Moderate Adverse Drug Reactions Research Articles

Safety and effectiveness of tofogliflozin in Japanese people with type 2 diabetes: A multicenter prospective observational study in routine clinical practice.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors effectively and safely reduce fasting and postprandial hyperglycemia while promoting weight loss. However, their unique mechanism of action contributes to concerns regarding their safety. We therefore carried out a large-scale, non-commercial, investigator-initiated study on the safety and effectiveness of the SGLT2 inhibitor tofogliflozin. This multicenter, open-label, uncontrolled, prospective observational study was carried out at hospitals and clinics across Japan in participants aged ≥20 years who were SGLT2 inhibitor-naïve and had an established diagnosis of type 2 diabetes. The primary endpoint was adverse drug reactions (ADRs) of special interest. Secondary endpoints included all other ADRs and adverse events, glycated hemoglobin (HbA1c), and weight loss. The study, carried out from June 2014 through February 2020, enrolled 11,480 participants from 1,103 medical institutions; 6,967 participants completed the 104-week follow up. The most common ADRs of special interest were urinary and genital tract infections (1.53%), followed by volume depletion (1.25%). Hypoglycemia occurred in 27 participants (0.24%), adverse events in 1,054 (9.18%) and ADRs in 645 (5.62%). HbA1c decreased by 0.85% (95% confidence interval 0.82%-0.88%) and bodyweight decreased by 3.05 kg (95% confidence interval 2.94-3.17 kg). The HbA1c target was achieved by 51.70% of participants for target HbA1c <7.0%, 85.3% for <8.0% and 5.4% for <6.0% at week 104. Tofogliflozin was associated with only mild or moderate ADRs characteristic of SGLT2 inhibitors, with no unpredictable, new, serious, or high-incidence adverse events or ADRs. This independent study confirmed the safety and effectiveness of tofogliflozin in adult type 2 diabetes patients.

Moderate and serious adverse reactions to antimicrobials among hospitalized children: A systematic review.

This systematic review aimed to investigate the occurrence of moderate and severe adverse drug reactions (ADRs) to antimicrobials among hospitalized children. The PubMed/Medline, Cochrane Library, Embase, Web of Science, Scopus, Lilacs and CINAHL databases were searched in April 2023 to systematically review the published data describing the characteristics of moderate and severe ADRs to antimicrobials among hospitalized children. The search was carried out without date restrictions, up to the search date (April, 2023). At the end of the selection process, 30 articles met the inclusion criteria. Cutaneous reactions were the primary serious clinical manifestations in most articles (19/30), followed by erythema multiforme (71 cases), Stevens-Johnson syndrome (72 cases), and toxic epidermal necrolysis (22 cases). The main antimicrobials involved in moderate and severe ADRs were penicillins, cephalosporins and sulfonamides. Regarding the primary outcomes, 30% (9/30) of the articles reported deaths, and 46.7% (14/30) of studies reported increased lengths of hospital stay, need for intensive care, and transfer to another hospital. Regarding the main interventions, 10% (3/30) of the articles mentioned greater monitoring, suspension, medication substitution or prescription of specific medications for the symptomatology. The findings of this review could be used to identify areas for improvement and help health professionals and policymakers develop strategies. In addition, we emphasize the importance of knowing about ADRs so that there is adequate management to avoid undesirable consequences.

Costs associated with adverse drug reactions in an older population admitted to hospital: a prospective cohort study

PurposeThis study examines healthcare costs associated with adverse drug reactions (ADR) in an older population admitted acutely to an Irish tertiary hospital. MethodsProspective cohort study involving older persons admitted to hospital with and without an ADR. Data was collected at baseline, during hospitalisation and post-discharge. Participants provided information on healthcare resource use three months before admission (baseline) and three months after discharge (follow-up). For each healthcare resource, unit costs were derived and applied. The average cost (standard deviation (SD)) associated with the hospital admission for the ADR and non-ADR are presented. In addition, baseline and follow-up care costs were compared using difference-in-difference analysis and presented with 95% confidence intervals (CI). Costs by preventability and severity of ADR are also presented.ResultsA total of n = 230 participants were included (n = 93 ADR and n = 137 without ADR). The average cost associated with hospital admission for an ADR was €9538 (SD €10442) and €9828 (SD €11770) for non-ADR. The additional follow-up costs (difference-in-difference) associated with the ADR was estimated at €2047 (95% CI: -€889 to €4983). The mean incremental follow-up cost of definite preventable ADRs was estimated at €1648 (95% CI: -€4310 to €7605), possible preventable ADRs €2259 (95 CI: -€1194 to €5712) and unavoidable ADRs €1757 (95% CI: -€3377 to €6890). The mean incremental follow-up cost associated with moderate severe ADRs was estimated at €1922 (95% CI: -€1088 to €4932) and €3580 (95% CI: -€4898 to €12,058) for severe ADRs. ConclusionADRs leading to hospital admission are associated with modest incremental healthcare costs during and three months after admission. Severe and possibly preventable ADRs were associated with higher costs.

