Impact of the COVID-19 outbreak on the reporting of adverse drug reactions associated with self-medication.

OBJECTIVES: The primary objective of the present study was to describe the characteristics of adverse drug reactions (ADRs) linked to self-medication that were notified to the French Pharmacovigilance Database (FPVD) during the COVID-19 outbreak in 2020 first wave. The secondary objective was to compare the characteristics of these ADRs in 2020 with those notified during the same calendar period a year previously. MATERIAL AND METHODS: We analyzed ADRs recorded in the FPVD between March 15th and May 31st, 2020 vs. the same dates in 2019. Only ADRs linked to self-medication were analyzed. Descriptive statistics were used to obtain an overview of the types and characteristics of these ADRs. RESULTS: Of 3114 ADRs notified to the FPVD during the COVID-19 period in 2020, 114 (3.7%) were linked to self-medication. The equivalent proportion in 2019 was 1.6% (113 out of 7097). Half of the ADRs notified in 2020 were "serious". The median age of affected patients was 30.5, and 22% of the ADRs concerned children. Of the 114 ADRs linked to self-medication, 107 (66%) were for prescription-only drugs. The three mostly frequently suspected ATC classes were analgesics, psycholeptics, and antibacterials for systemic use. The most frequent ADRs were general disorders, gastrointestinal disorders, and nervous system disorders. The main difference between the non-COVID-19 period and the COVID-19 period was the higher proportion of medication errors during the latter. CONCLUSION: The present study is the first to have reported on ADRs linked to self-medication and notified during a COVID-19 outbreak. Further studies of self-medication patterns and their consequences in a pandemic context are mandatory and effective information on medication use (including self-medication and its dangers) during a pandemic is essential.

[Eruptive granuloma after injection of Ellansé® successfully treated using methotrexate]. / Granulomes après injection d'Ellansé®, résolutifs sous méthotrexate.

BACKGROUND: Collagen stimulators such as Ellansé® are soft tissue fillers able to induce nucleogenesis. We describe a case of eruptive foreign body granulomas following injection of Ellansé® that were successfully treated using methotrexate. CASE REPORT: A 47-year-old woman received injections of Ellansé® for the wrinkled aspect of her cheeks. She had previously undergone injections of hyaluronic acid on the nasolabial folds. Nine months after the Ellansé® injections, the patient consulted for the recent appearance of multiple nodules on her face. Histological analysis of one of these nodules confirmed the presence of foreign-body granulomas developed in contact with spherical gaps of a size substantially identical to the Ellansé® vacuoles. Methotrexate 10mg per week for 3 months followed by 20mg per week for 9 months resulted in complete regression of the nodules. DISCUSSION: Ellansé® is composed of two biocompatible and bioabsorbable polymers: carboxymethylcellulose, responsible for immediate volume creation, and polycaprolactone, which promotes collagen synthesis. However, any injected product can cause varying degrees of granulomatous reaction. Hyaluronic acid was previously injected at several other sites on the patient's face. These lesions were not the result of poor injection technique. CONCLUSION: Although collagen stimulators are biocompatible and bioabsorbable substances, the development of foreign-body granulomas, while rare, is still possible. Methotrexate resulted in significant regression of nodules as of the third month of treatment.

[Cytopenia under topical imiquimod in two patients treated with oral hydroxyurea]. / Cytopénies sous imiquimod topique chez deux patients traités par hydroxyurée.

BACKGROUND: Aldara® is a topical immunomodulatory treatment. The risks of systemic passage are minimal. There have been rare reports of systemic adverse effects. PATIENTS AND METHODS: Case 1. Five sachets weekly of imiquimod were prescribed for Bowen's disease on the forearm in a patient known to have essential thrombocytosis under Hydrea®. His CBC was normal (6000 leukocytes/mm3, 2200 PMN/mm, 230,000 platelets/mm3). Imiquimod was given in 15 sachets weekly. Fifteen day later, the patient presented bicytopenia (3000 leukocytes/mm3, 1400 PMN/mm3, 119,000 platelets/mm3). Hydroxyurea and imiquimod were suspended until normalization of CBC. Hydroxyurea was resumed without recurrence of the bicytopenia. The patient's history included an identical episode following application of imiquimod. Case 2. Five sachets weekly of imiquimod were prescribed for actinic keratosis on the scalp in a patient known to have primary polycythemia under hydroxyurea. Her CBC was normal except for anemia (Hb 11.5g/L, 160,000 platelets/mm3, 1100 lymphocytes/mm3). Imiquimod was given in 12 sachets weekly. Ten days later, anemia increased (Hb 10g/dL) with lymphopenia (800/mm3) and thrombocytopenia (115,000/mm3). Suspension of imiquimod resulted in normalization of the previous CBC values. DISCUSSION: . The literature review identified reports of dose-dependent lymphopenia under oral imiquimod but not under Aldara®. The National Pharmacovigilance Database listed 10 cases of hematological disorders most likely caused by Aldara®. Hydroxyurea may induce cytopenia, and while it was not considered the sole causative agent in this case, it is likely to have had a triggering role in these patients with blood dyscrasias. Our findings show that misuse of imiquimod carries a potential risk of hematologic abnormality in patients receiving concomitant hydroxyurea, a commonly combined drug.

