Frequent Adverse Drug Reactions Research Articles

Impact of serotonin transporter (SERT) binding affinity on the risk of libido disorders related to antidepressants

IntroductionSexual dysfunction is a frequent adverse drug reaction (ADR) of antidepressants that considerably affects quality of life and adherence to therapy. We previously investigated the potential underlying neurofunctional mechanisms by neuroimaging methods and revealed a dampening of the dopaminergic mesolimbic-mesocortical reward system along with decreased sexual functioning under serotonergic antidepressants compared to placebo.ObjectivesWithin a combined pharmacoepidemiologic and pharmacodynamic approach, we examined the association between serotonin transporter (SERT) affinity of various antidepressants and corresponding alterations in sexual desire as ADR.MethodsUsing disproportionality analyses, reporting odds ratios (RORs) were calculated for reports indicating decreased sexual desire as ADR under the antidepressants. The data were extracted from the WHO global database of individual case safety reports VigiBase and several MedDRA terms were grouped for “Sexual Desire Disorders”. For the pharmacodynamic assessment, we calculated Pearson correlation coefficients between SERT affinity and corresponding RORsResults16 signals were detected for “Sexual Desire Disorders”. We observed a statistically significant (r (20) =. 65, p = 0.001) association between SERT affinity and decreased sexual desire. Higher SERT affinity was associated with higher risk of sexual desire.ConclusionsWhile sexual dysfunctions under serotonergic medication were previously described, we now elaborated that in particular attenuated sexual desire as ADR is associated with SERT affinity of the antidepressant. These results strengthen our previously described neurofunctional model regarding sexual dysfunction under antidepressant medication and indicate that the specific SERT affinity of the antidepressant drug should be considered in clinical practice to minimize the risk of this ADR.DisclosureNo significant relationships.

Safety and effectiveness of empagliflozin according to body mass index in Japanese patients with type 2 diabetes: a subgroup analysis of a 3-year post-marketing surveillance study

ABSTRACT Background Empagliflozin, a glucose-lowering drug licensed for type 2 diabetes (T2D), demonstrated tolerability and effectiveness overall in a post-marketing surveillance (PMS) study in Japan. However, the impact of body mass index (BMI) is unclear. Research design and methods This was a prespecified sub-analysis of the prospective, 3-year, PMS study of empagliflozin in Japan where the primary endpoint was adverse drug reactions (ADRs). We evaluated results according to BMI. Results We enrolled 7931 T2D patients treated with empagliflozin. Baseline mean age was 58.7 years; 63.01% were male. Baseline BMI was <20 kg/m2 in 2.06% of patients, while 21.28%, 37.35%, and 24.97% had BMI 20–<25, 25–<30 and ≥30 kg/m2, respectively. ADRs occurred in 19 (11.66%), 203 (12.03%), 411 (13.88%), and 295 (14.90%) patients with BMI <20, 20–<25, 25–<30 and ≥30 kg/m2, respectively. Excessive/frequent urination was the most frequent ADR of special interest in all BMI subgroups except 20–<25 kg/m2 (urinary tract infection). Mean change in glycated hemoglobin from baseline was –0.75%, with similar magnitude across BMI subgroups. Body-weight reduction seemed dependent on BMI, with almost no change in the <20 kg/m2 subgroup. Conclusions Empagliflozin appeared well tolerated and effective in Japanese T2D patients regardless of BMI, although the number of patients with BMI <20 kg/m2 was small in this study.

Pediatric Adverse Drug Reactions: An Observational Cohort Study After Health Care Workers' Training.

Adverse drug reactions (ADRs) in children are an important but underestimated public health issue. This study describes ADRs in a registered pediatric population of Bologna and demonstrates that ADRs might be better detected after health care personnel training. A prospective cohort was recruited from July 1, 2016, to June 30, 2019, after health care worker sensitization, and compared to a retrospective cohort enrolled from 2013 to 2016. The ADRs are classified by system organ classes and drugs are categorized according to the Anatomical Therapeutic Chemical classification system. We retrospectively recruited 78 pediatric patients with ADRs in the 2013 to 2016 period, and we prospectively enrolled 127 children in the 2016 to 2019 period. In both periods, most of the ADRs reported were classified as non-serious reactions (68.8%). The most frequent ADRs were general and administration site disorders. During 2013 to 2016 vaccines were the most frequent cause of ADRs (83.3%;) and the main reporters were health care workers other than physicians (84.6%), whereas during the second period, medical doctors become the main signalers (65.4%) and ADRs related to vaccines significantly decreased (55.1%). During the 2016 to 2019 period the number of drug categories was higher than in the 2013 to 2016 period (24 vs 8). Patients with ADRs due to vaccinations present more frequently a favourable outcome (63%). This study demonstrates that active pharmacovigilance and health care personnel sensitization are associated with improved ADR detection, providing valuable information about drugs' safety profile in pediatric patients.