Incidence and severity of nonionic low-osmolar iodinated contrast medium-related adverse drug reactions in the Republic of Korea: Comparison by generic.

We aimed to report the incidence and severity of nonionic low-osmolar iodine contrast medium (ICM)-related adverse drug reactions (ADRs) in the Republic of Korea, by analyzing data from our single tertiary institution and published Korean reports, and to determine whether there is a difference in the incidence of ICM-related ADR by ICM generics. A total of 1,161,419 consecutive contrast-enhanced computed tomography (CT) examinations between January 2016 and December 2021 at Asan Medical Center were included. A systematic search of the literature investigating the incidence of ICM-related ADR in the Republic of Korea published up to December 31, 2021 was performed. We pooled these outcomes with those of our study using a binomial-normal model, and the pooled incidences of ADRs were compared among ICM generics using chi-square tests. Seven studies with a total of 2,570,986 contrast-enhanced CT examinations from 12 institutions were included. The pooled incidences of overall, mild, moderate, and severe ICM-related ADRs in the Republic of Korea were 0.82% (95% CI: 0.61%-1.10%), 0.72% (95% CI: 0.50%-1.04%), 0.11% (95% CI: 0.08%-0.15%), and 0.013% (95% CI: 0.010%-0.018%), respectively. In multiple pairwise comparisons, there were no significant differences in the overall incidence of ADRs between ICM generics, except iomeprol versus iobitridol and iomeprol versus iohexol. For moderate and severe ADRs, there were no significant differences in ADR incidence between ICM generics. The incidence of moderate and severe ICM-related ADRs did not differ among ICM generics. Our results suggest that no restriction is required for selection among nonionic low-osmolar ICMs.

Safety of antituberculosis agents used for multidrug-resistant tuberculosis among patients attending the Jamot Hospital of Yaounde, Cameroon.

Recognized in 1994 as a global emergency by the World Health Organization, tuberculosis (TB) remains an ongoing health threat. In Cameroon, the mortality rate is estimated at 2.9%. Treatment of multidrug-resistant TB (MDR-TB) defined as the resistance to the two most effective antiTB drugs, and requires therapy of more than 7 drugs taken on a daily basis during 9-12 months. This study aimed to evaluate the safety profile of treatment regimens used for MDR-TB at Jamot Hospital of Yaounde (JHY). This was a retrospective cohort study of patients treated for MDR-TB at HJY from January 1, 2017, to December 31, 2019. Patients characteristics of the cohort, drugs regimen were collected and described. All possible adverse drug reactions (ADR) were described clinically and by severity grade. During the study period, 107 patients were included, and 96 (89.7%) experienced at least one ADR. Most parts of the patients (90) experienced mild or moderate ADR. Hearing loss was the most frequent ADR, and led mostly in aminoglycosides dose reduction (n = 30, 96.7%). Gastrointestinal events were commonly observed during the study period. Our findings suggested that ototoxicity was a prominent safety issue during the study period. The implementation of the new short treatment regimen could be effective in reducing the burden of ototoxicity among MDR-TB patients. Nevertheless, new safety issues could emerge.

Adverse drug reactions and associated patient characteristics in older community-dwelling adults: a 6-year prospective cohort study.

To date, research on adverse drug reactions (ADRs) has focused on secondary care, and there is a paucity of studies that have prospectively examined ADRs affecting older adults in general practice. To examine the cumulative incidence and severity of ADRs and associated patient characteristics in a sample of community-dwelling older adults. Prospective cohort study of older adults (aged ≥70 years, N = 592) recruited from 15 general practices in the Republic of Ireland. Manual review of the participant's general practice electronic medical record, linked to the national dispensed prescription medicine database, and a detailed, self-reported patient postal questionnaire. The primary outcomes were ADR occurrence and severity over a 6-year period (2010-2016). Unadjusted and adjusted logistic regression models examined potential associations between patient characteristics and ADR occurrence. A total of 211 ADRs were recorded for 159 participants, resulting in a cumulative incidence of 26.9% over 6 years. The majority of ADRs detected were mild (89.1%), with the remainder classified as moderate (10.9%). Eight moderate ADRs, representing 34.8% of moderate ADRs and 3.8% of all ADRs, required an emergency hospital admission. ADRs were independently associated with female sex (adjusted odds ratio [OR] 1.83, 95% confidence interval [CI] = 1.17 to 2.85; P = 0.008), polypharmacy (5-9 drug classes) (adjusted OR 1.81, 95% CI = 1.17 to 2.82; P = 0.008), and major polypharmacy (≥10 drug classes) (adjusted OR = 3.33, 95% CI = 1.62 to 6.85; P = 0.001). This prospective cohort study of ADRs in general practice shows that over one-quarter of older adults experienced an ADR over a 6-year period. Polypharmacy is independently associated with ADR risk in general practice and older adults on ≥10 drug classes should be prioritised for regular medication review.

