Recurrence of severe symptomatic late-onset neutropenia on ocrelizumab.

BACKGROUND: Late-onset neutropenia (LON), defined as an absolute neutrophil count (ANC) < 1500/mm3 that develops between 4 weeks and 6 months after the last drug administration, is a rare side effect of anti-CD20 drugs including ocrelizumab. Although continuation of ocrelizumab after LON is not contraindicated, the risk of LON recurrence is not well known. CASES: We report three cases of recurrent symptomatic agranulocytosis (ANC < 500/mm3) occurring under ocrelizumab. CONCLUSION: Given the risk of recurrence of symptomatic agranulocytosis and the availability of other treatments, a therapeutic switch may be discussed after the first episode of LON.

Peripheral neuropathies after BRAF and/or MEK inhibitor treatment: A pharmacovigilance study.

Reports suggested the potential occurrence of peripheral neuropathies (PN) in patients treated with BRAF (BRAFi) and/or MEK inhibitors (MEKi) for BRAF-activated tumours. We aimed to better characterize these PN. We queried the French pharmacovigilance database for all cases of PN attributed to BRAFi and/or MEKi. Fifteen patients were identified. Two main clinical PN phenotypes were seen. Six patients presented a length-dependent, axonal polyneuropathy: symptoms were mostly sensory and affecting the lower limbs; management and outcome were variable. Nine patients developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness and ataxia; cranial nerves were involved in four cases; most patients received intravenous immunoglobulins or glucocorticoids, with variable outcome; one patient was rechallenged with a different BRAFi/MEKi combination with a rapid relapse in symptoms. In conclusion, patients under BRAFi/MEKi therapy may develop treatment-induced PN. Two main phenotypes can occur: a symmetric, axonal, length-dependent polyneuropathy and a demyelinating polyradiculoneuropathy.

Leukoencephalopathy with transient splenial lesions related to 5-fluorouracil or capecitabine.

BACKGROUND: 5-Fluorouracil (5-FU) and its oral prodrug capecitabine have been rarely but consistently associated with acute central nervous system toxicity, including transient leukoencephalopathies involving the splenium of the corpus callosum. METHODS: We performed a retrospective search in the French Pharmacovigilance database (FPDB) (January 1985-July 2020) for adult patients affected by solid cancers who developed acute toxic leukoencephalopathies with splenial lesions following treatment with 5-FU or capecitabine. A comprehensive review of the literature helped to circumstantiate our findings. RESULTS: Our research in the FPDB identified six patients who, within 3 days from their first cycle of 5-FU or capecitabine, developed acute neurological symptoms, including gait ataxia (n = 4), dysarthria (n = 3), dysmetria (n = 2), headache (n = 2), and confusion (n = 2). Brain magnetic resonance imaging (MRI) showed T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities in the corpus callosum, with diffusion restriction and no contrast enhancement, generally accompanied by additional alterations in the bilateral supratentorial white matter (n = 5). All patients discontinued the agent supposedly responsible for the toxicity and experienced full recovery after a median of 8.5 days from symptom onset. Control MRI showed a progressive normalization of acute MRI abnormalities. Literature review identified 26 cases with similar clinical and paraclinical characteristics. A single patient from the literature resumed 5-FU at a lower dose, with no recurrent toxicity. CONCLUSIONS: 5-FU and capecitabine might be responsible for acute leukoencephalopathies with transient splenial lesions that are generally reversible upon drug discontinuation. Resuming the agent responsible for toxicity might be feasible in selected cases, after having excluded dihydropyrimidine dehydrogenase deficiency, if expected benefits outweigh the risks.

Drug-induced aseptic meningitis: 329 cases from the French pharmacovigilance database analysis.

