ABSTRACT
Introduction: After many months from the COVID-19 pandemic beginning, several anti-spike monoclonal antibodies (mAbs) and, more recently, other antiviral drugs for COVID-19 treatment in nonhospitalized patients have been marketed. Specifically, those drugs are indicated for SARS-CoV-2 infection early treatment in outpatient adults at high risk of developing severe COVID-19 [1]. Objective(s): To evaluate the post-marketing safety profile of antivirals drugs used for early COVID-19 treatment, using the World Health Organization global spontaneous reporting database (VigiBase). Method(s): From VigiBase we identified all the individual case safety reports (ICSRs) of marketed mAbs (regdanvimab, sotrovimab, casirivimab/imdevimab, bamlanivimab/etesevimab and, specifically for COVID-19 prevention in immunocompromised patients, tixagevimab/ cilgavimab) and other antiviral therapies for COVID-19 early treatment (remdesivir, nirmatrelvir/ritonavir, molnupiravir). We performed a descriptive analysis of ICSRs recorded in VigiBase of patients' demographics (age, sex, continent of origin) type of reporter, adverse drug reactions (ADRs) (Preferred Term level) and the Important Medical Events (IMEs), from their marketing date to May 4, 2022. In addition, we conducted a disproportional analysis using Reporting Odds Ratio (ROR), along with 95% confidence intervals (CIs), by comparing the frequency of ADRs (System Organ Class level) for each drug of interest with distribution of all ADRs from the whole database, excluding vaccines, reported in the same period. Result(s): Overall, up to 4th May,2022, 15,437 ICSRs of anti-spike mAbs (casirivimab/imdevimab: 27.2%;bamlanivimab/etesevimab: 7.3%;sotrovimab 3.3%;tixagevimab/cilgavimab 2.7% regdanvimab: 0.2%) and other antivirals (remdesivir: 54.5%;nirmatrelvir/ritonavir: 4.3%;molnupiravir 0.5%) from VigiBase were retrieved. ICSRs mainly involved females and 45-64 years old. The percentage of ICSRs that included IMEs was 32.4%. Overall, the most frequently reported ADRs were infusion-related reaction for both casirivimab/ imdevimab (20.1%) and bamlanivimab/etesevimab (19.3%), pyrexia for regdanvimab (30.0%) and sotrovimab (8.1%), increased alanine aminotransferase for remdesivir (13.3%), dysgeusia for nirmatrelvir/ ritonavir (39.5%), and diarrhoea for molnupiravir (18.8%). Overall, statistically significant RORs were observed for "Investigations" with remdesivir (N = 3163;ROR: 5.56;95% CI 5.32-5.81), "Gastrointestinal disorders" for molnupiravir (N = 178;ROR: 3.43;95% CI 2.82-4.17) and "Vascular disorders" for sotrovimab (N = 51;ROR: 2.07;95% CI 1.55-2.76). Conclusion(s): This study shows that the safety profile of anti-spike mAbs and other newly marketed antiviral therapies for the early treatment of COVID-19 is overall favourable. The most frequently reported ADRs in VigiBase are in line with those reported in the pivotal trials and Summary of Product Characteristics for all investigated antiviral drugs. The disproportional analysis identified some potential signals requiring further investigation.
