[Severe systemic vasculitis induced by ibrutinib]. / Vascularite systémique sévère induite par l'ibrutinib.

INTRODUCTION: The specific cutaneous toxicity of Bruton's tyrosine kinase inhibitors is poorly described. We report a case of severe systemic vasculitis induced by ibrutinib. OBSERVATION: A 73-year-old woman with chronic lymphocytic leukemia was treated with ibrutinib. Eighteen months after treatment onset, ulceronecrotic lesions on toes and tongue occurred. Skin biopsy found vasculitis of small and medium vessels. Biologic tests were negative. This vasculitis was refractory to systemic corticosteroid therapy and azathioprine. Ibrutinib was stopped on the hypothesis of drug-induced vasculitis. Skin lesions improved after discontinuation of ibrutinib. CONCLUSION: The mechanism of action of ibrutinib does not explain the occurrence of vasculitis and an immunoallergic mechanism is suspected.

Delayed eczematous skin reaction as an adverse drug reaction to immunoglobulin infusions: A case series.

BACKGROUND: Pompholyx and eczematous reactions are known adverse reactions to intravenous immunoglobulins (IVIg) infusion, but little is known about their clinical characteristics, associated outcomes and management. OBJECTIVE: To describe IVIg-induced eczematous skin reactions. METHODS: We conducted a retrospective study on cases of delayed skin reactions post-IVIg infusion notified to the French Regional Pharmacovigilance Centre from 1985 to 2020. RESULTS: A total of 27 patients were identified, of whom 85% were male. IVIg infusions were given in a neurological indication in 82% of cases. Eczematous skin reactions occurred in two-thirds of cases after the first infusion, with a median time to onset of 11 days. Palmoplantar pompholyx was the most common presentation, being seen in 63% of patients. Other eruptions were erythemato-squamous or maculopapular. Eight patients were classified as severely affected and developed extensive lesions (>50% BSA). One third of the 27 patients required hospitalization. All of the severe eczematous reactions involved males receiving high doses of IVIg for neurological diseases. Biopsies of severe cases revealed a common non-specific eczematous pattern. Relapses were frequent and more severe than the initial reaction. Reintroduction of the same IVIg product consistently resulted in relapse, whereas switching IVIg type produced relapse in only 53% of patients. CONCLUSION: We present the largest retrospective study of delayed skin reactions after IVIg infusions. This side-effect may be severe and have a polymorphic presentation. Relapse occurs frequently but less consistently after IVIg switch.

Antibiotic prophylaxis for the prevention of infective endocarditis for dental procedures is not associated with fatal adverse drug reactions in France.

BACKGROUND: One of the major reasons to stop antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) in the United Kingdom but not in the rest of the world was that it would result in more deaths from fatal adverse drug reactions (ADRs) than the number of IE deaths. The main aim of this study was to quantify and describe the ADRs with amoxicillin or clindamycin for IE AP. The second aim was to infer a crude incidence of anaphylaxis associated with amoxicillin for IE AP. STUDY DESIGN: The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs for IE AP using the broad Standardized MedDRA Queries "Anaphylactic reaction, Amoxicillin, Clindamycin, Clostridium Difficile infection" to the French Pharmacovigilance Database System. From this first-line collection, we selected all cases occurring for IE AP and ultimately, the cases for IE AP for a dental procedure. Then, each case was analyzed. RESULTS: Of 11639 first-line recorded ADRs, 100 were for IE AP but no fatal anaphylaxis to amoxicillin or clindamycin and no C. difficile infection associated with clindamycin were identified. Only 17 cases of anaphylaxis to amoxicillin related to dental procedures were highlighted. The estimation of the crude incidence rate of anaphylaxis associated with amoxicillin for IE AP for invasive dental procedure was 1/57 000 (95% CI 0.2-0.6). CONCLUSIONS: Fatal or severe ADRs with amoxicillin or clindamycin is not a rational argument to stop IE AP before invasive dental procedures.

