ADR, outcome, medical history and concomitant medication) was assessed in initial reports before and after review by a pharmacovigilance assessor. RESULTS: Overall, 240 reports concerning 522 ADR and involving 278 drugs were reported over this 4-year period. Mean number of available key elements of information in initial reports was increased from 11/16 to 15/16 after review of reports by the PVC. Time to onset and duration of the ADR were respectively available in only 51 and 58% of the reports before review compared to 83 and 90% after review. Medical history and concomitant medication were missing in 75% of the initial reports compared to less than 30% of the reports after review. Contacting the reporter enabled an increase of informativeness of most elements of information for more than 90% of the reports. CONCLUSION: Patient reports often need to be completed on key elements of information that are required to assess reports. Both upstream education of patients and downstream intervention of a pharmacovigilance assessor to complete missing information could help to enhance the informativeness of such reports.

[Treatment with ranibizumab for choroidal neovascularization secondary to a pseudoxanthoma elasticum: Results of the French observational study PiXEL]. / Traitement par ranibizumab des néovascularisations choroïdiennes secondaires à un pseudoxanthome élastique : résultats de l'étude observationnelle française PiXEL.

INTRODUCTION: Pseudoxanthoma elasticum (PXE), a rare hereditary connective tissue disorder, may be complicated by angioid streaks (AS) and choroidal neovascularization (CNV), which may lead to irreversible loss of visual acuity (VA). Here we describe the safety and efficacy of ranibizumab in patients with CNV secondary to PXE. METHODS: A multicenter (n=23), observational study of a retrospective/prospective cohort, performed under real world conditions in France in all patients with CNV secondary to PXE who received at least one ranibizumab injection as of October 2011. The study objectives were to describe the mean annual number and reason for ranibizumab injections since initiation, evolution of best-corrected visual acuity (BCVA by Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and safety. RESULTS: Patients (n=72; 98 eyes) had a mean age of 59.6±8.3years and consisted of 54.2% men. The criterion for retreatment was based mainly on loss of VA, progression of CNV and angiographic leakage. CNV was primarily subfoveal or juxtafoveal (73.4%), and the initial mean VA was 64.6 ETDRS letters. On average, visual acuity of all eyes analyzed was relatively stable during the 2-year follow-up (62.3 letters vs 64.6 letters at the first injection), and 88.6% of eyes maintained VA between -15 and +15 letters or gained over 15 letters. No deaths or new intolerances were described. CONCLUSIONS: These results showed that ranibizumab was able to maintain stable VA in clinical practice for at least 2years in patients with CNV secondary to PXE, and to significantly reduce the frequency of neovascularization relapses, with a limited number of injections. The treatment was well tolerated by the patients.

[Neuroleptic associated hypothermia: a new case report and study of spontaneous reports to the French pharmacovigilance network]. / L'hypothermie aux neuroleptiques, une complication méconnue : à propos d'un nouveau cas et revue de la base de la pharmacovigilance française.

INTRODUCTION: Neuroleptics are the main antipsychotic agents used in psychiatric or medicine departments. The occurrence of hyperthermia, particularly in the context of the neuroleptic malignant syndrome, is a well-known side effect of these treatments. Conversely, the occurrence of hypothermia is less known from clinicians. CASE REPORT: We reported a 72-year-old woman, who presented with hypothermia associated with treatment with neuroleptics. This patient had no other medical comorbidities. Because of persistent hypothermia, altered consciousness and bradycardia, exhaustive diagnostic work-up as well as a prolonged hospitalization were necessary. The results of a review of the national French pharmacovigilance database showed that nearly a quarter (153/614) of drug-related hypothermia are attributed to psychotropic drug, mainly neuroleptics (99/153). CONCLUSION: A better awareness of hypothermia associated to neuroleptics should facilitate early diagnosis and reporting this side effect of neuroleptics.

Ozonation of ibuprofen: a degradation and toxicity study.

This paper presents the results obtained in the degradation of ibuprofen by ozonation. This study aims to evaluate the degradation of ibuprofen by ozonation once the operating variables have been optimized, investigating the degradation and degradation efficiency of the compound and assessing the toxic effect of ibuprofen and of the intermediate compounds generated during oxidative treatment. Work was carried out to optimize the four operating variables: pH, conductivity, hydraulic retention time and the use of a maze of pipes to enhance contact between the ozone and the drug. All the trials were conducted in a purpose-built pilot-scale reactor. Analyses of the compound were carried out after solid-liquid phase extraction on high resolution liquid chromatography (HPLC). Working under optimal operating conditions (pH=9, HRT=20 min and 12 ± 2 gN/m(3)), a degradation value of 99% was obtained, although degradation efficiency or mineralization of the compound was not achieved. The toxicity of ibuprofen and its intermediate compounds formed during the oxidative process was likewise studied. This toxicity was found to increase with increasing initial concentrations of the compound, with the intermediate compounds thus formed being more toxic than the starting compound.

