Adverse drug effect in the context of drug shortage: the CIRUPT prospective study from the French pharmacovigilance network.

OBJECTIVES: Drug shortages are of increasing concern to worldwide public health. The consequences of drug shortages for patient safety have been little studied, especially from a pharmacovigilance point of view. In this context, the network of French pharmacovigilance centres conducted the CIRUPT study (Conséquences Iatrogènes des RUPTures de stock/iatrogenic consequences of drug shortages) based on a prospective campaign of adverse effects occurring in the context of drug shortage notifications. METHODS: All notifications involving a shortage drug submitted to the French pharmacovigilance centres between 1 January 2020 and 30 June 2021 were collected and registered in the French national pharmacovigilance database with the standardised high level term 'product supply and availability issues' and with predefined keywords in the narrative section. RESULTS: 224 cases were included, involving mainly adverse drug reactions (ADRs) (n=131/224, 59%) and medication errors (n=51/224, 23%); 29% of the cases were serious. The most represented classes of shortage drugs were: vaccines (n=78/224, 35%); drugs for acid-related disorders (H2-receptor antagonists) (n=27/224, 12%); antineoplastic agents (n=17/224, 8%); and antiepileptics (n=15/224, 7%). In 82% of cases, the involved shortage drug was the subject of information delivered to health professionals by the National Agency for the Safety of Medicines and Health Products. Drug shortages were associated with an ADR related to replacement drugs in 59% (n=131/224) of the cases, drug inefficacy in 18% (n=41/224), and/or an aggravation of the underlying disease in 11% (n=25/224). CONCLUSIONS: From a pharmacovigilance point of view, a large diversity of anatomical therapeutic classes is involved and the risk related to drug shortages is not limited to drugs registered on 'major therapeutic interest or essential drug' lists. Information from health agencies is not sufficient to avoid the risks, and further strategies should be developed.

Renal Safety Profile of BCR-ABL Tyrosine Kinase Inhibitors in a Real-Life Setting: A Study Based on Vigibase®, the WHO Pharmacovigilance Database.

BACKGROUND: Alongside their BCR-ABL specificity, TKIs used in chronic myeloid leukemia also target other tyrosine kinases expressed in the kidney such as PDGFR, c-KIT, SRC, and VEGFR, which may result in specific renal adverse drug reaction (ADR). To evaluate the renal safety profile in real-life conditions, a case/non-case study was performed on VigiBase®, the WHO global safety database. METHODS: From 7 November 2001 to 2 June 2021, all cases in which the involvement of imatinib, dasatinib, nilotinib, bosutinib, and ponatinib was suspected in the occurrence of renal ADR were extracted from VigiBase®. Disproportionality analyses were assessed using the reporting odds ratio. RESULTS: A total of 1409 cases were included. Imatinib accounts for half of the reported cases. A signal of disproportionate reporting (SDR) of renal failure and fluid retention was found for the five TKIs. Only dasatinib and nilotinib were related to an SDR for nephrotic syndrome. Nilotinib and ponatinib were related to an SDR for renal artery stenosis, while dasatinib was related to an SDR for thrombotic microangiopathy. No SDR for tubulointerstitial nephritis was observed. CONCLUSION: This study identified a new safety signal, nephrotic syndrome, for nilotinib and highlights the importance of post-marketing safety surveillance.

Pustular Lichenoid Eruptions Induced by Immune Checkpoint Inhibitors: Two Case Reports and a Review of the Literature.

Immune checkpoint inhibitors (ICIs) have become the standard treatment for many types of cancer. After several years of using these therapies, many adverse events related to ICIs have been observed. Dermatologic toxicities such as nonspecific morbilliform rash, vitiligo, Stevens-Johnson syndrome/toxic epidermal necrolysis, and more rarely, lichenoid eruptions have been described in the literature. We report 2 cases of pustular lichenoid eruptions, 1 in a patient with nonsmall cell lung carcinoma and 1 in a patient with metastatic melanoma, induced by pembrolizumab and nivolumab, respectively. The 2 patients were treated with topical corticosteroids, and complete healing of lesions was slowly obtained. Due to the severity of the cutaneous eruptions, pembrolizumab and nivolumab were discontinued. We identified 6 cases of pustular lichenoid eruptions induced by ICIs in the published literature and in the French Pharmacovigilance Database and reviewed their main clinical features and courses.