Acute Kidney Injury and Drugs Prescribed for COVID-19 in Diabetes Patients: A Real-World Disproportionality Analysis.

Background: The information is relatively scarce regarding the occurrence of drug-induced acute kidney injury (AKI) when anti-coronavirus disease 2019 (COVID-19) drugs are prescribed for patients with diabetes mellitus (DM). Objective: The objective of this study was to evaluate a pharmacovigilance signal for AKI upon the use of common drugs prescribed for COVID-19 treatment, especially in patients with DM. Methods: The FDA Adverse Event Reporting System (FAERS) database were used, and data from the first quarter of 2020 to the third quarter of 2021 were retrieved. A disproportionality analysis was performed to determine whether AKI was more frequently reported with anti-COVID-19 drugs compared to that with other drugs in different populations. Further, reporting odds ratios (RORs) and their 95% confidence intervals (CIs) were used to calculate disproportionality. Results: We identified 33,488 COVID-19 patients and 2397 COVID-19 patients with DM. AKI was the most frequent adverse drug reaction (ADR) reported in this patient population. The primary suspected drugs related to AKI in more than half of the reports (75.60%, 127/168) were four common anti-COVID-19 drugs (remdesivir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir). Compared with other drugs in the same time window, remdesivir and lopinavir/ritonavir were associated with an increased risk of AKI in all COVID-19 patients (ROR: 3.97, 95% CI: 3.51–4.50; ROR: 4.02, 95% CI: 3.11–5.19, respectively). In COVID-19 patients with DM, remdesivir was significantly associated with AKI (ROR: 5.65, 95% CI: 4.06–7.87); meanwhile, there was a new AKI signal associated with tocilizumab (ROR: 2.37, 95% CI: 1.19–4.72). After sensitivity analyses in COVID-19 patients with DM, consistent results for remdesivir were observed; however, the AKI signals for tocilizumab were unstable. Conclusion: Our study confirmed the association of AKI with the usage of common anti-COVID-19 drugs (especially remdesivir and tocilizumab) in DM patients. These safety signals suggested more individualized treatments for COVID-19 patients with comorbidities. Cross-disciplinary collaborative is needed to improve current strategy of clinical treatment and develop new approaches to management.

Adverse Drug Reactions of Antihypertensives and CYP3A5*3 Polymorphism Among Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) patients may be more susceptible to adverse drug reactions (ADRs), given their complex medication regimen and altered physiological state driven by a decline in kidney function. This study aimed to describe the relationship between CYP3A5*3 polymorphism and the ADR of antihypertensive drugs in CKD patients. This retrospective, multi-center, observational cohort study was performed among adult CKD patients with a follow-up period of up to 3 years. ADRs were detected through medical records. CYP3A5*3 genotyping was performed using the direct sequencing method. From the 200 patients recruited in this study, 33 (16.5%) were found to have ADRs related to antihypertensive drugs, with 40 ADRs reported. The most frequent ADR recorded was hyperkalemia (n = 8, 20.0%), followed by bradycardia, hypotension, and dizziness, with 6 cases (15.0%) each. The most common suspected agents were angiotensin II receptor blockers (n = 11, 27.5%), followed by angiotensin-converting enzyme inhibitors (n = 9, 22.5%). The CYP3A5*3 polymorphism was not found to be associated with antihypertensive-related ADR across the genetic models tested, despite adjustment for other possible factors through multiple logistic regression (p > 0.05). After adjusting for possible confounding factors, the factors associated with antihypertensive-related ADR were anemia (adjusted odds ratio [aOR] 5.438, 95% confidence interval [CI]: 2.002, 14.288) and poor medication adherence (aOR 3.512, 95% CI: 1.470, 8.388). In conclusion, the CYP3A5*3 polymorphism was not found to be associated with ADRs related to antihypertensives in CKD patients, which requires further verification by larger studies.