Bevacizumab-induced serious side-effects: a review of the French pharmacovigilance database.

PURPOSE: Bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor, is widely used in association with standard chemotherapy in metastatic cancer. Well tolerated, bevacizumab is sometimes associated with serious adverse drug reactions (ADRs). The objective of this study is to describe the profile of ADRs related to bevacizumab and reported to the French Pharmacovigilance system. METHOD: All serious cases of ADRs associated with bevacizumab recorded in the French Pharmacovigilance database up to November 31, 2010 were identified and analyzed, focusing on patient information, drug exposure, and characteristics of the ADRs. Categorical variables were compared using the chi-square test when appropriate. RESULTS: A total of 351 serious cases involving 626 ADRs were recorded in the database during the study interval. The most frequent ADRs reported involved the gastrointestinal system (21.9%). The most frequent ADRs included gastrointestinal perforation (4.8%), thromboembolic events (4.0%), pulmonary embolism (3.2%), hypertension (2.7%), gastrointestinal hemorrhage (2.7%), and cerebral hemorrhage or vascular accident (2.6%). The median duration of bevacizumab exposure was four cycles (range 1-30) when ADRs occurred. In 18 cases of death directly caused by ADRs, 50% occurred after only one cycle. In cases of disability, 40% of ADRs were neurologic: neuropathy, paralysis, and paresis. CONCLUSION: To the best of our knowledge, this is the first analysis of bevacizumab safety profile using data collected in a national pharmacovigilance database. Our study confirms the frequency and seriousness of gastrointestinal, thromboembolic, and hemorrhage events with bevacizumab use and provides a picture of the bevacizumab safety profile in daily medical practice, despite intrinsic limitations.

[Severe hypoglycemia induced by tramadol: two new cases of an unlisted side effect]. / Hypoglycémies sévères au tramadol : deux nouvelles observations d'un effet indésirable non référencé

INTRODUCTION: Tramadol is a weak opioid analgesic used as a step two analgesic, approved in France for the treatment of moderate to severe pain in adult patients. The most common side effects are gastrointestinal and neurologic. Hypoglycaemia is an almost unknown side effect. CASE REPORTS: We report two patients who presented with severe hypoglycaemia related to oral administration of tramadol in non diabetic patients. The underlying mechanisms of hypoglycaemia induced by tramadol are unclear. The only weak opioid analgesic drug reported to cause hypoglycaemia is propoxyphene, which has been widely used in France. The recent withdrawal of dextropropoxyphene in France might increase the prescriptions of tramadol and healthcare professionals should be aware of the risk of hypoglycaemia. CONCLUSION: The risk of hypoglycaemia should be added to the summary of product characteristics of tramadol.

[Cutaneous events during anti-TNF alpha therapy: a prospective observational study of 41 cases]. / Evénements cutanéomuqueux au cours des traitements par anti-TNF alpha : étude observationnelle prospective de 41 cas.

BACKGROUND: The cutaneous adverse effects of TNFalpha inhibitors and their potential implication in the onset of associated dermatoses remain poorly understood. PURPOSE: To describe the different clinical dermatological situations seen in patients treated with TNFalpha inhibitors. PATIENTS AND METHODS: We conducted a prospective, observational study of patients followed at the Dermatology Department of the CHU Nord university teaching hospital of Marseilles. All patients, referred by various departments, were treated with TNFalpha inhibitors and presented cutaneous events. RESULTS: Forty-one patients were included in the study. Various cutaneous manifestations were observed, including: 15 psoriatic rashes, six skin infections, three eczema rashes, three cases of lupic syndrome, two anaphylactic reactions to infusion and two cutaneous drug reactions. An original case of parapsoriasis was observed. Cutaneous tumors are rarely described. DISCUSSION: This study confirms the multiple clinical dermatological situations observed in patients treated with TNFalpha inhibitors and illustrates the need for good coordination between dermatologists and other specialists in order to ensure optimal management of this population.

[Carbamazepine and clarithromycin: a clinically relevant drug interaction]. / Carbamazépine et clarithromycine: une interaction médicamenteuse cliniquement significative.