AIMS: Drug-induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify suspected drugs. METHODS: Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All cases were initially analysed according to the French imputability method by institutional pharmacologists (clinicians or pharmacists). Further analyses of well documented cases were then performed. RESULTS: In this study, 329 cases of aseptic meningitis were retrieved from the French Pharmacovigilance Database for a total of 429 suspected drugs. Analysis of 203 well documented cases, including 282 drugs, showed that the main reported classes were intravenous polyvalent immunoglobulin, nonsteroidal anti-inflammatory drugs (NSAIDs), vaccines, antimicrobials, intrathecal antimetabolites, corticosteroids and antalgics/anaesthetics (except NSAIDs). Lymphocytic (33.0%) and purulent (44.8%) meningitis represented the majority of cases of aseptic meningitis. In other cases, the cerebrospinal fluid was mixed (45-55% of neutrophils +45-55% of lymphocytes) or data about cerebrospinal fluid composition were lacking. Most DIAM cases (96%) had a favourable reported outcome with full recovery or minimal residual symptoms. CONCLUSION: The most frequently involved drugs in DIAM were intravenous polyvalent immunoglobulin, NSAIDs, vaccines, and antimicrobials and this without being able to differentiate them in terms of biological characteristics. Although further studies are needed to better understand the pathophysiological mechanisms of DIAM, a continuous enrichment of pharmacovigilance databases is essential to identify new signals and to help clinicians in the understanding of DIAM.

Influence of diluent volume of colistimethate sodium on aerosol characteristics and pharmacokinetics in ventilator-associated pneumonia caused by MDR bacteria.

Objectives: Nebulized colistimethate sodium (CMS) can be used to treat ventilator-associated pneumonia caused by MDR bacteria. The influence of the diluent volume of CMS on aerosol delivery has never been studied. The main objectives of the study were to compare aerosol particle characteristics and plasma and urine pharmacokinetics between two diluent volumes in patients treated with nebulized CMS. Methods: A crossover study was conducted in eight patients receiving nebulized CMS every 8 h. After inclusion, nebulization started with 4 million international units (MIU) of CMS diluted either in 6 mL (experimental dilution) or in 12 mL (recommended dilution) of normal saline in a random order. For each diluent volume, CMS aerosol particle sizes were measured and plasma and urine samples were collected every 2 h. Nebulization time and stability of colistin in normal saline were assessed. Results: The mass median aerodynamic diameters were 1.4 ±âŸ0.2 versus 0.9 ±âŸ0.2 µm (P < 0.001) for 6 and 12 mL diluent volumes, respectively. The plasma area under the concentration-time curve from 0 to 8 h (AUC0-8) of colistinA+B was 6.6 (4.3-17.0) versus 6.7 (3.6-14.0) µg·h/mL (P = 0.461) for each dilution. The total amount of colistin and CMS eliminated in the urine represented, respectively, 17% and 13% of the CMS initially placed in the nebulizer chamber for 6 and 12 mL diluent volumes (P = 0.4). Nebulization time was shorter [66 (58-75) versus 93 (69-136) min, P = 0.042] and colistin stability was better with the 6 mL diluent volume. Conclusions: Nebulization with a higher concentration of CMS in saline (4 MIU in 6 mL) decreases nebulization time and improves colistin stability without changing plasma and urine pharmacokinetics or aerosol particle characteristics for lung deposition.

Determination of Colistin and Colistimethate Levels in Human Plasma and Urine by High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Colistin is a polypeptide antibiotic from the polymyxin E group used for the treatment of infections caused by multidrug-resistant gram-negative bacteria. The main constituents, accounting for approximately 85% of this mixture, are colistin A (polymyxin E1) and colistin B (polymyxin E2). The aim of this study was to develop and validate new and fast methods of quantification of colistin A and B and its precursors [colistin methanesulfonate sodium (CMS) A and B] by ultraperformance liquid chromatography-tandem mass spectrometry in plasma and urine with short pretreatment and run times. METHODS: Chromatography was performed on an Acquity UPLC-MS/MS system (WATERS) with a WATERS Acquity UPLC C18 column (4.6 × 150 mm, 3.5 µm particle size). The pretreatment of samples consists of precipitation and extraction into microcolumns plate and HLB 96-well plate 30 µm-30 mg (OASIS) with a Positive Pressure-96 (WATERS). RESULTS: Quantification was performed using a multiple reaction monitoring of the following transitions: m/z 390.9 → 385.1 for colistin A, m/z 386.2 → 101.0 for colistin B, and m/z 602.4 → 241.1 for polymyxin B1 sulfate. In plasma and urine, calibration curves were linear from 30 to 6000 ng/mL for colistin A and from 15 to 3000 ng/mL for colistin B. With an acceptable accuracy and precision, the lower limit of quantification were set at 24.0 ng/mL and 12.0 ng/mL for colistin A and B in plasma, and at 18.0 ng/mL and 9.0 ng/mL for colistin A and B in urine. CONCLUSIONS: These LC-MS/MS methods of quantification for colistin A and B and its precursors (CMS A and B) in plasma and urine are fast, simple, specific, sensitive, accurate, precise, and reliable. Furthermore, they are linear and repeatable. These procedures were successfully applied to a pharmacokinetic study of a critically ill patient suffering from ventilator-associated pneumonia, who was treated with nebulized CMS.