Abstract P2-13-26: Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France

Abstract Background Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an HER2-directed antibody and a topoisomerase I inhibitor covalently linked via a tetrapeptide-based cleavable linker. In DESTINY-Breast01, tolerability and efficacy of T-DXd including overall response rate, progression-free survival, duration of response and overall survival have been demonstrated for HER2-positive metastatic and/or unresectable BC in patients (pts) relapsing after 2 or more anti-HER2-based regimens. In France, rapid and fair access to innovative drugs outside clinical trials, prior to their marketing authorization in a given indication, is granted by the French Health Agency, ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé), through cATU program. Here we report first real world evidence data from cATU program in HER2+ BC pts treated with T-DXd. Methods T-DXd 5.4mg/kg was given intravenously in monotherapy every 3 weeks in HER2-positive metastatic and/or unresectable BC pts who had previously received at least 2 lines of anti-HER2 regimens in the metastatic setting. Eligible pts needed to have normal neutrophil count and no left ventricular dysfunction. Pts with active or history of interstitial lung disease (ILD), pneumonitis, severe pulmonary disease were excluded. Clinical, biological and safety data were collected until the end of cATU, as well as treatment response according to RECIST 1.1., dose modification, treatment interruption and discontinuation. Analysis was performed on March 31th, 2021 on the basis of available collected data. Results From September 30th, 2020 to March 31th, 2021, 155 centers requested at least one ATU for a total of 539 adult pts; 468 requests were accepted and 71 were refused as they did not meet eligibility criteria. T-DXd was received by 459 pts with the following characteristics: 99.1% were women, median age was 58 years, 90.4% had a ECOG score of 0-1, 98.9% had initial HER2-positive BC (IHC 3+ or IHC 2+/ISH+), 67% were hormone receptor positive. The main sites of metastases were bones (57.3%), lymph nodes (51.6%), lungs (36.2%), liver (33.1%), brain (28.1%) and cutaneous/subcutaneous (13.9%). Median time between initial diagnosis of primary BC and inclusion was 6.6 years (range: 6.6 months - 33.9 years). 81.7% of pts had previously received radiotherapy and 76.5% underwent surgery. The median number of prior cancer regimens in the metastatic setting was 4 (range: 2-22). 21.1% received 2 prior lines of metastatic treatments, 19.6% received 3 lines and 59.3% received 4 lines or more. 94.8% pts received prior trastuzumab emtansine, and 79.3% had prior pertuzumab. During follow-up, data on tumor assessment were available for 160 pts. Of these, 56.7% had complete or partial response and 12.1% had progression. Of the 459 treated pts, 97 pts (21.1%) experienced ≥ 1 Adverse Drug Reaction (ADR) including 41 pts (8.9%) with ≥ 1 serious ADR. Most frequent ADRs were related to gastrointestinal toxicity (35.4%). During cATU, 17 cases (3.7%) with ILD or considered as ILD were reported but no cases had a fatal outcome (only grade 1 or 2 when reported by physicians). 13 fatal cases were reported (no drug-related deaths, attributed by physician). ADRs leading to T-DXd discontinuation were reported in 4 pts (0.9%). Dose reductions were reported in 17 pts (3.7%) and 21 pts (4.6%) had temporary interruptions. Conclusions We report here the first real world data from the French cATU in HER2-positive BC pts treated by T-DXd. The enrolment of 468 pts in 6 months illustrated the unmet medical need for this population. T-DXd had antitumor activity with a similar response rate to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed. Citation Format: Thierry Petit, Nawale Hajjaji, Eric-Charles Antoine, Marc-Antoine Benderra, Michel Gozy, Cyril Foa, Jean-Loup Mouysset, Julien Grenier, Mireille Mousseau, Audrey Mailliez, Mahasti Saghatchian, Emma Lachaier, Isabelle Desmoulins, Audrey Hennequin, Patricia Maes, Delphine Loirat, Francesco Ricci, Véronique Diéras, Dominique Berton, Florence Lai Tiong, Luis Teixeira, Nadine Dohollou, Christelle Lévy, Thomas Bachelot, Jean-Yves Pierga. Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-26.