Costs Associated with Adverse Drug Reactions Among HIV/TB Patients in Thailand.

PurposeTo assess the direct and indirect costs associated with adverse drug reactions (ADRs) in patients receiving treatment regimens for human immunodeficiency virus (HIV) infection and tuberculosis (TB) in selected Thai hospitals.Patients and MethodsThis was a retrospective study conducted between October 2014 and September 2019 at three public hospitals in Thailand. Data were obtained from a medical database and spontaneous ADR reporting system of each study site. The out-of-pocket health payments and indirect costs were determined via interviewing. All costs were updated to 2021.ResultsA total of 432 eligible patients who experienced ADRs due to HIV and TB treatment, and 93 patients were interviewed to determine direct non-medical and indirect costs. The average direct medical cost for ADR was USD 5.65 for mild cases, USD 156.54 for moderate cases, and USD 1,242.45 for severe cases. For direct non-medical costs, the average cost per episode was USD 27.29 in mild ADR, USD 70.86 in moderate ADR and USD 270.66 in severe ADR. The indirect cost incurred in each mild, moderate and severe ADR was USD 41.86, USD 89.34, and USD 552.60, respectively. The Stevens-Johnson syndrome (SJS) had the highest management costs.ConclusionADRs associated with anti-tuberculosis drugs and antiretroviral drugs seem to have a substantial economic impact from a societal perspective. These findings would be useful for increasing awareness and encouraging early avoidance of ADRs.

Knowledge, Attitude and Practices of Pharmacovigilance and Adverse Drug Reaction Reporting Among Pharmacists Working at Alkarak Governorate, Jordan

Background: Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem. Since adverse drug reactions (ADRs) are considered worldwide as one of the most common public health problems that affect all groups of patients; the assessment of healthcare providers' knowledge, attitude, and practice of PV and ADRs reporting will provide an in-depth look at the reasons behind the lack of reports. Objectives: This study aims to assess the overall knowledge, attitude, and practice of PV and ADRs reporting among pharmacists working at Alkarak Governorate, Jordan. Methods: A cross-sectional study was conducted during the period from 20th February till 20th April 2021. All employed pharmacists working at Alkarak Governorate were eligible to participate using a structured-interview based-questionnaire. The Bivariate correlation test with the Pearson's (r) was used to assess the correlations between metric variables, independent samples t-test and the one-way ANOVA tests were also applied. The SPSS IBM program version 21 and the Stand-Alone FACTOR program were used for the statistical data analysis. The level of significance was set to be ≤ 0.050. Results: The majority of the pharmacists were females (74.4%), most of respondents (84.9%) had a Bachelor's degree in pharmacy. The pharmacists showed a moderately overall knowledge of PV (58.7%), positive attitudes toward their perceived ADRs reporting importance (78%), and toward selective ADRs reporting (62.8%), a moderate effort exerted by those pharmacists regarding the practice of ADRs reporting process (55.8%). The main barrier was that pharmacists did not know how to report (72.1%). Conclusion: Pharmacists had a moderate PV and ADRs reporting knowledge on average. Positive attitudes toward perceived ADRs reporting importance and moderate level of agreement on focusing on the well-known and serious ADRs. The result denotes a moderate effort exerted by those pharmacists on ADRs reporting practices. Pharmacists faced a moderately high perceived difficulties and extra burden (barriers).

Adverse Drug Reactions to First-line Anti-tubercular Drugs Based on Individual Case Safety Report in a Single Tertiary Hospital

