Nirmatrelvir/ritonavir (Paxlovid®): French pharmacovigilance survey 2022.

INTRODUCTION: Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. METHOD: All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. RESULTS: Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. CONCLUSION: Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.

Pharmacovigilance follow-up of patients in the context of the COVID-19 pandemic.

INTRODUCTION: In the context of COVID-19 pandemic, a national pharmacovigilance survey was set up in March 2020. The purpose of this survey was to ensure continuous monitoring of adverse drug reactions (ADRs) in patients with COVID-19, not only related to the drugs used in this indication but also related to all drugs administered to these patients or suspected of having promoted the infection. MATERIAL AND METHODS: This descriptive study was based on data extracted from the French Pharmacovigilance Database from 1 January 2020 to 30 September 2021. Misuse was also analysed through the MESANGE project. The ADRs were classified according to three groups: "drugs used to treat COVID-19", "other drugs administered to COVID-19 positive patients" and "drugs suspected of having promoted COVID-19". The data were also presented according to 2 periods (period one was from January to June 2020 and period two from July 2020 onwards). RESULTS: Among 2189 included cases, 67.1% were serious. Cases were mainly related to "other drugs administrated to COVID-19 positive patients" (58.5%) followed by "drugs used to treat COVID-19" (33.7%) and "drugs suspected of having promoted COVID-19" (7.8%). Drugs used to treat COVID-19 and their main safety profile were different depending on the period: mostly hydroxychloroquine (51%) with heart injury and lopinavir/ritonavir (42%) with liver injury for the first period, and dexamethasone (46%) with hyperglycemia and tocilizumab (28%) with liver injury for the second period. The drugs suspected of worsening COVID-19 differed in both periods especially for non-steroidal anti-inflammatory drugs mainly reported in period 1 (41.5% versus 8.2% in period 2). Other immunosuppressive drugs were in the majority in the second period (85.7%), with mainly methotrexate (15.3%), anti-CD20 (15.3%) and anti-TNF alpha (10.5%). No confirmed safety signal was identified among other drugs administered to patients with COVID-19. The profile of ADRs and suspected drugs was similar between the 2 periods. The study of misuse in outpatient settings identified in both periods mainly hydroxychloroquine, azithromycin, ivermectin and zinc±vitamin C. DISCUSSION: This survey, based on real-time pharmacological and medical assessment of ADRs and weekly meetings in a specific national committee, made it possible to identify relevant safety signals which contribute to patient care with no delay. The main safety signal highlighted was serious cardiac damage under hydroxychloroquine, alone or combined with azithromycin and also with lopinavir/ritonavir. This signal has contributed to the evolution of the recommendations for these 2 drugs. The methodology of this survey has been taken over and is still going on for the pharmacovigilance monitoring of vaccines against COVID-19, for monoclonal antibodies used against COVID-19 and also for Paxlovid® (nirmatrelvir/ritonavir) which benefit from dedicated surveys.

[Management of medication errors in general medical practice: Study in a pluriprofessionnal health care center]. / Gestion des erreurs médicamenteuses en médecine générale : étude en maison de santé pluridisciplinaire.

BACKGROUND: Medication errors are the most frequent medical care adverse events in France. Their management process used in hospital remains poorly applied in primary ambulatory care. OBJECTIVES: The main objective of our study was to assess medication error management in general ambulatory practice. The secondary objectives were the characterization of the errors and the analysis of their root causes in order to implement corrective measures. METHODS: The study was performed in a pluriprofessionnal health care house, applying the stages and tools validated by the French high health authority, that we previously adapted to ambulatory medical cares. RESULTS: During the 3 months study 4712 medical consultations were performed and we collected 64 medication errors. Most of affected patients were at the extreme ages of life (9,4 % before 9 years and 64 % after 70 years). Medication errors occurred at home in 39,1 % of cases, at pluriprofessionnal health care house (25,0 %) or at drugstore (17,2 %). They led to serious clinical consequences (classified as major, critical or catastrophic) in 17,2 % of cases. Drug induced adverse effects occurred in 5 patients, 3 of them needing hospitalization (1 patient recovered, 1 displayed sequelae and 1 died). In more than half of cases, the errors occurred at prescribing stage. The most frequent type of errors was the use of a wrong drug, different from that indicated for the patient (37,5 %) and poor treatment adherence (18,75 %). The systemic reported causes were a care process dysfunction (in coordination or procedure), the health care action context (patient home, not planned act, professional overwork), human factors such as patient and professional condition. The professional team adherence to the study was excellent. CONCLUSION: Our study demonstrates, for the first time in France, that medication errors management in ambulatory general medical care can be implemented in a pluriprofessionnal health care house with two conditions: the presence of a trained team coordinator, and the use of validated adapted and simple processes and tools. This study also shows that medications errors in general practice are specific of the care process organization. We identified vulnerable points, as transferring and communication between home and care facilities or conversely, medical coordination and involvement of the patient himself in his care.

Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services.

AIMS: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy. METHOD: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group. RESULTS: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference. CONCLUSION: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.

Pregnancy outcome following in utero exposure to azathioprine: A French comparative observational study.

AIM OF THE STUDY: To evaluate whether azathioprine exposure during pregnancy increases the risk of birth defects and prematurity. METHOD: Prospective comparative observational study using the French pregnancy database TERAPPEL. To evaluate birth defects, outcomes of pregnancies exposed to azathioprine during the 1st trimester were prospectively assessed and compared to that of pregnancies exposed to another drug used for the same indications. Secondly, the rate of preterm births was compared between fetuses exposed to azathioprine at least during the third trimester and those exposed during the first trimester only. RESULTS: From 447 requests for a risk assessment for women receiving azathioprine during pregnancy, 193 pregnancies meet inclusion criteria. One hundred and twenty-four of them were exposed to azathioprine during the 1st trimester and were compared to that of 124 pregnancies exposed to another drug used for the same indication. Azathioprine use during the first trimester was not statistically associated with the risk of all birth defects ([7.3% vs. 5.4%]; [OR=1.36; 95%CI: 0.44-4.20]) nor with major birth defects (5.2% vs. 1.8% [OR=2.96; 95%CI: 0.56-15.64]). The rate of preterm births (22.5% vs. 27.3%, P=0.579) was similar regardless of the exposure period to azathioprine (at least during the third trimester or during the first trimester only). CONCLUSIONS: This study confirms that first trimester exposure to azathioprine is not associated with an elevated rate of birth defects and that the high rate of preterm births among women exposed to azathioprine is probably explained by the underlying maternal disease.

[Serious adverse drug reactions with tramadol reported to the French pharmacovigilance database between 2011 and 2015]. / Effets indésirables « graves ¼ du tramadol : bilan 2011­2015 de pharmacovigilance en France.

BACKGROUND: Tramadol is an opioid and a serotonin reuptake inhibitor drug. It is approved for moderate to severe pain in adults. The aim of this study was to assess tramadol safety through a national pharmacovigilance study in France since dextropropoxyphen withdrawal in 2011. METHODS: We described all serious adverse drug reactions (SADRs) reported with tramadol in adults in the French National PharmacoVigilance Database from August 1st, 2011 to December 31st, 2015. RESULTS: We identified 1512 SADRs during the study period. The most frequently reported SADRs were neurological (29.4%, including troubles of consciousness [13.2%] and seizures [6.7%]), psychiatric (22.8%, including confusions [14.6%] and hallucinations [7.3%]) and gastrointestinal (17.0%, mostly nausea and vomiting [9.6%]). Unexpected SADRs were also reported: hyponatremia, cholestatic hepatitis, serotonin syndrome. CONCLUSIONS: This study demonstrates new unexpected hepatic and metabolic SADRs. Tramadol alone can induce serotonin syndrome in overdose situations.

Safety profile of etifoxine: A French pharmacovigilance survey.

Etifoxine chlorhydrate is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety since 1979. Previously labeled adverse drug reactions (ADRs) only include drowsiness, benign cutaneous reactions, and acute hypersensitivity reactions. The objectives were to examine recent data on etifoxine-related ADR by reviewing Individual Case Safety Reports (ICSRs) recorded in France especially unexpected ADRs. Etifoxine-related ICSRs were extracted from the French Pharmacovigilance database from 1 January 2000 to 30 April 2012 and data from the marketing authorization holder up to 31 December 2011 were also obtained. Of the 350 cases retained for analysis, 123 (35%) were considered serious. Dermatological or acute hypersensitivity reactions were the most frequent ADRs (59%) mainly isolated cutaneous eruptions. However, there were 24 cases of severe toxidermia (DRESS in 5, erythema multiforme in 10 and Stevens-Johnson syndrome in 5) with etifoxine as the most suspected drug in 11 patients, and seven cases of vasculitis or serum sickness-like reaction. Liver disorders were reported in 34 patients of whom 25 developed acute hepatitis with a cytolytic biological pattern in 16. Other unexpected ADRs included 16 reversible cases of metrorrhagia with positive rechallenge in 5, and three cases of biopsy-proven microscopic colitis of which one recurred after etifoxine re-administration. Although etifoxine has been marketed for more than 30 years, this survey identified a number of unexpected and sometimes serious ADRs, in particularly severe toxidermia and acute cytolytic hepatitis. A recent update of the French etifoxine summary of the product characteristics (SPC) was based on these findings.