ABSTRACT
Introduction: Gastrointestinal stromal tumors (GISTs), soft tissue sarcomas of the digestive tract, are associated with oncogenic mutations that led to the approval of tyrosine kinase inhibitors (TKIs) [1-2]. Considering the increased use of TKIs in clinical practice, it may be useful to identify unexpected adverse drug reactions (ADRs). Objective(s): The aim of this study was to describe better ADRs and to identify unexpected potential safety signals through the analysis of individual case safety reports (ICSRs) among TKIs approved for GIST collected into the European Spontaneous Reporting System (SRS) database. Method(s): All ICSRs recorded starting from the drug approval up to 31 December 2021 with one of the following TKIs reported as suspected drug were included: imatinib (IM), sunitinib (SU), avapritinib (AVA), regorafenib (REG), and ripretinib (RIP). A descriptive analysis was conducted to assess all demographic characteristics. Moreover, a disproportionality analysis was performed using the Reporting Odds Ratio (ROR) with the corresponding 95% Confidence Interval (CI) to evaluate the frequency of ADRs for each TKI compared to all other TKIs. Results The number of analyzed ICSRs was 8,512 (Figure 1 Flowchart of ICSRs selection process): the 57.9% were related to IM, followed by SU (24.2%), AVA (13.1%), REG (2.7%), and RIP (2.1%). ICSRs were mainly serious (87.5%), related to males (51.7%), and to adults (44.7%);moreover, the 25.5% were fatal. The disproportionality analysis showed a higher reporting frequency of some unexpected ADRs for each TKI: gait disturbance (ROR 2.86;95% CI 1.90-4.29), hyperhidrosis (2.57;1.06-6.20), and hyperammonemia (3.92;1.05-14.60) for SU;cerebrovascular accident (6.23;2.18-17.84), hemoglobin decreased (2.23;1.08-4.61), and internal haemorrhage (14.44;3.94-52.92) for RIP;gastrointestinal ulcer (10.88;2.98-39.81) for REG;hepatic and lung cancer for IM (12.79;8.04-20.37 and 7.71;3.33-17.84, respectively);hallucination (24.33;9.02-65.68), mood swings (8.02;2.44-26.33), and stress (6.68;1.93-23.11), nephrolithiasis (6.69;2.15-20.77), pollakiuria (3.08;1.17-8.13), and dialysis (6.68;1.67-26.73), sinusitis (3.34;1.14-9.78), cellulitis (4.17;1.36-12.78), and COVID-19 (7.25;3.40-15.45), chills (2.36;1.22-4.58), limb fracture (3.53;1.63-7.60), hernia (9.23;3.71-23.00), diabetes mellitus (5.02;2.11-11.95), hyposideraemia (5.02;2.11-11.95), tinnitus (3.64;1.34-9.87), parosmia (5.00;1.12-22.38), Raynaud's phenomenon (5.00;1.12-22.38), and thyroid function test abnormal (8.90;1.99-39.83) for AVA. Conclusion(s): This study is largely consistent with results from literature but some unexpected ADRs were shown. Further studies are necessary to increase the awareness about the safety profiles of new TKIs approved for GISTs.
ABSTRACT
Introduction: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines such as interleukin (IL)-4, IL5, and IL13. Options for treatment-resistant CRSwNP include aspirin desensitization, recurrent topic and systemic corticosteroid use, and functional endoscopic sinus surgery (FESS). However, frequent relapses after medical and surgical treatment have been observed. Thus, dupilumab, a human recombinant monoclonal IgG4 antibody, changes radically the treatment of CRSwNP because of its binding effects on major drivers of human type 2 inflammatory processes [1- 3]. Considering its recent approval, it may be useful to evaluate its safety profile. Objective(s): The aim of this study was to describe better adverse drug reactions (ADRs) related to dupilumab in the treatment of CRSwNP analyzing all individual case safety reports (ICSRs) collected into the European Spontaneous Reporting System (SRS) database. Method(s): All ICSRs recorded starting from the drug approval up to 31 December 2021 with dupilumab reported as suspected and having the specific indication of CRSwNP were considered. A descriptive analysis was conducted to assess demographic characteristics and dupilumab-related variables. Result(s): Out of 10,400 ICSRs related to dupilumab, only 481 (4.6%) had CRSwNP indication, of which 68.2% were related to adults and 54.3% to females. The 68.4% were serious;however, ICSRs mainly led to a completely or partial recovering (25.4%) and 8 cases were fatal (1.7%). The time to onset (TTO) of ADRs was 25 (1-84.75) days while the time to resolution (TTR) was 5 (1.75-15.75) days. Analyzing ADRs by System Organ Classes (SOCs), the most reported were general and administration site conditions (36.4%) followed by injuries (21.6%), infections (21.2%), respiratory (19.1%), skin (16.6%), and nervous system disorders (16.4%). Looking at Preferred Terms (PTs), arthralgia (7.3%), eosinophilia (6.9%), COVID-19 (6.0%), pyrexia (5.8%), asthenia (5.6%), rash (5.4%), and dyspnoea (5.2%) were the most reported. The 7.5% of ICSRs described an aggravated condition with persistent nasal polyps: in 4 cases (0.8%) a nasal polypectomy was required. Considering fatal ICSRs, two cases were related to progression of COVID-19, one to road traffic accident, one to accidental death and the others were not fully specified. Conclusion(s): These results showed that dupilumab-related ICSRs are not commonly reported in CRSwNP. However, given the good treatment response and the minimal adverse effects observed, clinicians should consider treating CRSwNP with dupilumab. Moreover, additional analyses are necessary to better outline the safety profile of dupilumab in this particular setting.