CONTRAST-INDUCED NEPHROPATHY: PREVALENCE, DIAGNOSIS, PREVENTION AND TREATMENT

Resume. Medical imaging has become an important diagnostic and therapeutic tool in clinical medicine in the era of great technological advances. One of the most frequent and important adverse drug reactions during angiographic studies is contrast-induced nephropathy. Study of epidemiology, risk factors for the development of contrast-induced nephropathy, possible ways of prevention and treatment to reduce the frequency and severity of this complication, improve the quality of patient therapy and reduce the cost of treating complications. Materials and methods. The search for information in the database PubMed, Scopus, Web of Science, e-library, etc. was carried out using the following words and phrases: percutaneous coronary intervention, coronary angiography, contrast-induced nephropathy. Results. The incidence of contrast-induced nephropathy during coronary angiography varies from 2 to 25 %, however, in high-risk groups it can reach 50 %. To prevent the development of contrast-induced nephropathy, there are a number of pharmacological and non-pharmacological approaches. Its prevention is most relevant in high-risk patients. Conclusions. Minimizing the volume of the radiopaque agent, preventing and correcting hypovolemia, preventing the activation of vasoconstriction are the most effective measures to prevent contrast-induced nephropathy.

P466 Real-world effectiveness and safety of golimumab in patients with ulcerative colitis: 52-weeks of post-marketing surveillance data in Japan

Abstract Background Golimumab (GLM) is an anti-TNF-α drug approved for treating ulcerative colitis (UC). Although its efficacy and safety were well established in clinical trials, real-world evidence was still limited. In the present study, we evaluated 52-week effectiveness and safety of GLM treatment for UC based on post-marketing surveillance data. Methods The prospective, post-marketing study was conducted in 393 patients from 163 medical facilities. Patients who had been prescribed GLM were enrolled between May 2017 and September 2019 in Japan. In accordance with Japanese indication, patients received subcutaneous injections of GLM, 200 mg at week 0, 100 mg at weeks 2 and 6, followed by 100 mg every 4 weeks. Clinical remission (partial Mayo score ≤2), predictors of remission, adverse drug reactions (ADRs), and predictors of ADR development were determined at week 52. Results Of 393 enrolled patients, 391 and 386 were included in safety and efficacy analysis set, respectively (Table 1). Overall, clinical remission in the intention-to-treat population was 13.0%, 53.9%, 52.6%, 48.2%, and 43.3% at baseline (BL) and at week 6, 22, 36, and 52, respectively (Table 2). In biologic naïve group, clinical remission was 9.2%, 59.1%, 61.0%, 52.4%, and 47.0% at BL and week 6, 22, 36, and 52, respectively, while in biologic experienced group, it was 15.8%, 50.0%, 46.4%, 45.0%, and 40.5% at BL and week 6, 22, 36, and 52, respectively. At week 52, clinical remission rate in the patients who concomitantly used corticosteroid (CS) at BL was significantly lower than that in the patients who did not receive CS (p=0.017, 37.3% vs 49.2%) (Fig. 1). No significant difference in remission rate was observed between immunomodulator (IM) users and IM non-users at baseline. From multivariate analysis, concomitant use of CS (p=0.001, odds ratio [OR] =0.488, 95% CI [confidence interval] 0.314–0.759) and partial Mayo remission at BL (p&amp;lt;0.001, OR=4.329, 95% CI 2.056–9.115) were identified as independent factors associated with clinical remission. ADRs occurred in 71 patients (18.2%). The most common ADR was rash, reported in 9 patients (2.3%). Serious ADRs occurred in 40 patients (10.2%). The most frequent serious ADR was UC, reported in 8 patients (2.0%). In multivariate analysis, the presence of comorbidities was associated with ADR incidence (OR=2.000, 95% CI 1.183–3.380). Conclusion From the Japanese post-marketing data, the real-world effectiveness of GLM treatment was confirmed in both biologic naïve and experienced populations. Safety profile was generally consistent with previous findings, and no additional safety signals were identified. Concomitant use of CS, but not IM, may be likely to affect outcome of GLM therapy.

Assessment of the Radio-contrast Media-Induced Self-Reported Adverse Drug Reactions in a Tertiary Care Hospital of North India: A Prospective Study.

Background:Radio-contrast media are the agents which are used on daily basis in the radiological practice for either diagnostic or therapeutic purpose. Currently used agents are considered to be safe but not devoid of side effects.Objectives:Objectives of the study were to assess the incidence of adverse drug reactions (ADRs) in the patients who receive radiographic contrast media for computed tomography (CT) and intravenous pyelography (IVP), to stratify the ADRs into different types based on their time of appearance and as per their severity.Materials and Methods:A prospective and observational study of 1-year duration was done on all the patients who received radio-contrast media (Iohexol) intravenously for CT and IVP in the radiodiagnosis department. Patients who experienced ADRs were recorded for the basic demographic characteristics and types of ADRs. Stratification of ADRs as per their severity was done using common terminology criteria for adverse events scale and Modified Hartwig and Siegel ADR Severity Assessment Scale, and casualty assessment was done using Naranjo's Algorithm.Results:Out of the total 3522 patients who were included in the study, eight patients got 12 suspected ADRs with some of the patients having more than one type of ADR. The most frequent ADR was nausea and vomiting (25%), followed by fever, chills, or sweating. Incidence of ADRs was 0.23%. All the ADRs were acute and occurred within 30 min of contrast administration. As per the severity scales used, all the ADRs were mild (75%) to moderate (25%) in nature with none of the reactions to be severe. Causality assessment showed 87.5% of the reactions to be “probable” in nature.Conclusion:Low osmolar nonionic radio contrast media are associated with very low incidence of ADRs in the North Indian population.