[Pristinamycin/Vitamin k antagonists drug interaction: a French pharmacovigilance database study]. / Interaction pristinamycine/antivitamine K: analyse de la base française de pharmacovigilance.

OBJECTIVE: To analyse pristinamycin/vitamin K antagonists (VKA) drug interaction by using data recorded in the French pharmacovigilance database (FPVB). METHODS: All cases with an increase effect of a VKA and an association with pristinamycin recorded in the FPVB between 1985 and 2013 were included. Data concerning patients, VKA treatments and side effects were recorded for a descriptive analysis. RESULTS: During this period, 31 reports with a VKA overdose after an association with pristinamycin were included. Fluindione is the most often involved VKA (77% of cases). In 20 cases (65.4%), VKA overdose caused bleeding and 24 cases (77.4%) were serious. CONCLUSION: Although mechanism is unknown, pristinamycine/AVK drug interaction is a reality that needs to be reported in the summary of product characteristics of these drugs and better known by practitioners to act in patients' interest.

Decrease in factor V activity in patients treated with azathioprine or 6-mercaptopurine.

BACKGROUND AND OBJECTIVE: A decrease in factor V activity has been reported in some patients treated with azathioprine or 6-mercaptopurine. This may lead to unnecessary treatment discontinuation in otherwise asymptomatic patients. Our aim was to review spontaneously reported cases of decreased factor V activity associated with both drugs and to identify the possible impact on patient care. METHODS: Cases of decrease in prothrombin (PT) or factor V activity involving purine analogs were extracted from the French pharmacovigilance database. Reports with evidence of disseminated intravascular coagulation, signs of acute hepatocellular failure, liver cirrhosis or concomitant vitamin K antagonist treatment were excluded. RESULTS: Twenty-four cases (azathioprine: 13 and 6-mercaptopurine: 11) were retained. Therapeutic indications were inflammatory bowel diseases in 11 patients, acute leukemia in eight, and other autoimmune diseases in five. PT activity before treatment was normal in all nine tested patients. The decrease in PT or factor V activity occurs after a median of 10 weeks of treatment and all patients were asymptomatic. The median PT and factor V activities values were 51.5% and 36.4%, respectively. Other coagulation factors were inconsistently decreased. Full recovery was observed within 3-60 days following purine analogs discontinuation. In four patients, drug rechallenge was associated with recurrence of the coagulation disorders. CONCLUSIONS: Although the mechanism remains unknown, this series that includes cases with positive drug reintroduction strongly suggests the causative role of these drugs. As all patients remained asymptomatic, treatment discontinuation should be carefully considered in patients who clearly benefits from this treatment.

Cytochrome P450 interactions and clinical implication in rheumatology.

There are many potential drug interactions that involve the complex cytochromes P450 (CYP) enzyme system when treatments for chronic inflammatory rheumatic diseases are used. This iatrogenic risk is increased in patients taking multiple drugs such as those with rheumatoid arthritis or gout, whatever the type of CYP interaction (substrate, inducer, or inhibitor of one of the CYP isoenzymes). Some of these CYP interactions may have clinical consequences, sometimes serious (overdose or therapeutic failure) and are often unrecognized by clinicians. The aim of this article is first of all to act as a reminder of the metabolic role of membrane-bound CYP enzymes in the liver in the oxidation of drugs and the potential types of interaction (drug substrate, inducer, or inhibitor or indirectly by the modulation of CYP activity through its powerful antiinflammatory activity). Secondly, the different factors that modulate the enzymatic activity of CYP will be described that may contribute to variations in drug metabolism and therefore modify the benefit-risk ratio of the drug. Thirdly, an analysis based on a review of the literature will present the different known interactions via CYP for drugs used in clinical practice in rheumatic diseases: analgesics, antiinflammatory drugs, conventional disease-modifying antirheumatic drugs and biologic agents. To limit the clinical consequences of these CYP interactions, it is recommended to focus on drugs that are really essential, to systematically identify the rheumatic patients most at risk before prescribing, and thus to adopt therapeutic strategies that reduce iatrogenic risk.

Cetuximab infusion reactions: French pharmacovigilance database analysis.