[Eruptive epidermoid cysts during topical imiquimod treatment]. / Éruption de kystes épidermiques après application d'imiquimod topique.

BACKGROUND: Imiquimod is a local immune-response modifier that works by stimulating innate and acquired immunity. It is frequently used to treat superficial basal cell carcinoma, the most common form of skin cancer. Marked local inflammatory reaction is common during treatment. We report a case of the rare condition, multiple eruptive milia, during topical imiquimod therapy. PATIENTS AND METHODS: A 67-year-old male patient presented infiltrating basal cell carcinoma above the left eyebrow. The patient underwent surgery and skin grafting. He presented superficial relapse at the periphery of the graft and was initially treated with Aldara®. Fifteen days after initiation, Aldara® was withdrawn due to a critical inflammatory reaction. A few weeks after complete healing, an erythematous annular plaque of milia, excluding the graft zone, appeared. This element was confirmed by histopathology. DISCUSSION: The most common local side effects reported with Aldara® are erythema, irritation and crusting. Reports of eruptive milia following Aldara® therapy are rare and they are never mentioned in the summary of product characteristics. Application of imiquimod in fact induces local inflammatory reaction due to stimulation of local cytokines, which can result in marked reaction in the infundibular epithelium of hair follicles and thus in the production of abnormal keratin that can cause pilosebaceous duct obstruction and thus the formation of epidermoid cysts. This pathological mechanism explains the absence of lesions on the skin graft of the inner arm. CONCLUSION: The occurrence of eruptive milia during treatment with Aldara® is rarely described. The timing of occurrence of these eruptive milia as well as the mechanism of action of the drug made such a reaction highly probable in our patient.

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.

Parkinsonism and/or cognitive impairment with valproic acid therapy: a report of ten cases.

BACKGROUND: Valproic acid (VPA) is commonly prescribed and is generally considered to have a good safety profile. Severe neurological side effects, such as acute encephalopathy or tremor, are well-known. Parkinsonian syndromes and cognitive impairment have been very rarely reported with this drug. METHODS: Ten cases of reversible parkinsonism associated with VPA in 6 women and 4 men, associated with marked cognitive impairment in six cases, are described. These side effects sometimes occurred after several years of good tolerability. RESULTS: All patients had serum levels within the therapeutic range (50-100 microg/ml). Symptoms improved several weeks or months after discontinuation of VPA therapy in every case. CONCLUSIONS: Several cases of parkinsonian syndromes have been reported in the literature, but usually in children or young adults. These symptoms had an insidious and progressive onset. Clinical features can mimic Parkinson's disease and may be confusing, especially when they occur in older patients. The mechanism of these disorders is currently unknown, but several hypotheses have been proposed. Despite the good safety of VPA therapy for several years, a drug-induced mechanism of parkinsonism or cognitive impairment must be considered in all patients treated with VPA, as discontinuation of the drug can induce significant improvement of the patient's neurological and mental status.

[Extrapyramidal adverse effects of veralipride (Agreal), a drug used to treat hot flushes: a propos of 17 cases]. / Troubles extrapyramidaux sous véralipride (Agréal), traitement symptomatique des bouffées de chaleur: à propos de 17 cas.