S115: LONG-TERM EFFICACY AND SAFETY OF DEFERIPRONE FOR PATIENTS WITH SICKLE CELL DISEASE OR OTHER ANEMIAS

Background: FIRST-EXT was a prospective, multicenter, single-arm, open-label extension of the FIRST study in patients with sickle cell disease (SCD) and other transfusion-dependent anemias. In FIRST, patients were randomly assigned 2:1 to receive oral deferiprone (DFP) or parenteral deferoxamine (DFO) for 12 months. The noninferiority of DFP versus DFO was previously reported.1 Here we report the efficacy and safety of DFP in FIRST-EXT. Aims: To evaluate the long-term efficacy and safety of DFP in iron-overloaded patients with SCD or other anemias. Methods: Patients who completed FIRST could enter FIRST-EXT for up to 2 years. Patients previously treated with DFP continued on DFP (DFP-DFP), while those previously treated with DFO were switched to DFP (DFO-DFP). Baseline was defined as the start of FIRST for DFP-DFP patients, and the start of FIRST-EXT for DFO-DFP patients. Efficacy endpoints were yearly changes from baseline in liver iron concentration (LIC), cardiac MRI T2*, and serum ferritin (SF). We also report adverse drug reactions (ADRs), defined as adverse events at least possibly related to DFP. All patients provided informed consent or assent. Results: Patients (N=134: 89 DFP-DFP; 45 DFP-DFO) were 60.4% male, with a mean (SD) age of 16.2 (8.6) years. Most (85.8%) had SCD; 14.2% had other anemias. At baseline, all patients had elevated (≥1.8 mg/g dry weight [dw]) LIC; all but one had elevated (females >300 µg/L, males >400 µg/L) SF; and all had cardiac MRI T2* in the normal range (≥20 ms). A significant, progressive decline was seen in LIC, with mean (SD) changes from baseline to years 1, 2, and 3 of -2.64 (4.64), -3.91 (6.38), and -6.64 (7.72) mg/g dw, respectively (P<0.01 for all). A decline was also seen in SF, with mean (SD) changes from baseline to years 1, 2, and 3 of -1 (1986), -771 (2171), and -1016 (3617) µg/L, respectively (P<0.05 for years 2 and 3). Cardiac MRI T2* values changed little from baseline. The most frequent ADRs were neutropenia (9.0%), decreased neutrophil count (9.0%), and abdominal pain (7.5%); 2 patients (1.5%) experienced agranulocytosis. One patient withdrew due to ADRs of thrombocytopenia and neutropenia, which resolved. Another patient withdrew due to generalized edema and died for reasons unknown 17 days after withdrawal from the study. Conclusions: DFP long-term use (≤3 years) was effective in controlling body iron load in patients with SCD and other anemias. There were no new safety concerns.

The Immunogenetics of Cutaneous Drug Reactions.

Adverse drug reactions (ADRs) are the cause of nearly three to six percent of inpatient admissions and are associated with high morbidity and mortality rates. Cutaneous adverse drug reactions (cADRs) represent the most frequent ADRs observed among patients during hospital stay. Recent investigations have found that various HLA genotypes have a significant association with ADRs, especially immune-mediated ADRs. This chapter is devoted to the description of the immunopathogenic mechanism of these reactions and the specific HLA-drug associations. Also, we discuss the association of other non-HLA genes with the development of cADRs and provide a summary of the currently approved recommendations on pre-treatment HLA genotyping tests.