OBJECTIVES: To compare characteristics of patients exhibiting cetuximab infusion reactions or another adverse drug reaction related to cetuximab and to identify factors associated with the severity of cetuximab infusion reactions. METHODS: All cases of adverse drug reaction reported with cetuximab from 1985 to 2010 were extracted from the French Pharmacovigilance database. The severity of infusion reactions was assessed according to the NCI-CTCAE criteria (v4.0). Multiple logistic regression analysis was performed to identify factors associated with the severity of infusion reactions. RESULTS: Among the 602 adverse drug reaction reported with cetuximab during the study period, 374 infusion reactions were identified. Indication is more likely to be head and neck than colorectal cancer among patients experiencing an infusion reaction (p < 0.001). Among the seven deaths related to an infusion reaction, five patients were treated for head and neck cancer. Infusion reactions were more likely to be severe when they occurred during the first administration (OR = 7.40 95% CI [2.21-24.71]), adjusted for age, sex, region of France, quarter of the year, indication, year of occurrence, and premedication. CONCLUSION: Our study found that reports of infusion reactions more often concerned patients treated for head and neck cancer, that in these patients the adverse drug reaction was more often fatal and severe infusion reactions were more likely during the first administration. In daily practice, the close monitoring of patients during the first infusion, especially patients with head and neck cancer, is recommended. Considering the possible immunoglobulin E-mediated mechanism, reliable tests for their detection need to be readily available.

Assessment of the use of hypolipidemic agents (HAs), mainly statins, in elderly subjects aged 80 years and more in Burgundy: analysis of 13,211 patients.

Only few studies have investigated the use of HA in elderly subjects and there are no data in very elderly subjects. We assessed the prescription of HA and analyzed the relationship between such prescriptions and frailty markers among persons aged 80 and more in an observational study. We recorded the prescriptions for 13,211 patients aged 80-109 years and affiliated to the "Mutualité-Sociale-Agricole (MSA)" of Burgundy over a 1-month period. The prescription of a HA among all included patients, and the existence of serious long-term disease(s) (LTD), polypharmacy or a prescription of cardiovascular drugs among patients receiving a HA were recorder. Among the 13,211 patients, 3412 aged 80-98 years were treated with an HA. The main HA were statins (70.4%), and fibrates were used in 27.3% of cases. Of these 3412 patients, 2250 had one or several LTD mainly coronaropathy, hypertension, diabetes mellitus or peripheral artery disease. The mean number of drugs per prescription was 6.37. Among subjects treated with HA, 40% also received antiplatelets, 35.6% ß-blockers and 30% inhibitors of the renin-angiotensin system. For 99% of the patients, the prescription of HA was a renewal. Prescribers were mainly general practitioners (96.8%). Statins are the most widely prescribed HA even among very elderly subjects. However, after 80 years the prescription of HA, mainly statins, decreases with aging. This could be explained by polypathology, polypharmacy and the deterioration in metabolic functions which are markers of frailty. This study should encourage research into the use of statins in very elderly subjects.

[Tramadol-induced hypoglycemia. 2 cases]. / Hypoglycémie lors d'un traitement par tramadol. A propos de deux cas.

INTRODUCTION: Tramadol has been approved in France since 1994 for the treatment of moderate to severe pain. The most commonly reported adverse effects involve the central nervous system and gastrointestinal tract. To our knowledge, hypoglycemia has not previously been reported. CASE: We report 2 cases of hypoglycemia related to tramadol, one in a nondiabetic 88-year-old woman, and the other in a diabetic 8-year-old girl. Hypoglycemia resolved after tramadol discontinuation. DISCUSSION: The French Pharmacovigilance (Adverse Drug Reports) database includes several cases of hypoglycemia in patients receiving tramadol. Reports from the literature of dextropropoxyphene-induced hypoglycemia and a pharmacological study of tramadol in rats suggest that the micro opioid receptor is the principal target involved in this hypoglycemic mechanism.

Joint symptoms in patients on bupropion therapy.

OBJECTIVE: To describe joint symptoms related to bupropion therapy. METHODS: We retrospectively reviewed adverse events in bupropion-treated patients reported to the Bourgogne Drug Surveillance Center, France, between October 2001 and December 2002. Joint symptoms classified by the causality assessment as related to bupropion were identified and examined. RESULTS: Four cases were found. Three patients had semi-delayed hypersensitivity reactions resembling serum sickness, manifesting as urticaria and arthralgia with or without a fever. The remaining patient had an unusual presentation consisting in acute monoarthritis of the wrist that started a few days after bupropion initiation. CONCLUSION: Hypersensitivity reactions to bupropion are fairly common and include rare cases of serum sickness-like reaction. Urticaria and incapacitating arthralgia are at the forefront of the clinical picture and may require a brief period of inpatient care. Antihistamines are the treatment of choice. Other manifestations such as acute monoarthritis might occur, although this awaits confirmation as we identified a single case.