PURPOSE: Extrapyramidal disorders associated with veralipride therapy are rarely reported and often due to a drug misuse. METHODS: We evaluated cases of extrapyramidal disorders associated with veralipride. Cases were extracted from the regional pharmacovigilance centre of Amiens database. From January 1, 1995 to September 30, 2004, cases were selected on the basis of the occurrence of extrapyramidal disorders under veralipride therapy. RESULTS: Seventeen cases of veralipride-induced extrapyramidal disorders were found. They consist of 16 menopausal women and one old man with LH-RH antagonist-induced hot flushes. Mean age was 61 years (48-73). Adverse effects were acute dyskinesia (n=2) or parkinsonian syndrome, which occurred after several months or years of treatment (n=15). Parkinsonism was associated with other extrapyramidal symptoms in 8 cases: tardive dyskinesia (n=6), postural tremor (n=3), myoclonia (n=1), and trunk dystonia (n=1). In all cases, outcome was favorable after drug discontinuation. In most cases the tablet-free interval was not respected: this may lead to prolonged striatal D2 receptors blockade. It must be added that the diagnosis was often delayed and patients were considered as suffering from idiopathic Parkinson's disease. CONCLUSIONS: Prescribers should be aware that veralipride is a neuroleptic and could induce potentially severe extrapyramidal disorders. Increase veralipride prescription is expected due to the recent restriction of hormonal replacement therapy for menopause. The physicians should also use veralipride according to the Summary of the Product Characteristics.

[Intracranial hemorrhages associated with oral anticoagulant therapy. Analysis of 38 cases]. / Hémorragies intracrâniennes associées à un traitement anticoagulant oral. Analyse de 38 observations.

The major risk of oral anticoagulant therapy is haemorrhage potentially affecting all organs. Bleeding in the central nervous system is a rare but severe complication of anticoagulant therapy. This study aimed to analyse a series of intracranial haemorrhages. This series from the Regional Pharmacovigilance Center of Amiens included spontaneously reported and retrospectively collected cases from January 1999 to December 2000. During this period, 38 cases of intracranial bleeding possibly related to oral anticoagulant administration were reported; 19 women and 19 men, median age 69.5 (29 to 87) years. In 34% of the cases, patients died and in 18% neurologic sequelae were still present at the time of the evaluation. In 21 cases (62%), the INR (International Normalized Ratio) was higher than the therapeutic range recommended for the indication. Among the most frequent risk factors, hypertension and recent minor trauma are highlighted in this series. In 17 cases, oral anticoagulants were associated with potentially potentiating drugs. Mental status changes or headache were prominent early symptoms which had often been present for days. Our data confirm that anticoagulant-associated intracranial haemorrhages are not rare, can be severe, potentially fatal and are probably underestimated by physicians. The fact that more than 50% of patients in this series were overanticoagulated at the time of bleeding suggests that many cases of intracranial haemorrhage could be prevented by improved anticoagulation control. Epidemiological studies are needed in order to prospectively evaluate the incidence of this type of complication and its avoidance. The value of anticoagulation clinics can be discussed.

[Physiology and pharmacology of lacrymal and salivary secretions]. / Physiologie et pharmacologie des sécrétions lacrymale et salivaire.

Salivary and lacrymal glands have secretory mechanisms similar to those of other exocrine glands. Saliva results from two different but integrated processes i.e. hydroelectrolytic transport and protein secretion by regulated exocytosis. Both cellular processes are regulated by the autonomic nervous system with complementary effects without antagonism, and parasympathetic innervation predominates. Signal transduction mechanisms in salivary cells include: increases in cytosolic calcium, cyclic AMP and cyclic GMP. The tear film consists of three layers: mucous inner layer, middle aqueous layer, and outer lipid layer. Each layer secretion is strongly regulated. Aqueous layer secretion is controlled by autonomic nervous system and signal transduction depends from cyclic AMP and intracellular calcium levels. A review of drugs used in France modulating lacrymal and salivary secretions is proposed.

[Dementia and extrapyramidal problems caused by long-term valproic acid]. / Démence et troubles extra-pyramidaux sous acide valproïque au long cours.

Among the side-effects attributed to valproic acid (VPA), the occurrence of Parkinsonian syndromes and cognitive impairment is very uncommonly reported. We describe five cases of reversible associated Parkinsonism. These cases were observed in epileptic patients, 57 to 74 years old, two women and three men. Extrapyramidal disorders appeared after various durations of treatment (from 6 months to 10 years). Dementia characterized by an insidious onset was associated in three cases and bradypsychia in one case. Brain pseudoatrophy was present in three patients. In all cases the signs and symptoms improved some weeks or months after discontinuation of VPA. In the literature some cases, usually in young adults or children, have been reported. In a prospective study, Armon et al. found various abnormal symptoms and signs related to motor and cognitive function impairment in patients with long-term VPA therapy. These side-effects may be related to a disturbance in the gabaergic pathways in the basal ganglia system. It is of interest to consider that delta 2-valproic acid, a metabolite of VPA, is especially accumulated in selected areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus and medulla.