Pristinamycin-induced arthralgia and myalgia: Analysis of the French Pharmacovigilance Database.

INTRODUCTION: Pristinamycin is an antibiotic of the streptogramin family; few adverse effects of this drug are reported, only cutaneous and digestive ones. Arthralgia and myalgia may however be observed although not mentioned in the summary of product characteristics. OBJECTIVE: Description and analysis of cases of pristinamycin-induced arthralgia and/or myalgia registered in the French database of pharmacovigilance. METHOD: We carried out a targeted search of the database, selecting case patients presenting with arthralgia and muscle pain and excluding those associated with sensitivities or allergies to pristinamycin. RESULTS: We retrieved 15 case patients of pristinamycin-induced arthralgia and myalgia. Pristinamycin was the only potentially incriminated drug for seven case patients. CONCLUSION: Although not serious, this adverse effect deserves to be better known by physicians to optimize therapeutic management.

Aripiprazole: a new risk factor for pathological gambling? A report of 8 case reports.

OBJECTIVE: It is commonly accepted that pathological gambling results from the interaction of multiple risk factors. Among these, dopamine replacement therapy (DRT) prescribed for Parkinson disease can be cited. Another dopamine agonist, aripiprazole, could be a new risk factor. We decided to explore this potential adverse drug reaction (ADR). METHOD: Based on a cohort of 166 pathological gamblers starting treatment in our department, data of each of the 8 patients treated by aripiprazole at inclusion were analyzed. RESULTS: The patients involved were schizophrenic or bipolar, mostly young men with a history of addictive disorders and regular gambling prior to the prescription of aripiprazole. For each one of them, the causality of aripiprazole was considered, using an algorithm. The probability that pathological gambling is actually due to aripiprazole is "possible" in 7 cases out of 8, and "doubtful" in one. CONCLUSIONS: Adverse drug reactions were confronted with other already published case reports. Dopamine partial agonist mechanism of aripiprazole could explain the occurrence of pathological gambling.

The PREGVAXGRIP study: a cohort study to assess foetal and neonatal consequences of in utero exposure to vaccination against A(H1N1)v2009 influenza.

BACKGROUND: In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high risk of developing complications following infection by this virus. OBJECTIVE: The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine. METHODS: This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term. RESULTS: Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department. CONCLUSIONS: This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.

A statement on cefazolin immediate hypersensitivity: data from a large database, and focus on the cross-reactivities.

BACKGROUND: More perioperative cefazolin use has resulted in an increased risk of cefazolin-associated reactions. OBJECTIVE: The aim of this article is to study immediate reactions to cefazolin and attempt to determine possible allergic cross-reactivity with other ß-lactams using data from the Drug Allergy and Hypersensitivity Database (DAHD). METHODS: All 25 cefazolin-associated reactions in the DAHD were reviewed. The cases identified were then investigated according to the European Network for Drug Allergy (ENDA) recommendations by skin testing and challenges. RESULTS: A total of 10 individuals with proven IgE-mediated cefazolin hypersensitivity were identified between January 1999 and July 2009. All the index reactions were compatible with an acute IgE-mediated process, six with anaphylaxis, two with systemic allergic reactions without hypotension, and two with urticaria/angioedema. Cefazolin skin tests were positive in seven individuals and cefazolin challenges were positive in three more individuals. In the eight cefazolin allergic patients who had challenges with other ß-lactams, there was no positive reaction noted. CONCLUSION AND CLINICAL RELEVANCE: In this cohort of patients with IgE-mediated reactions to cefazolin, a majority tolerated amoxicillin and several patients tolerated other cephalosporins. This implies that the R1 side-chain may play an essential role in IgE-mediated reactions to cefazolin. No clear rule to predict cross-reactivity with other ß-lactams could be determined. More research on IgE-mediated hypersensitivity to cefazolin and other cephalosporins is needed.