Development and validation of a rapid and simple LC-MS/MS method for quantification of vemurafenib in human plasma: application to a human pharmacokinetic study.

BACKGROUND: Vemurafenib (Zelboraf) is a new tyrosine kinase inhibitor that selectively targets activated BRAF V600E gene and is indicated for the treatment of advanced BRAF mutation-positive melanoma. We developed a simple method for vemurafenib quantification using liquid chromatography-tandem mass spectrometry. A stability study of vemurafenib in human plasma was also performed. METHODS: (13)C(6)-vemurafenib was used as the internal standard. A single-step protein precipitation was used for plasma sample preparation. Chromatography was performed on an Acquity UPLC system (Waters) with chromatographic separation by the use of an Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7-mm particle size; Waters). Quantification was performed using the monitoring of multiple reactions of following transitions: m/z 488.2 → 381.0 for vemurafenib and m/z 494.2 → 387.0 for internal standard. RESULTS: This method was linear over the range from 1.0 to 100.0 mcg/mL. The lower limit of quantification was 0.1 mcg/mL for vemurafenib in plasma. Vemurafenib remained stable for 1 month at all levels tested, when stored indifferently at room temperature (20 °C), at +4 °C, or at -20 °C. This method was used successfully to perform a plasma pharmacokinetic study of vemurafenib in a patient after oral administration at a steady state. CONCLUSIONS: This liquid chromatography-tandem mass spectrometry method for vemurafenib quantification in human plasma is simple, rapid, specific, sensitive, accurate, precise, and reliable.

Impact of the vaccination against SARS-CoV-2 campaign on disproportionality indicator from the WHO pharmacovigilance database: A competition bias study from case/non-case analysis.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) vaccination campaign has resulted in numerous pharmacovigilance's safety reports which were recorded in the World Health Organization (WHO) pharmacovigilance database (VigiBase) and represent in July 2022 more than 10% of cases recorded. The information component (IC) is a statistical disproportionality measure based on the observed and expected numbers of case reports. A positive value of the lower endpoint of a 95% credibility interval for the information component (IC0.25) suggests a possible causal relationship between the drug and the adverse reaction. This study aimed to evaluate the impact of the wave of COVID-19 vaccines safety declarations on IC0.25 from Vigilyze and thus illustrate with a concrete example the competition bias. METHODS: We arbitrarily selected 21 adverse drug reactions using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs), divided in two types: PTs known to be related to COVID-19 vaccines ("expected") and others (type "unexpected"). Data were extracted from VigiLyze. We created two groups: V+ (the full database, including COVID-19 vaccines reports) and V- (the same extraction without COVID-19 vaccine reports). IC0.25 was recomputed for the group V- and we compared the positive signal evolution in the two settings of selection (V+ and V- groups). RESULTS: The number of positive potential signals was significantly different in the groups V+ and V- for IC0.25. We observed that most of the "unexpected" PTs lost potential signal after the withdrawal of COVID-19 reports. On the contrary, the majority of 'expected' PTs had potential new signals after the withdrawal of COVID-19 reports. DISCUSSION: This study is one of the first to evaluate the effect of COVID-19 vaccines reporting on Automated Signal Detection of Pharmacovigilance. In this study, we observed that a wave of pharmacovigilance reporting can affect disproportionality estimators such as IC0.25 and then have an impact on automated signal detection; some signals disappear (almost with all PTs related to COVID-19 vaccines) and others appear (mostly with PTs not related to COVID-19 vaccines), illustrating the competition bias. CONCLUSION: We show that a health crisis involving a change in drug use can affect adverse drug reactions reporting and pharmacovigilance databases, leading to competition bias and a change in the disproportionality analyses. For health professionals who use quantitative disproportionality analysis, it is important not only to use the crude values of indicators but also the kind of PTs and the evolution of the signal over time (take into account major events such as crises).

Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective.

Background: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. Methods: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. Findings: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (<1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. <3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio>5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951). Interpretation: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. Funding: Paul Gougis was supported by the academic program: "Contrats ED: Programme blanc Institut Curie PSL" for the conduct of his PhD. Baptiste Abbar was supported by "the Fondation ARC Pour le Rechercher Sur le Cancer". The RT2L research group (Institut Curie) was supported by the academic program "SHS INCa", Sanofi iTech award, and by Monoprix∗.

Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns.

Importance: With the widespread use of immune checkpoint inhibitors (ICIs), concerns about their pregnancy outcomes through maternal exposure have emerged, and clinical comparative data are lacking. Objective: To assess the risk of pregnancy-, fetal-, and/or newborn-related adverse outcomes associated with exposure to ICIs compared with exposure to other anticancer agents. Design, Setting, and Participants: In this cohort study, all reports mentioning a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) used for a cancer indication registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. Exposure: Anticancer agents, including ICIs, used during pregnancy for a cancer indication. Immune checkpoint inhibitors included blockers of programmed cell death 1 (PD1) or its ligand (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Main Outcomes and Measures: The main outcome was the reporting odds ratio (ROR) for maternal, fetal, or newborn complications in patients treated with ICIs vs any other anticancer drug. Adverse events, categorized into 45 individual maternofetal adverse outcomes, were directly mapped to Medical Dictionary for Regulatory Activities preferred terms in VigiBase. Results: A total of 3558 reports (ICI: 91 [2.6%]; other anticancer drugs: 3467 [97.4%]) were included in the analysis. In the ICI group, most reports were from the US (60 [65.9%]), and the mean (SD) patient age was 28.9 (10.2) years; in 24 of 55 reports with data on cancer type (43.6%), patients were treated for melanoma. The molecules involved in the ICI group were anti-PD1 (58 reports [63.7%]), anti-PD1 plus anti-CTLA4 (15 [16.5%]), anti-CTLA4 (13 [14.3%]), anti-PD-L1 (4 [4.4%]), and anti-PD1 plus anti-lymphocyte activation gene 3 (1 [1.1%]). An ICI was used in combination with a non-ICI anticancer agent in 10 participants (11.0%). Compared with other anticancer drugs, none of the 45 adverse outcomes identified were overreported in the group exposed to ICIs. However, preterm birth was significantly overreported for the anti-PD1 plus anti-CTLA4 combination compared with other anticancer drugs (12 of 15 [80.0%] vs 793 of 3452 [23.0%]; ROR, 13.87; 95% CI, 3.90-49.28; P < .001) but not for anti-PD-L1 or anti-CTLA4 monotherapy. Three reports of possibly immune-related maternofetal events were identified: 1 case of maternal antiphospholipid syndrome leading to spontaneous abortion, 1 case of pneumonitis leading to neonatal respiratory distress syndrome and death, and 1 case of transient congenital hypothyroidism. Conclusions and Relevance: In this cohort study of 91 individuals exposed to ICIs during pregnancy, ICI exposure was not associated with overreporting of specific adverse pregnancy, fetal, and/or newborn outcomes compared with other anticancer treatments. However, due to possible rare immune-related neonatal adverse events, ICI use in pregnant women should be avoided when possible, especially the anti-PD1 plus anti-CTLA4 combination.

Drug-induced delusion: A comprehensive overview of the WHO pharmacovigilance database.