Incidence and preventability of hospital admissions for adverse drug reactions in France: A prospective observational study (IATROSTAT).

AIMS: In the last French study in 2007, the incidence of hospital admissions (HAs) related to adverse drug reactions (ADRs) was 3.6%. The objective was to assess the current ADR-HA incidence in France and to describe both its characteristics and preventability. METHODS: A prospective multicentre study was conducted among randomly selected French public hospital medical wards (April-July 2018). Patients admitted during a week period were included. ADR-HA cases were collected by the French Regional Pharmacovigilance Centres network. An independent committee validated potential cases and ADR preventability. RESULTS: ADR-HA incidence was 8.5% (95% confidence interval [CI]: 7.6-9.4%), increasing with age (3.3% [95%CI: 1.8-5.5%] ≤16 y vs. 10.6% [95%CI: 9.3-12.0%] ≥65 y). The most common ADRs were haemorrhagic events (8.8%), haematological disorders (6.5%), acute renal failure (6.3%), fluid and electrolyte disorders (6.0%), and falls (5.2%). New drugs were involved: targeted therapies (22.8% of antineoplastics), direct oral anticoagulants (29.6% of antithrombotics) and incretin-based drugs (20.0% of antidiabetics). ADRs were preventable in 16.1% of cases because the drugs involved had not been used in accordance with monographies, package leaflets or other therapeutic guidelines. The main situations of noncompliance addressed either dose or duration of use (27.9%), warning (23.2%), use precaution (18.6%) and inappropriate self-medication or misuse by patients (11.6%). CONCLUSION: In France, ADR-HA incidence dramatically increased over the last decade. A significant proportion was related to new pharmacological classes and considered as preventable. These findings should lead to in-depth thought on preventive actions on at-risk drug classes.

Adverse drug reaction related to drug shortage: A retrospective study on the French National Pharmacovigilance Database.

AIM: Drug shortages are a growing global health issue. The aim of the study was to evaluate the consequences of drug shortages on patient safety based on data recorded in the French National Pharmacovigilance Database. METHODS: All cases involving drug shortages reported from 1985 to the end of 2019 were extracted from the database. RESULTS: Following the selection process, 462 cases were included. The number of cases increased significantly from 2004 to 2019. Cases mainly involved drugs from the nervous system (22.1%, 95% confidence interval [CI] 17.5-27.0%), the cardiovascular system (16.4%, 95% CI 11.9-21.4%) and anti-infectives for systemic use (14.3%, 95% CI 9.7-19.2%) ATC classes. Most of the cases reported an adverse drug reaction (ADR) belonging to the SOC nervous system (21%, 95% CI 18-24%), skin and subcutaneous (14%, 95% CI 11-17%), general (13%, 95% CI 10-17%) and gastrointestinal (8%, 95% CI 5-11%) disorders. Disease worsening was observed in 15.9% of the cases, mostly related to a lack of efficacy of the replacement drug. Half of the cases were considered as serious. Evolution was favourable in 79.4% of the cases. Death and/or life-threatening situations were reported in 5.8% of the cases. Medication errors (MEs) were identified in 51 cases (11%), mostly occurring at the administration step and involving a human factor. CONCLUSION: This study emphasizes the clinical impact of drug shortage in terms of ADRs, ME and inefficiency. These observations underline the importance of a global health policy programme to limit the occurrence of drug shortages and to reinforce the information provided to patients and health care professionals in this context to limit risk.

Renal Safety Profile of EGFR Targeted Therapies: A Study from VigiBase® the WHO Global Database of Individual Case Safety Reports.