A Five-Year Review of Adverse Cutaneous Drug Reaction in a Tertiary Care Hospital in Yogyakarta, Indonesia

Background: The prevalence of adverse drug reactions is likely to increase, and it is associated with increased usage of various drugs. Adverse Cutaneous Drug Reaction (ACDR) is the most frequent adverse drug reaction (30–45%). In Indonesia, the study on the prevalence of ACDR is still limited. Purpose: This study investigated the prevalence, clinical features, causative agents, and mortality rate of ACDR with a type-IV hypersensitivity reaction among patients attending the Department of Dermatology and Venereology in Dr. Sardjito Hospital, Yogyakarta. Methods: This retrospective study was conducted examining medical records undertaken for five years (2011–2015). Of 68,375 patients medicated in the Department of Dermatology and Venereology, 397 patients were diagnosed as ACDR with a type-IV hypersensitivity reaction. Detailed history, including age, sex, past history, and family history of drug reaction taken by the patient, were obtained. Patch testing was done wherever feasible. Result: Of 68,375 patients, 397 patients were included in ACDR with type-IV hypersensitivity (0.58%), giving a 5% of mortality rate. The mean age of the patients was 40.42 years (±16.30; range 18 to 89 years). The female to male ratio was 1.1: 1. The Maculopapular rash was the most common ACDR manifestation (50.88%), followed by Stevens-Johnson Syndrome (13.85%), Fixed Drug Eruption (12.85%), and Drug Reaction with Eosinophilia and Systemic Symptoms (10.08%). The most common causative agents were beta-lactam (16.55%), NSAIDs (12.18%), and acetaminophen (8.62%). Conclusion: Prescription of those drugs should be considered carefully so the incidence of ACDR can be reduced.

Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital.

The pediatric population is a vulnerable group for adverse drug reactions (ADRs), and data on spontaneous reporting of ADRs in the hospital setting are scarce. We conducted a retrospective analysis of ADRs in pediatric patients spontaneously reported by health care professionals to a Pharmacovigilance Program in a tertiary hospital between 2010 and 2020, and we compared characteristics of ADRs between pediatric age subgroups. From 1787 spontaneously reported ADRs in an 11-year period, 103 (5.85%) were pediatric ADRs. The median age of patients with ADRs was 8.4 years (range 1 day–17 years) and 57.3% were male. The most frequent ADRs reported were nervous system disorders (13.6%) and the most frequently involved drugs were antineoplastics and immunodulators (32.4%). A 59.2% of the ADRs were serious and 55.3% were classified as being type B reactions. Medication errors were involved in 7.8% of the ADRs and 11.9% of the suspected drugs were used off-label. Spontaneous reports of ADRs in newborns, infants, and toddlers were more serious and less often described in the product data sheet than in children and adolescents (p < 0.001 and p = 0.004 respectively). Medication errors were more frequent in patients under two years of age. These results should be interpreted with caution due to under-reporting and biases in spontaneous reporting of ADRs.

A double-blind, placebo-controlled, single-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue, in healthy subjects.

To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue under development, in healthy males and females presenting with no childbearing potential. A randomized, double-blind, placebo-controlled, single-ascending dose study was conducted in 56 subjects who randomly received a single subcutaneous dose of HM15136 or its matching placebo at a ratio of 6:2 at 10, 20, 30, 50, 80, 100, and 120 μg/kg. All adverse events were mild and transient. Neither serious adverse events nor discontinuation as a result of adverse events occurred. The most frequent adverse drug reaction was nausea (5.3%, only in the 100- and 120-μg/kg groups). HM15136, particularly at doses of 50 μg/kg or higher, increased fasting blood glucose, with a maximum increase and area under the curve of 1.5 mmol/L at day 10 (P= .006) and 166.3day·mmol/L (P= .022) at the dose of 80 μg/kg, while suppressing the secretion of endogenous glucagon, which continued until day 17. HM15136 also significantly reduced gluconeogenic and ketogenic amino acids. Compensatory changes in endogenous insulin and incretin hormones by HM15136 were not apparent. HM15136 was slowly but steadily absorbed and reached a peak concentration at 46-68 hours after a single subcutaneous injection. HM15136 was eliminated with a terminal phase half-life of 77.1-101.1hours. A single subcutaneous dose of HM15136 at 10-120 μg/kg was safe and well tolerated. The long half-life of HM15136, coupled with an increase in blood glucose for ~2 weeks, may warrant a weekly dosing regimen.

Effects of Cytochrome P450 and Transporter Polymorphisms on the Bioavailability and Safety of Dutasteride and Tamsulosin.

Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Despite being more effective than monotherapies, they produce frequent adverse drug reactions (ADRs). Institutions such as Food and Drug Administration and European Medicines Agency recommend precaution with CYP2D6 poor metabolizers (PMs) that receive CYP3A4 inhibitors and tamsulosin. However, no specific pharmacogenetic guideline exists for tamsulosin. Furthermore, to date, no pharmacogenetic information is available for dutasteride. Henceforth, we studied the pharmacokinetics and safety of dutasteride/tamsulosin 0.5 mg/0.4 mg capsules according to 76 polymorphisms in 17 candidate pharmacogenes. The study population comprised 79 healthy male volunteers enrolled in three bioequivalence, phase-I, crossover, open, randomized clinical trials with different study designs: the first was single dose in fed state, the second was a single dose in fasting state, and the third was a multiple dose. As key findings, CYP2D6 PMs (i.e., *4/*4 and *4/*5 subjects) and intermediate metabolizers (IMs) (i.e., *1/*4, *1/*5, *4/*15 individuals) presented higher AUC (p = 0.004), higher t1/2 (p = 0.008), and lower Cl/F (p = 0.006) when compared with NMs (*1/*1 individuals) and UMs (1/*1 × 2 individuals) after multiple testing correction. Moreover, fed volunteers showed significantly higher tmax than fasting individuals. Nominally significant associations were observed between dutasteride exposure and CYP3A4 and CYP3A5 genotype and between tamsulosin and ABCG2, CYP3A5, and SLC22A1 genotypes. No association between the occurrence of adverse drug reactions and genotype was observed. Nonetheless, higher incidence of adverse events was found in a multiple-dose clinical trial. Based on our results, we suggest that dose adjustments for PMs and UMs could be considered to ensure drug safety and effectiveness, respectively. Further studies are warranted to confirm other pharmacogenetic associations.

Leflunomide: modern look at safety problem (literature review)

In accordance with the recommendations of EULAR and ARR methotrexate (MTX) is the first-line drug in patients with rheumatoid arthritis (RA). In cases where the use of MTX is impossible due to its ineffectiveness or adverse drug reactions (ADRs), leflomide (LEF) or sulfasalazine is most commonly used in routine clinical practice. This article presents generalized data on the safety of LEF in the treatment of patients with RA. It was shown that ADRs associated with the LEF were most often met in the first year of treatment. The most frequent ADRs were arterial hypertension, hair loss, diarrhea, dermatitis of different localization, increasing the level of transaminases, pancytopenia and others.

A comprehensive analysis of the efficacy and safety of COVID-19 vaccines

The numbers of cases and deaths from coronavirus disease 2019 (COVID-19) are continuously increasing. Many people are concerned about the efficacy and safety of the COVID-19 vaccines. We performed a comprehensive analysis of the published trials of COVID-19 vaccines and the real-world data from the Vaccine Adverse Event Reporting System. Globally, our research found that the efficacy of all vaccines exceeded 70%, and RNA-based vaccines had the highest efficacy of 94.29%; moreover, Black or African American people, young people, and males may experience greater vaccine efficacy. The spectrum of vaccine-related adverse drug reactions (ADRs) is extremely broad, and the most frequent ADRs are pain, fatigue, and headache. Most ADRs are tolerable and are mainly grade 1 or 2 in severity. Some severe ADRs have been identified (thromboembolic events, 21–75 cases per million doses; myocarditis/pericarditis, 2–3 cases per million doses). In summary, vaccines are a powerful tool that can be used to control the COVID-19 pandemic, with high efficacy and tolerable ADRs. In addition, the spectrum of ADRs associated with the vaccines is broad, and most of the reactions appear within a week, although some may be delayed. Therefore, ADRs after vaccination need to be identified and addressed in a timely manner.

Real-world data for golimumab treatment in patients with ulcerative colitis in Japan: interim analysis in post-marketing surveillance.