INTRODUCTION: A number of prescribed medicines have been reported in cases of drug-induced delusion, such as dopaminergic agents or psychostimulants. But to this day, most studies are based on a limited number of cases and focus on a few drug classes, so a clear overview of this topic remains difficult. To address this issue, we provide in this article a comprehensive analysis of drug-induced delusion, based on the World Health Organization (WHO) pharmacovigilance database. METHODS: We performed a disproportionality analysis of this database using the information component (IC). The IC compares observed and expected values to find associations between drugs and delusion, using disproportionate Bayesian reporting. An IC0.25 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. RESULTS: Here we present an analysis of 4559 suspected drug-induced delusion reports in the WHO pharmacovigilance database. These results identified 66 molecules statistically associated with delusion and an extensive analysis of confounding factors and coprescriptions was performed, using full database as background with an IC0.25 > 0. The main drug classes involved were antidepressants, antiepileptics, dopaminergic agents, opioids, antiinfective agents, benzodiazepines, anti-dementia drugs and psychostimulants. CONCLUSION: These results will help clinicians identify potential suspected drugs associated with delusion and decide which drug to discontinue and eventually lead to a re-evaluation of drug labels for some molecules.

Drugs associated with posterior reversible encephalopathy syndrome, a worldwide signal detection study.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) can occur in a variety of clinical conditions, such as severe hypertension, pregnancy, inflammatory diseases, hematopoietic stem cells or solid organ transplantation. Apart increased blood pressure levels and altered renal function, several drugs have been reported as potential triggering factor. These descriptions are nevertheless limited to case reports or small case series. Systematic analysis of drugs associated with PRES using global pharmacovigilance database is lacking and can be useful. METHODS: We performed a disproportionality analysis using VigiBase, the World Health Organization pharmacovigilance database, using the information component (IC). The IC compares observed and expected values to find associations between drugs and PRES using disproportionate Bayesian reporting. An IC0.25 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. RESULTS: Here we present an analysis of 3278 cases of PRES reported in VigiBase. These results identified 73 molecules statistically associated with PRES using full database as background with an IC0.25 > 0. Only 34% (N = 25/73) of them had this information written in the summary of product characteristics. The main drug classes involved were antineoplastic and immunomodulating agents and the drugs with the greatest number of cases were tacrolimus, cyclosporin, bevacizumab, methotrexate, and vincristine. An overall mortality of 8.1% (N = 267/3278) was identified in cases of drug-associated PRES. CONCLUSION: These results will help clinicians identify potential suspected drugs associated with PRES and decide which drug to discontinue and eventually lead to a re-evaluation of drug labels for some molecules.

Management of cancer treatments in hemodialysis patients.

INTRODUCTION: The number of cancer patients receiving long-term hemodialysis (HD) is increasing, and HD could jeopardize treatments' safety and efficacy. Therefore, managing anticancer drugs is critical in this frail population. In addition, evidence of HD safety or risk is regularly released both for cytotoxic chemotherapy (CT) or hormone therapy (HT) as well as new therapies with molecularly targeted therapies (MTT), immune checkpoint inhibitors (ICI), and a summary of current knowledge is needed. METHODS: We aimed to synthesize available data on cancer treatments in HD patients using PubMed database, FDA labels, summary of product characteristics (SmPC), FDA and EMA approval documents, guidelines and finally case reports for which relevant pharmacokinetic (PK) data is available. RESULTS: For CT, recently proposed guidelines were balanced by the publication of particular toxic reports following them. SmPC was helpful in some cases, but no data was found for most CTs. MTT, both oral and monoclonal antibodies, were rarely modified by HD. However, HD patients have particular frailty that could require dose adaptation despite no substantial PK modification. Similarly, exposure to ICIs is unlikely to be modified by HD since immunoglobulins are not dialyzable. For HT, PK characteristics and HD impact were more heterogeneous and were reviewed molecule by molecule. CONCLUSIONS: We summarized current knowledge on HD and cancer treatments. Data remains scarce, and the latest guidelines rely on few clinical data. There is a need to collect both retrospective and prospective data to better characterize the safety and relevant dose and schedule adaptations whenever needed in this situation to reinforce future guidelines.

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.

Treatments During Pregnancy Targeting ERBB2 and Outcomes of Pregnant Individuals and Newborns.

Importance: Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy. Objectives: To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents. Design, Setting, and Participants: For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included. Exposure: The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents. Main Outcome and Measures: The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis. Results: A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P < .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P < .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P < .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]). Conclusions and Relevance: In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.