Bullous haemorrhagic dermatitis induced by heparins and other anticoagulants: 94 cases from French pharmacovigilance centres and a literature review.

BACKGROUND: Bullous haemorrhagic dermatitis (BHD) is an uncommon and highly particular side effect of various forms of heparins. METHODS: To better characterise the disease, we collected all cases from French Pharmacovigilance centres recorded over a 20-year period (37 cases) and performed a Medline literature search up to June 2020 (57 cases). RESULTS: In all, 94 patients were identified (male/female ratio: 2.2) of mean age 73.5±12.1 years (31-94). Patients were treated with enoxaparin (n=66), unfractionated heparin (n=11), fondaparinux (n=10), tinzaparin (n=4), bemiparin (n=1), reviparin (n=1), dalteparin (n=1), and 4 with other anticoagulants: warfarin (n=3) and rivaroxaban (n=1). All cases presented with 1 to more than 100 haemorrhagic vesicles and bullae, distant from the injection sites, located mainly on the lower (75%) or upper limbs (69%). The lesions were asymptomatic, except in 5 patients who had pruritic or painful lesions. The interval between treatment initiation and BHD ranged from 6 hours to 30 days (mean: 8.4±7 days). Biopsy (n=53) showed intraepidermal or subcorneal cavity with red cells (n=39) or junctional blisters (n=10), with eosinophilic infiltrate only rarely. Direct immuno-fluorescence was negative in 19/20 cases and indirect immunofluorescence was negative in 8/8. The outcome was favourable in all cases, including in 12 patients for whom heparin was maintained. A 93-year-old patient died of compressive haematomas unrelated to BHD. We found 5 cases similar to BHD due to other anticoagulants. DISCUSSION: This is the largest comprehensive series of this adverse effect due to heparins or, more rarely, to other anticoagulants. Dermatologists must be aware of BHD, since this benign side effect does not necessarily require interruption of treatment. It is rare, considering the large-scale prescription of heparins, and occurs mainly in male patients aged over 70. Although the presentation is highly typical, the physiopathology is difficult to understand, as coagulation parameters are usually normal. Aging, skin fragility or mechanical factors might play a role.

Specific features of amoxicillin-associated Drug Reaction with Eosinophilia and Systemic Symptoms syndrome: a nationwide study.

BACKGROUND: Growing evidence indicates that amoxicillin induces herpesvirus replication in vitro. As these play a central pathophysiological role in Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (DRESS), amoxicillin could present with specific DRESS features. OBJECTIVE: To characterize the onset patterns of amoxicillin-associated DRESS. METHODS: All cases of DRESS (Kardaun score ≥4) involving amoxicillin and reported in the French Pharmacovigilance Database between January 1, 2004 and November 30, 2019 were included. Onset circumstances for these cases were categorized considering the onset delay from amoxicillin initiation, and the presence of concomitant medications with a compatible time to onset. RESULTS: A total of 146 probable cases or definite cases of DRESS were included. Three onset circumstances were identified: (i) 'amoxicillin clear culprit' where amoxicillin was the sole suspect drug or when concomitant drugs of compatible time to onset were not reported to cause DRESS (n = 62); (ii) 'amoxicillin possible culprit' in the presence of other potentially culprit drugs in addition to amoxicillin (n = 44) and (iii) 'flare' where amoxicillin, used after DRESS onset, induced flare-up reactions (n = 40). The median time to onset was 5 days (IQR 2-11) in 'clear culprit', and 18 days (IQR 7-26) in 'possible culprit' cases. In 'flare' cases, the median latency between amoxicillin initiation and flare-up reactions was 3 days (IQR 2-5). CONCLUSIONS: Amoxicillin can induce DRESS with a specific early onset and exacerbate DRESS from another drug.

Transient major hypothermia associated with acetaminophen: A pediatric case report and literature review.

We report the case of a 4-month-old baby boy who presented hypothermia (rectal temperature 36°C) after acetaminophen intake for post-vaccination fever. A recurrence of the hypothermia was observed after acetaminophen rechallenge for fever. We reviewed 14 other pediatric cases of hypothermia secondary to therapeutic doses of acetaminophen. Hypothermia after a therapeutic dose is a very rare side effect of acetaminophen. Several hypotheses have been made but the exact mechanism remains unknown.

[Post-licensure safety surveillance for Prevenar 13® in France]. / Bilan français des effets indésirables du vaccin Prévenar 13®.

OBJECTIVE: To describe the profile and the incidence of adverse events (AEs) reported with Prevenar 13® since its commercialization. METHOD: Analysis of all adverse events reported with Prevenar 13® in France between 1st July 2010 and 31 October 2014. RESULTS: In 4 years and 4 months, 376 AEs, including 252 severe (67%), were recorded, 83 of which occurred following an injection of Prevenar 13® alone: 39 cutaneous AEs, 16 neurological AEs, four cases of collapse or shock, nine cases of fever, and one of thrombocytopenia. For the serious AEs, the outcome was favorable in 88% of cases and none of the 12 reported deaths were attributed to a side effect of vaccination. Fifty-nine cases of pneumococcal disease that suggest an ineffective vaccine were reported, but only 16 can be considered as a real failure of the vaccination. DISCUSSION: In many cases, Prevenar 13® was administered on the same day as a hexavalent vaccine with which the AEs reported were expected. The profile of AEs reported following Prevenar 13® alone is similar to that seen with Prevenar 7®. CONCLUSION: Since its release in 2010, the Prevenar 13® pharmacovigilance survey, which includes more than 11,800,000 distributed doses, did not show any new information in terms of tolerance safety.

[Safety profile of etonogestrel contraceptive implant (Nexplanon® and Implanon®) reported in France]. / Profil des effets indésirables de l'implant d'étonogestrel (Nexplanon®, Implanon®) déclarés en France.

OBJECTIVES: The aim of the study was to assess the incidence of adverse effects (AE) reported with etonogestrel contraceptive implant in France (Implanon® and Nexplanon®). MATERIALS AND METHODS: All cases of AE or unintended pregnancies reported to health authorities or to the firm were analyzed. RESULTS: During 10 years, 5433 AE and 789 unintended pregnancies were reported. Only 388 (7 %) were serious. There were 1137 reports of difficulties to remove, failure to locate or migration, 430 of insertion difficulties and 203 of deformation or expulsion of the implant. Among other AE, the most common were 1694 gynecological AE, 524 skin reactions and 437 metabolic AE. Since the marketing of Nexplanon® which causes less deep insertions, the incidence of migrations, removal or insertion difficulties has decreased overall (0.92 vs. 1.31/1000 patients), particularly the incidence of removal difficulties, location failures or migrations (0.12 vs 1.01/1000). The infrequent but serious AE were infectious complications at the implant site and pregnancies. When the circumstances of the pregnancy were known, the contraceptive failure was due to the apparent inefficiency of the implant (n=224), to a technique failure (n=203) or to a drug-drug interaction (n=59). CONCLUSION: This study confirms that AE of this implant are frequent but not serious, except for the pregnancies. The incidence of complications related to insertion decreased with Nexplanon®. Among other preventable AE, unintended pregnancies due to a drug-drug interaction would require to be better known by the practitioner.