ABSTRACT
Introduction: After many months from the COVID-19 pandemic beginning, several anti-spike monoclonal antibodies (mAbs) and, more recently, other antiviral drugs for COVID-19 treatment in non-hospitalized patients have been marketed. Specifically, those drugs are indicated for SARS-CoV-2 infection early treatment in outpatient adults at high risk of developing severe COVID-19 [1]. Objective: To evaluate the post-marketing safety profile of antivirals drugs used for early COVID-19 treatment, using the World Health Organization global spontaneous reporting database (VigiBase). Methods: From VigiBase we identified all the individual case safety reports (ICSRs) of marketed mAbs (regdanvimab, sotrovimab, casirivimab/imdevimab, bamlanivimab/etesevimab and, specifically for COVID-19 prevention in immunocompromised patients, tixagevimab/cilgavimab) and other antiviral therapies for COVID-19 early treatment (remdesivir, nirmatrelvir/ritonavir, molnupiravir). We performed a descriptive analysis of ICSRs recorded in VigiBase of patients' demographics (age, sex, continent of origin) type of reporter, adverse drug reactions (ADRs) (Preferred Term level) and the Important Medical Events (IMEs), from their marketing date to May 4, 2022. In addition, we conducted a disproportional analysis using Reporting Odds Ratio (ROR), along with 95% confidence intervals (CIs), by comparing the frequency of ADRs (System Organ Class level) for each drug of interest with distribution of all ADRs from the whole database, excluding vaccines, reported in the same period. Results: Overall, up to 4th May,2022, 15,437 ICSRs of anti-spike mAbs (casirivimab/imdevimab: 27.2%;bamlanivimab/etesevimab: 7.3%;sotrovimab 3.3%;tixagevimab/cilgavimab 2.7% regdanvimab: 0.2%) and other antivirals (remdesivir: 54.5%;nirmatrelvir/ritonavir: 4.3%;molnupiravir 0.5%) from VigiBase were retrieved. ICSRs mainly involved females and 45-64 years old. The percentage of ICSRs that included IMEs was 32.4%. Overall, the most frequently reported ADRs were infusion-related reaction for both casirivimab/imdevimab (20.1%) and bamlanivimab/etesevimab (19.3%), pyrexia for regdanvimab (30.0%) and sotrovimab (8.1%), increased alanine aminotransferase for remdesivir (13.3%), dysgeusia for nirmatrelvir/ritonavir (39.5%), and diarrhoea for molnupiravir (18.8%). Overall, statistically significant RORs were observed for "Investigations" with remdesivir (N = 3163;ROR: 5.56;95% CI 5.32-5.81), "Gastrointestinal disorders" for molnupiravir (N = 178;ROR: 3.43;95% CI 2.82-4.17) and "Vascular disorders" for sotrovimab (N = 51;ROR: 2.07;95% CI 1.55-2.76). Conclusion: This study shows that the safety profile of anti-spike mAbs and other newly marketed antiviral therapies for the early treatment of COVID-19 is overall favourable. The most frequently reported ADRs in VigiBase are in line with those reported in the pivotal trials and Summary of Product Characteristics for all investigated antiviral drugs. The disproportional analysis identified some potential signals requiring further investigation.