[Characteristics of hypersensitivity syndrome to lamotrigine: review of one case reported in the Regional Center of Pharmacovigilance of Nantes]. / Caractéristiques du syndrome d'hypersensibilité à la lamotrigine: revue à partir d'un cas observé au CRPV de Nantes.

Drug-induced hypersensitivity syndrome is an uncommon but potentially life-threatening idiosyncratic drug reaction. In the literature, about five cases have been reported concerning hypersensitivity syndrome with lamotrigine. Most cases concern aromatic anticonvulsants but we report a case induced by lamotrigine which is a non aromatic anticonvulsant. A 73-year-old man was treated with lamotrigine for epilepsy due to a cerebrovascular stroke for 5 weeks. After 2 weeks with a single oral dose of 50 mg lamotrigine, the patient received 100 mg. Quickly thereafter fever, erythema and edema involving the periorbital area appeared. He was then admitted to hospital and lamotrigine was immediately discontinued. He developed acute hepatic and renal failure. During his hospital stay, he was treated with systemic and topical corticosteroids. After slow improvement, he was discharged 4 weeks later. Concerning this typical case, we review the characteristics of hypersensitivity syndrome and the different etiopathogenesis. The hypersensitivity syndrome typically develops two to six weeks after a drug is first administered, later than most other serious skin reactions. This syndrome manifests as rash, fever, tender lymphadenopathy, hepatitis and eosinophilia. The mechanism of hypersensitivity syndrome is unknown. Several theories have been proposed. The reaction is secondary to circulating antibodies or concerns toxic metabolities. On the other hand, association of human herpes virus 6 infection may play a role in the development of hypersensitivity syndrome. Hypersensitivity reactions to the aromatic antiepileptic drugs appear to have an immune etiology much like lamotrigine: bioactivation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T-cell immune effectors. Another theory involves toxic metabolites; the aromatic antiepileptic agents are metabolised by cytochrome P-450 to an arene oxide metabolite. This is normally detoxified by epoxide hydrolase. This enzyme may be lacking or mutated in persons that develop the syndrome, and this is genetically determined. Lamotrigine is mainly metabolised by hepatic glucuronidation, but hypersensitivity may involve similar processes such aromatic antiepileptic drugs, except that the toxic metabolite has not yet been found. Because of slow evolution and clinical similarity to many infectious illnesses, the diagnosis of hypersensitivity syndrome may be delayed. Prompt recognition and withdrawal of the suspected drug is essential. The goal of research is to describe a "susceptibility profile" identifying individuals at risk for these forms of drug toxicity.

[Results of a French nationwide survey of cutaneous side effects of ketoprofen gel reported between September 1996 and August 2000]. / Bilan de l'enquête nationale sur les effets indésirables cutanés du kétoprofène gel enregistrés entre le 01/09/1996 et le 31/08/2000.

A French nation-wide pharmacovigilance survey of ketoprofen topic collated, from September 1996 to August 2000, 770 cutaneous side-effects. The frequency varies from 0.013@1000 to 0.028@1000 according to the commercial gel. Analysis concerns spontaneous notifications of French nation-wide pharmacovigilance. Sex ratio is well distributed, population is young. Treatment lasted about 12 days, the side-effects appearing after about 13 days, 25 per cent of cases are delayed to discontinuance of treatment, mainly after exposure to sunlight. Co-administered drugs are in most cases systemic or topical NSAIDs and/or fibrates and then increase the seriousness of the iatrogenic pathology. 75 per cent of cutaneous side-effects appear in summer, 50 per cent have been reported as "photosensitivity". Reactions are severe in 30 per cent of the cases. More than 80 per cent of cases present an extension beyond the site of application. The course is usually favourable and neither topical nor systemic corticosteroid treatment influence the duration of evolution. Photopatchtests testing in 23 per cent of cases show evidence of photoallergy to ketoprofen and crossed photoallergy with tiaprofenic acid, fenofibrate, oxybenzone and benzophenone. These results confirm that photoallergy is due to the common benzoylketone structure but not to their arylpropionic function. Some cases of persistent or recurrent photosensitivity must be more explored. The results lead to request a modification of marketing authorizations.