BACKGROUND: Carbamazepine is associated with clinically relevant drug interactions especially with macrolide antibiotics such as troleandomycin and erythromycin. These drugs inhibit the metabolism of carbamazepine. Clarithromycin, a macrolide antibiotic similar to erythromycin, is widely used to treat respiratory tract infections and is used for the treatment of atypical mycobacterial infections and Helicobacter pylori-associated peptic ulcer disease. METHODS: To report an interaction between carbamazepine and clarithromycin, we present a study that includes three regular attenders at the epilepsy department of Montpellier and seven cases reported by the French national drug safety center. RESULTS: In patients receiving carbamazepine alone or in combination with other drugs, administration of clarithromycin led to a transitory overdosage (ataxia, dizziness, diplopia, nausea, vomiting, drowsiness). Blood level was available in 8 patients with a concentration of carbamazepine ranging from 13.3 to 28.5 mg/l. CONCLUSION: Carbamazepine is extensively metabolized by cytochrome P450 enzymes, especially CYP34A. As clarithromycin is also metabolized by CYP3A4, this drug has the propensity to inhibit the metabolism of carbamazepine. Clarithromycin should be thus avoided in patients taking carbamazepine.

[Cutaneous side-effects in drug assessment]. / Critères d'imputabilité des atteintes cutanées médicamenteuses.

Drug-induced cutaneous side-effects are very frequent. All dermatitis may be induced by drugs. It is difficult to identify the drug responsible because patients take many drugs (prescriptions, self medication). For each pathology, physicians may use assessment methods based on specific chronological criteria (challenge, dechallenge, rechallenge) and specific semeiological criteria (promoting factors, alternate non-drug related explications, specific laboratory tests) to identify the drug responsible.

[Retrospective of national pharmacovigilance surveys on drug-induced bullous, vesicular eruptions: methods and results ]. / Rétrospective d'enquêtes nationales de pharmacovigilance sur les toxidermies: méthodologies et résultats.

UNLABELLED: The academic interest for pharmacovigilance appears to be very low, because of the judged weakness of a "significant" relationship between drug utilisation and pathological events. We have tried to collect the relevant surveys of the French pharmacovigilance network on cutaneous toxic reactions to show the use of this work for current medical knowledge. This study was limited to the most relevant reports: 1--Cutaneous disorders induced by local reactions to ketoprofen, bufexamac, paracetamol (i.v.) 2--Cutaneous disorders observed in systemic hypersensitivity syndromes: allopurinol, chlormezanone, pristinamycine 3--Photosensitisation (toxicity), including: Individual characteristics of patients Nature of the observed syndromes Induction time and evolution of the disease Imputation and apparent incidence of the cases observed RESULTS: 1--Concerning "contact" dermitis, erythematous skin reactions are the most frequently observed. The causality link is proved in 272 patients of the cases. The mean age of the patients is 40-50 and the induction time from one to ten days. 2--In the hypersensitisation syndromes, severe skin reactions, combined with general reactions (fever), are the most frequently observed. The mean age is 50-60 and the number of serious cases is high (4.5%). 3--Severe burns with bullous skin reactions are observed in phototoxicity cases. The mean age of the patients is 50. Time induction is short (ten days), the cases are frequently serious, but evolution appears good. In conclusion, the synthesis of pharmacovigilance surveys shows the value of this epidemiological approach to drug-induced skin reactions. It is regrettable that the results of this work are not more widely distributed.

[Cutaneous adverse effects during selective serotonin reuptake inhibitors therapy: 2 cases]. / Toxidermie aux antidépresseurs sérotoninergiques: 2 cas.

BACKGROUND: Selective serotonin reuptake inhibitors are widely used in the treatment of depressive and obsessive-compulsive disorders because of their low-frequency adverse effects. We report two cases of cutaneous adverse effects during selective serotonin reuptake inhibitors therapy. CASE REPORTS: A man who complained of chronic anal idiopathic pruritus was treated with citalopram (Seropram(R)) 10 mg b.i.d. Six days after the beginning of the antidepressive treatment, he developed an extensive papular and purpuric erythema with keratinocytes necrosis and dermal leucocytoclastic vasculitis. Cutaneous lesions remained for several weeks, as the half-life of citalopram is very long (33 to 36 hours) but did not relapse. A women developed painful papular and purpuric erythema mainly located in sun-exposed sites, during therapy with paroxetine (Deroxat(R)) 20 mg b.i.d., which had been introduced one month before to treat depression. Cutaneous lesions healed spontaneously in 2 weeks after the discontinuation of paroxetine and with sun avoidance and didn't relapse. DISCUSSION: Adverse cutaneous effects of selective serotonin reuptake inhibitors are rare but the knowledge of these reactions is important because toxic epidermal necrolysis and Stevens-Johnson syndrome had been reported during fluoxetine (Prozac(R)) and fluvoxamine (Floxyfral(R)) treatment. Different serotonin uptake blockers could be involved in the same allergic reaction, suggesting cross reactivity, although these drugs have different chemistry structures. It is advisable to substitute after an adverse effect a medication from one of the other classes of antidepressants.