Background/AimsGolimumab (GLM) is an anti-tumor necrosis factor-α drug approved for treating moderate-to-severe active ulcerative colitis (UC). A 52-week post-marketing surveillance (PMS) was initiated to evaluate its safety and effectiveness in patients with UC in Japan. We present an interim report of the ongoing PMS.MethodsPatients received 200 mg of subcutaneous GLM at week 0, 100 mg at week 2, and 100 mg 4 weekly thereafter. The safety analysis set included 392 patients with UC, and the effectiveness analysis set 387 patients. Safety and effectiveness were assessed at week 6.ResultsAdverse drug reactions (ADRs) were reported in 8.2% (32/392) and serious ADRs in 4.6% (18/392). The most frequent ADRs were infection and infestation (3.3%), with herpes zoster being the most common. ADRs were significantly higher in patients with concomitant corticosteroid use (odds ratio [OR], 3.45; 95% confidence interval [CI], 1.40–9.68). No significant difference in ADR incidence was observed between patients aged ≥65 and <65 years (OR, 1.23; 95% CI, 0.35–3.47). Six-week effectiveness of GLM was confirmed by a decrease in the partial Mayo score (–2.3; 95% CI, –2.6 to –2.1) and C-reactive protein levels (–0.64; 95% CI, –0.92 to –0.36), including in the biologics-experienced population.ConclusionsThe safety and effectiveness of GLM at week 6 in a real-world setting were demonstrated in patients with UC in Japan. ADR patterns were consistent with previous reports with no new safety signals. Concomitant corticosteroid use may be associated with increased ADR incidence. The final results of the ongoing PMS are necessary for further evaluation.

Real-life burden of adverse reactions to biological therapy in inflammatory bowel disease: a single-centre prospective case series.

Biologics represent a key therapeutic option in inflammatory bowel disease (IBD), but are associated with several side effects. Post-marketing surveillance, through a spontaneous adverse drug reactions (ADRs) monitoring system, is essential to assess the safety profile of biologics. The aim of the study was to prospectively evaluate the occurrence of ADRs in IBD patients treated with biologics from a single centre in Southern Italy. Data from patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) who underwent biological therapy were prospectively collected. ADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA®). Overall, 68 (54% male, 68% with UC and 32% with CD) biologic-naïve IBD patients underwent biological therapy. Mean follow-up was 11.7 ± 6.2 months. As a results of switches, for 68 patients we obtained 96 biologic prescriptions. Overall, 45 ADRs occurred in 36 (53%) patients, distributed as follows (ADRs/prescriptions): 19/37 with IFX-Remicade, 5/12 with IFX-Remsima, 8/9 with GOL, 11/26 with ADA, and 2/12 with VDZ. Mild ADRs were 29 (64%), moderate 15 (34%) and 1 (2%) severe. General disorders and administration related reactions were the most frequent ADRs (35%), followed by skin and subcutaneous tissue disorders (20%), infections (15%), musculoskeletal (11%), respiratory (6%) blood (4%), gastrointestinal (4%), and vascular disorders (2%). In 9 cases (20%) the ADRs resulted in definitive discontinuation of biologic therapy. In a prospective cohort of IBD patients, more than half experienced ADRs during biologic therapy. General disorders and administration related reactions were the most common ADRs, while infections were less common and rarely led to discontinuation of therapy. Findings underline the importance of surveillance in management of IBD patients during biologic therapy and implementing safety protocols with data from real-life settings.

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study.

Chimeric-antigen-receptor T cells directed against CD19 (CAR-T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To determine the clinical features and incidence of adverse-drug reactions (ADR) associated with CAR-T. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase and meta-analysis of data from CAR-T trials and cohorts in the literature was also performed through March, 2020. The primary objective was to identify ADR associated with approved CAR-T (axicabtagene-ciloleucel; tisagenlecleucel). We conducted a Bayesian disproportionate analysis with the 95% lower credibility-interval of information component (IC025 , significance > 0). We also performed a systematic-review and meta-analysis of CAR-T trials and cohorts in the literature to evaluate ADR incidence. Nine ADR classes were associated with CAR-T: Cytokine release syndrome (CRS, n=1378, IC025 =4.24), neurological disorders (n=963, IC025 =2.42), hematological disorders (n=532, IC025 =3.32), infections (n=287, IC025 =2.38), cardiovascular disorders (n=256, IC025 =2.81), pulmonary disorders (n=186, IC025 =3.80), reno-metabolic disorders (n=123, IC025 =1.89), hemophagocytic-lymphohistiocytosis (n=36, IC025 =5.01) and hepatic disorders (n=32, IC025 =2.49). ADR-related fatalities accounted for 99/1783 (5.5%) of the reports and 262/1783 (14.7%) for all-cause mortality. These ADR-related fatalities were associated with hemophagocytic-lymphohistiocytosis, cerebral vascular disorder, infections, and respiratory failure. In meta-analyses, the most frequent any-grade ADRs were CRS, hematological disorders, and neurological disorders. Fatal ADR were most found with neurological disorders, CRS, and infections. Note, CAR-T infusion may be associated with severe ADR mainly following the week of administration, though rarely fatal. Infections, hemophagocytic-lymphohistiocytosis and end organ failures including neurological or lung involvements require scrutiny.