Kidney EGFR expression together with reported cases of glomerular diseases in the context of anti-EGFR drug administration raise concerns about the renal safety profile of these drugs. This issue is addressed in a case/non-case study carried out on VigiBase®, the WHO global database of individual case safety reports (ICRS). Disproportionality analysis of renal adverse effects related to the selected anti-EGFR drugs, erlotinib, gefitinib, afatinib, osimertinib, cetuximab and panitumumab, was assessed using the reporting odds ratio (ROR). Nine hundred and eighty-nine ICRSs were included. A signal of disproportionate reporting (SDR) was found for afatinib (ROR = 2.70; 95% CI [2.22-3.29]) and erlotinib (ROR = 1.73; 95% CI [1.46-2.04]) with acute kidney injury, and for afatinib (ROR = 2.41; 95% CI [1.78-3.27]), cetuximab (ROR = 1.42; 95% CI [1.14-1.78]) and erlotinib (ROR = 2.23; 95% CI [1.80-2.77]) with renal failure. The preferred term "diarrhoea" was frequently reported in the included cases. An SDR was found for erlotinib with haemolytic and uremic syndrome (ROR = 4.01; 95% CI [1.80-8.94]) and thrombotic microangiopathy (ROR = 4.94; 95% CI [2.80-8.72]). No SDR was seen for glomerular or tubule-interstitial diseases. This study showed that the anti-EGFR drug renal toxicity is mainly related to renal failure in the context of digestive toxicity.

Delayed thrombocytopenia following administration of abciximab: Pharmacovigilance survey and literature review.

BACKGROUND: Abciximab (ABX) is used for acute coronary syndrome and unstable angina. Thrombocytopenia is a frequent adverse effect described as occurring in the first 24hours. The aim of this study was to evaluate, in a context of pharmacovigilance survey, the occurrence of delayed thrombocytopenia following ABX infusion in pharmacovigilance database reports and in the literature. METHODS: Individual case safety reports (ICSRs) of delayed thrombocytopenia-between 3 and 30 days - with ABX presented as a single suspect were selected in VigiBase®, the WHO global database of ICSRs. The French cases were then extracted from the French national pharmacovigilance database. In addition, a literature review of published cases was performed using PubMed. RESULTS: Among the 84 ICSRs selected from VigiBase®, 43 were also reported in the FPVD. Mean age was 60.1±12.3 years with a majority of male patients (77.4%). The average time to onset (TTO) was 8.9±5.2 days. Thrombocytopenia regressed in 5.1±2.7 days. Haemorrhagic complications were reported in 15% of ICSRs. In the French cases, the median nadir of platelet count was 28×109/L (range 1-110) with a majority of grade 4 thrombocytopenia (39.5%). The literature review identified 42 cases and provided additional information on administered therapies, which include platelet units, corticosteroids, and IV immunoglobulins. GPIIb/IIIa-ABX complex antibodies were described in 26 published cases. CONCLUSION: Delayed thrombocytopenia, probably due to immune reaction, is a possible life-threatening adverse effect of ABX with a mean TTO of 9 days, supporting the recommendation of a platelet count monitoring during at least two weeks. This recommendation was added to the abcximab SmPC in 2019.

High Incidence of Amoxicillin-Induced Crystal Nephropathy in Patients Receiving High Dose of Intravenous Amoxicillin.

BACKGROUND: Amoxicillin (AMX)-induced crystal nephropathy (AICN) is considered as a rare complication of high dose intravenous (IV) AMX administration. However, recently, its incidence seems to be increasing based on French pharmacovigilance centers. Occurrence of AICN has been observed mainly with IV administration of AMX and mostly under doses over 8 g/day. Given that pharmacovigilance data are based on declaration, the real incidence of AICN may be underestimated. Thus, the primary objective of the present study was to determine the incidence of AICN in the current practice. MATERIALS AND METHODS: We conducted a retrospective study between 1 January 2015 and 31 December 2017 in Angers University Hospital. Inclusion criteria were age over 18 years-old and IV AMX administration of at least 8 g/day for more than 24 h. Patients admitted directly into the intensive care units were excluded. Medical records of patients that developed Kidney Disease:Improving Global Outcome (KDIGO) stage 2-3 acute kidney injury (AKI) were reviewed by a nephrologist and a specialist in pharmacovigilance. AICN was retained if temporality analysis was conclusive, after exclusion of other causes of AKI, in absence of other nephrotoxic drug administration. RESULTS: A total of 1303 patients received IV AMX for at least 24 h. Among them, 358 (27.5%) were exposed to AMX doses of at least 8 g/day and were included. Patients were predominantly males (68.2%) with a mean age of 69.1 years-old. AMX was administered for a medical reason in 78.5% of cases. Patients received a median dose of AMX of 12 g/day (152.0 mg/kg/day). Seventy-three patients (20.4%) developed AKI, 42 (56.8%) of which were KDIGO stage 2 or 3. Among the latter, AICN diagnosis was retained in 16 (38.1%) patients, representing an incidence of 4.47% of total patients exposed to high IV AMX doses. Only female gender was associated with an increased risk of AICN. AMX dose was not significantly associated with AICN development. CONCLUSION: This study suggests a high incidence of AICN in patients receiving high IV AMX doses, representing one third of AKI causes in our study. Female gender appeared as the sole risk factor for AICN in this study.

Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments.

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.

Drug-induced vitiligo: a case/non-case study in Vigibase® , the WHO pharmacovigilance database.

Vitiligo is a common depigmenting disorder ensuing the loss of epidermal melanocytes. It is a multifactorial disease with immunological, genetic and environmental factors including drug exposure. The purpose of the study was to investigate the drugs and therapeutic subclasses associated with vitiligo occurrence reported in VigiBase® , the WHO pharmacovigilance database. A case/non-case study was carried out by defining cases as vitiligo reports and non-cases as all other reports. The reporting odds ratio (ROR) was calculated for the 'suspected' drugs and drug classes according to ATC level 4. During the study period, 741 cases of vitiligo were registered. Mean age was 49 ± 20 years. The disproportionality analysis showed an association between vitiligo and pembrolizumab (ROR 116.9, 95% Confidence Interval (CI) 94.8, 144.3), nivolumab (ROR 22.6, 95% CI 15.8, 32.4), ipilimumab (ROR 41.7, 95% CI 25.0, 69.7), imiquimod (ROR 152.8, 95% CI 103.0, 226.7), adalimumab (ROR 3.8, 95% CI 2.5,5.8), infliximab (ROR 2.6, 95% CI 1.65, 4.01), alemtuzumab (ROR 27.8, 95% CI 17.6, 43.9), and ustekinumab (ROR 9.3, 95% CI 5.6, 15.6). Concerning the pharmacological classes ATC level 4, a significant association was found with monoclonal antibodies, interferons, selective immunosuppressants, TNF-alpha inhibitors, interleukin inhibitors, and topical antivirals. This study confirmed the expected associations between vitiligo and immune checkpoint inhibitors and strengthened the emerging signal about the association between vitiligo and imiquimod, TNF-alpha inhibitors and interferons. New signals were shown with selective immunosuppressants including alemtuzumab and interleukin inhibitors.

In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field. TAKE HOME MESSAGES.

Drug interactions related to self-medication: a French pharmacovigilance database study.

Self-medication (SM) is a common practice perceived by patients as harmless which can, however, entail health risks. The aim of the study was to identify drug-drug interactions (DDIs) involving SM drugs leading to adverse drug reactions (ADRs) in the National French Pharmacovigilance Database. All ADR reports from 1 January 1985 to 31 July 312018, coded as 'interaction' and 'self-medication', were selected and studied. Patient characteristics, the level and type of interaction, and the therapeutic classes of the drugs were examined. Adverse drug reactions were analysed and classified according to the system organ classes of the Medical Dictionary for Regulatory Activities. One hundred and three reports totalling 158 ADRs (71% severe cases) were included; 153 DDIs (59.5% pharmacodynamic) involving 234 drugs were identified. The latter included 119 SM drugs (51% available on prescription), mainly analgaesics, anti-inflammatory drugs, dietary supplements and antibiotics. Haemostasis disorders and renal failure were the most frequently reported ADRs. The analysis of reference documents raised concerns on the lack of information provided by package leaflets. In conclusion, the present study highlights the risks of medically unapproved re-use of prescription drugs or the consumption of dietary supplements without monitoring possible interactions and ADRs. Patient awareness could be improved by more regular updates of medication package inserts.

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.