First report of mirtazapine-induced arthralgia.

OBJECTIVE: The aim of our work is to describe the first two cases of arthralgia associated with the antidepressant drug mirtazapine. METHOD: Descriptive analysis of two iatrogenic cases. The review of the literature was achieved by the traditional electronic methods. The French database of iatrogenic cases was consulted. RESULTS: A 53-year-old man presented with gonalgia after some weeks of mirtazapine treatment. The intensity of the arthralgia was correlated with the dosage and the adverse effect rapidly disappeared after the antidepressant therapy was stopped. A 38-year-old woman received mirtazapine for 3 months and complained of arthralgia and myalgia. This clinical picture was suspended as the drug was stopped and a positive reintroduction was observed. No other cause was found in these two patients. DISCUSSION: No similar case has been reported in the international literature, but several observations of arthralgia with mianserin are mentioned. As mirtazapine is the 6-aza derivative of the tetracyclic antidepressant mianserin, the similarities of their chemical structures begs the responsibility of mirtazapine for arthralgia.

[Clinical data on COX-1 and COX-2 inhibitors: what possible alerts in pharmacovigilance?]. / Les inhibiteurs de COX-1 et COX-2, données cliniques: quelles alertes possibles en pharmacovigilance?

Adverse effects of NSAIDs are serious, mainly related to gastrointestinal bleeding, and throughout the world cause about 260,000 hospitalizations and 26,000 deaths a year, but each day at least thirty million patients take NSAIDs. Selective COX-2 inhibitors (i.e. celecoxib, rofecoxib) have demonstrated in clinical trials better gastrointestinal tolerability but their safety in patients with active ulcer, cardiovascular or renal disease has still to be further investigated. When their long-term safety has been established by pharmacovigilance studies they could be prescribed in the at-risk population or for other indications, including pre-term labour, colorectal cancer and Alzheimer's disease, provided they have shown efficacy and safety in controlled trials.

Warning! One buflomedil may hide another one!

A 75-year-old woman experienced fever and convulsions. She was treated for diabetes mellitus, angina pectoris and also for arteritis with Buflomedil Merck (3 tab/d). Further investigations failed to find any aetiology. Buflomedil dosage was elevated to 6.3 mg/l (N = 4-4.5 mg/l). The drug was discontinued and there was no recurrence of symptoms. There was no evidence of error in dosage or interaction. A failure of the generic product was suspected. Only a pharmacist solved the problem. Fonzylane (buflomedil) had recently been switched to Buflomedil Merck. The patient misunderstood the change and took both drugs! Our purpose is not to report a known effect but to emphasize the importance of extending the information given to the patient and the risk of misuse of the generic product.

A 2-year evaluation of questions concerning "Drugs--Pregnancy" at the CRPV in Nantes March 1992--March 1994. / Bilan de 2 années du suivi des questions "Médicaments--Grossesse" au CRPV de Nantes entre Mars 1992 et Mars 1994.

Since 1990, the 'Centre Regional de Pharmacovigilance' of Nantes has systematically monitored pregnant women exposed to drugs. To increase physicians' participation in this study (34 per cent), the protocol was modified in 1992. Phoned answers are confirmed by mail. At the supposed time of the delivery, the physician receives a questionnaire about the outcome of pregnancy. A second letter and phone call are planned. With this method, 89 per cent of the pregnancies were fully documented between March 92 and March 94. Answers are classified according to the type of the practice. Pregnancy outcome is studied according to the drugs and the moment of exposure during pregnancy. Quality of the information, motivation of the physicians, and the benefits and difficulties of this method are discussed.