[Should folic acid be given to women treated with valproic acid and/or carbamazepine? Folic acid and pregnancy in epilepsy]. / Faut-il prescrire de l'acide folique aux femmes traitées par acide valproïque et/ou carbamazépine? Acide folique et grossesse chez l'épileptique.

Fetal exposure to valproic acid or carbamazepine increases the risk of neural tube defect (NTD). The risk of a mother having a baby with spina bifida has been estimated at 1-2 p. 100, close to the rate of risk of recurrent cases. No study has evaluated the effect of folic acid in neonates of women treated with valproic acid or carbamazepine although the protective effect against NTD has been proven in other populations. Periconceptional folic acid supplementation, 0.4 to 1 mg/day, for at least one month prior to conception and until the date of the second missed menstrual period or later decreases the incidence of a first occurrence of neural tube defect. Periconceptional folic acid supplementation, 4 mg/day, decreases the recurrence of NTD in women who had previously had a child with NTD. It seems pertinent to recommend periconceptional folic acid supplementation in women treated with carbamazepine or valporic acid. There are very few data in women on which to base a decision to advise taking 4 mg/day (as used in recurrence prevention) or low doses of 0.4 mg/day (used in primary prevention).

[Acute pancreatitis induced by drugs derived from 5-aminosalicylic acid: case report and review of the literature]. / Pancréatites aiguës induites par les médicaments dérivés de l'acide 5-aminosalicylique: un cas et revue de la littérature.

The pancreatic toxicity of oral 5-aminosalicylic acid (5ASA) derivatives used for the treatment of inflammatory bowel diseases remains controversial. A new case of mesalazine-induced acute pancreatitis (AP), with positive rechallenge, and an analysis of the previous published cases are presented. Twenty-nine patients (17 women, 12 men), aged 26.4 +/- 9.9 (12-43) years, were involved, receiving sulfasalazine (n = 11), mesalazine (n = 16), olsalazine (n = 1) or 5ASA without further informations (n = 1), for ulcerative colitis (n = 15), Crohn's disease (n = 13) or another indication (n = 1). The AP occurred in the first month of treatment in 71.4 per cent of the cases (n = 28). The clinical course was essentially benign in most of the cases. Recurrence of AP after rechallenge was observed in 17 of the 19 cases, even if the molecule, the dose or the form were modified. These results show that all 5ASA derivatives are potentially pancreatotoxic. An AP must be considered when an occurrence or increase of abdominal pain occurs during such therapy and warrants serum amylase assay and discontinuation of the drug.

[Syncope with long QT interval in a 39 day-old infant treated with cisapride]. / Malaise avec allongement de l'espace QT chez un nourrisson de 39 jours traité par cisapride.

UNLABELLED: Cardiotoxicity of cisapride may increase when this drug is associated with ranitidine. CASE REPORT: A 37-day old term infant, treated with cisapride (1.2 mg/kg/d) and ranitidine for regurgitations, was hospitalized for malaise. A prolonged QT interval (with isolate ventricular extrasystoles), noted at admission, disappeared rapidly after cisapride withdrawal. Linkage to cisapride was probable, promoted by high dosage and cisapride metabolism inhibition by ranitidine, but its plasma concentration was not measured. CONCLUSION: This case report stresses the problem of cisapride dosage in infants and the question of an interaction between cisapride and ranitidine.

[Esophageal involvement after tetracycline ingestion]. / Atteines oesophagiennes secondaires à l'ingestion de tétracyclines.

Between 1985 and 1992, 81 spontaneous oesophageal injuries associated with tetracycline were notified to the French Regional Pharmacovigilance Centres. The side effects were oesophageal ulcers (79 per cent), esophagitis (11 per cent) and dysphagia (10 per cent). Esophagitis and dysphagia appeared sooner (4 days) than the ulcers (15 days). The mean age of the patients was 29 +/ 13 years and 73 per cent were women. In 92 per cent of cases, the recommendations for administration were not observed (medication taken at bedtime with not enough or without water). With 96 per cent of patients, doxycycline was the tetracycline in question; this prevalence could be explained by its irritant and cytotoxic properties. The oesophageal injuries were 22 times more frequent with capsules than with tablets, because of their easier adhesion to the oesophageal surface. Oesophageal injuries are potentially serious and must be avoided by clear information to patients and prescribers on tetracycline administration; consumption in the middle of a meal with an adequate quantity of water and never less than one hour before bedtime.