ABSTRACT
Introduction: Gastrointestinal stromal tumors (GISTs), soft tissue sarcomas of the digestive tract, are associated with oncogenic mutations that led to the approval of tyrosine kinase inhibitors (TKIs) [1-2]. Considering the increased use of TKIs in clinical practice, it may be useful to identify unexpected adverse drug reactions (ADRs). Objective: The aim of this study was to describe better ADRs and to identify unexpected potential safety signals through the analysis of individual case safety reports (ICSRs) among TKIs approved for GIST collected into the European Spontaneous Reporting System (SRS) database. Methods: All ICSRs recorded starting from the drug approval up to 31 December 2021 with one of the following TKIs reported as suspected drug were included: imatinib (IM), sunitinib (SU), avapritinib (AVA), regorafenib (REG), and ripretinib (RIP). A descriptive analysis was conducted to assess all demographic characteristics. Moreover, a disproportionality analysis was performed using the Reporting Odds Ratio (ROR) with the corresponding 95% Confidence Interval (CI) to evaluate the frequency of ADRs for each TKI compared to all other TKIs. Results The number of analyzed ICSRs was 8,512 (Figure 1 Flowchart of ICSRs selection process): the 57.9% were related to IM, followed by SU (24.2%), AVA (13.1%), REG (2.7%), and RIP (2.1%). ICSRs were mainly serious (87.5%), related to males (51.7%), and to adults (44.7%);moreover, the 25.5% were fatal. The disproportionality analysis showed a higher reporting frequency of some unexpected ADRs for each TKI: gait disturbance (ROR 2.86;95% CI 1.90-4.29), hyperhidrosis (2.57;1.06-6.20), and hyperammonemia (3.92;1.05-14.60) for SU;cerebrovascular accident (6.23;2.18-17.84), hemoglobin decreased (2.23;1.08-4.61), and internal haemorrhage (14.44;3.94-52.92) for RIP;gastrointestinal ulcer (10.88;2.98-39.81) for REG;hepatic and lung cancer for IM (12.79;8.04-20.37 and 7.71;3.33-17.84, respectively);hallucination (24.33;9.02-65.68), mood swings (8.02;2.44-26.33), and stress (6.68;1.93-23.11), nephrolithiasis (6.69;2.15-20.77), pollakiuria (3.08;1.17-8.13), and dialysis (6.68;1.67-26.73), sinusitis (3.34;1.14-9.78), cellulitis (4.17;1.36-12.78), and COVID-19 (7.25;3.40-15.45), chills (2.36;1.22-4.58), limb fracture (3.53;1.63-7.60), hernia (9.23;3.71-23.00), diabetes mellitus (5.02;2.11-11.95), hyposideraemia (5.02;2.11-11.95), tinnitus (3.64;1.34-9.87), parosmia (5.00;1.12-22.38), Raynaud's phenomenon (5.00;1.12-22.38), and thyroid function test abnormal (8.90;1.99-39.83) for AVA. Conclusion: This study is largely consistent with results from literature but some unexpected ADRs were shown. Further studies are necessary to increase the awareness about the safety profiles of new TKIs approved for GISTs.
ABSTRACT
Introduction: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines such as interleukin (IL)-4, IL5, and IL13. Options for treatment-resistant CRSwNP include aspirin desensitization, recurrent topic and systemic corticosteroid use, and functional endoscopic sinus surgery (FESS). However, frequent relapses after medical and surgical treatment have been observed. Thus, dupilumab, a human recombinant monoclonal IgG4 antibody, changes radically the treatment of CRSwNP because of its binding effects on major drivers of human type 2 inflammatory processes [1-3]. Considering its recent approval, it may be useful to evaluate its safety profile. Objective: The aim of this study was to describe better adverse drug reactions (ADRs) related to dupilumab in the treatment of CRSwNP analyzing all individual case safety reports (ICSRs) collected into the European Spontaneous Reporting System (SRS) database. Methods: All ICSRs recorded starting from the drug approval up to 31 December 2021 with dupilumab reported as suspected and having the specific indication of CRSwNP were considered. A descriptive analysis was conducted to assess demographic characteristics and dupilumab-related variables. Results: Out of 10,400 ICSRs related to dupilumab, only 481 (4.6%) had CRSwNP indication, of which 68.2% were related to adults and 54.3% to females. The 68.4% were serious;however, ICSRs mainly led to a completely or partial recovering (25.4%) and 8 cases were fatal (1.7%). The time to onset (TTO) of ADRs was 25 (1-84.75) days while the time to resolution (TTR) was 5 (1.75-15.75) days. Analyzing ADRs by System Organ Classes (SOCs), the most reported were general and administration site conditions (36.4%) followed by injuries (21.6%), infections (21.2%), respiratory (19.1%), skin (16.6%), and nervous system disorders (16.4%). Looking at Preferred Terms (PTs), arthralgia (7.3%), eosinophilia (6.9%), COVID-19 (6.0%), pyrexia (5.8%), asthenia (5.6%), rash (5.4%), and dyspnoea (5.2%) were the most reported. The 7.5% of ICSRs described an aggravated condition with persistent nasal polyps: in 4 cases (0.8%) a nasal polypectomy was required. Considering fatal ICSRs, two cases were related to progression of COVID-19, one to road traffic accident, one to accidental death and the others were not fully specified. Conclusion: These results showed that dupilumab-related ICSRs are not commonly reported in CRSwNP. However, given the good treatment response and the minimal adverse effects observed, clinicians should consider treating CRSwNP with dupilumab. Moreover, additional analyses are necessary to better outline the safety profile of dupilumab in this particular setting.