Background/Aims: Tuberculosis has incidence and mortality rates that are among the highest for all communicable diseases. Adverse drug reactions (ADRs) to anti-tubercular drugs are common, and have a major impact on treatment maintenance and prognosis. It is important to understand the characteristics of ADRs and establish a suitable management plan. Methods: We retrospectively reviewed patients with ADRs during treatment with first-line antitubercular drugs such as isoniazid, rifampicin, ethambutol, and pyrazinamide from 2009 to 2018. Age, sex, and total treatment period, and the onset, severity, seriousness, and system organ class of ADRs, were analyzed to understand the characteristics of first-line anti-tubercular drug-related ADRs. Results: A total of 1,606 of 5,482 patients (29.3%) experienced ADRs after administration of first-line anti-tubercular drugs. The incidence of ADRs related to isoniazid, rifampicin, ethambutol, and pyrazinamide was 22.2%, 21.3%, 24.5%, and 29.6%, respectively. A total of 2,098 ADR reports were made (mean of 1.3 ± 0.6 per patient). The rates of mild, moderate, and severe ADRs were 32.4%, 61.1%, and 6.5%, respectively. There were 127 reports (6.1%) of serious ADRs. Skin and appendage disorders were most frequently reported (27.5%), followed by gastrointestinal disorders (17.5%), and liver and biliary system disorders (13.1%). The total treatment period was longer in patients who experienced ADRs (224.0 ± 3.1 days vs. 247.0 ± 4.7 days, &lt;i&gt;p&lt;/i&gt; = 0.009). Conclusions: The incidence of ADRs to first-line anti-tuberculosis drugs was 29.3%, and 6.5% were severe ADRS. ADRs prolonged the overall treatment duration, indicating the importance of their detection and management.

Lower starting dose of afatinib for the treatment of metastatic lung adenocarcinoma harboring exon 21 and exon 19 mutations

BackgroundAfatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib.MethodsWe designed a retrospective study, enrolling all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg daily afatinib as their initial treatment in three Kaohsiung Medical University-affiliated hospitals in Taiwan.ResultsA total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (75% vs. 83%, p = 0.1672), median PFS (14.5 vs. 14.8 months, log-rank p = 0.4649), and median OS (34.0 vs. 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients initially receiving 30 mg afatinib daily had fewer ADRs compared with those using 40 mg daily. The overall incidence of moderate and severe ADRs was significantly lower in patients receiving 30 mg afatinib daily compared with those using 40 mg daily (49% vs. 77%, p = 0.002); similar findings was observed in terms of severe ADRs (7% vs. 24%, p < 0.0001).ConclusionPatients receiving 30 mg afatinib daily as their initial treatment had similar RR, PFS, OS, but significantly fewer serious ADRs, as compared with those using 40 mg as their starting dose.

Title Assessing Potentially Inappropriate Medications in Seniors: Differences between American Geriatrics Society and STOPP Criteria, and Preventing Adverse Drug Reactions.

Key problems for seniors are their exposure to “potentially inappropriate medications” and “potential medication omissions”, which place them at risk for moderate, severe, or fatal adverse drug reactions. This study of 82,935 first admissions to acute care hospitals in Calgary during 2013–2018 identified 294,160 Screening Tool of Older People’s Prescriptions (STOPP) potentially inappropriate medications (PIMs) (3.55/patient), 226,970 American Geriatric Society (AGS) Beers PIMs (2.74/patient), 59,396 START potential prescribing omissions (PPOs) (0.72/patient), and 85,288 STOPP PPOs (1.03/patient) for which a new prescription corrected the omission. This represents an overwhelming workload to prevent inappropriate prescriptions continuing during the hospitalisation and then deprescribe them judiciously. Limiting scrutiny to the most frequent PIMs and PPOs will identify many moderate, severe, or fatal risks of causing adverse drug reactions (ADRs) but to identify all PIMs or PPO involving moderate or severe risks of ADRs also involves searching lower in the frequency list of patients. Deciding whether to use the STOPP or AGS Beers PIM lists is an important issue in searching for ADRs, because the Pearson correlation coefficient for agreement between the STOPP and AGS Beers PIM totals in this study was 0.7051 (95% CI 0.7016 to 0.7085; p < 0.001). The combined lists include 289 individual PIM medications but STOPP and AGS have only 159 (55%) in common. The AGS Beers lists include medications used in the US and STOPP/START those used in Europe. The AGS authors recommend using both criteria. The ideal solution to the problem is to implement carefully constructed Clinical Decision Support Systems (CDSS) as in the SENATOR trial, then for an experienced pharmacist to focus on the key PIMs and PPOs likely to lead to moderate, severe, or fatal ADRs. The pharmacist and key decision makers on the services need to establish a collegial relationship to discuss frequently changing the medications that place the patients at risk. Then, the remaining PIMs and PPOs that relate to chronic disease management can be discussed by phone with the family physician using the discharge summary, which lists the medications for potential deprescribing.

Direct costs of managing adverse drug reactions during rifampicin-resistant tuberculosis treatment in South Africa.

To estimate the provider costs of managing adverse drug reactions (ADRs) to standard long-course treatment for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) according to South African guidelines. We parameterised a published Markov health state model for MDR/RR-TB with guidelines-based, bottom-up public-sector provider costing of ADR management. Frequency of ADR occurrence was extracted from the literature. Costs were estimated over 10 years, discounted 3% annually and tested using probabilistic sensitivity analysis. On average, guidelines-based costing of moderate ADRs weighted by the frequency of occurrence was US$135.76 (standard deviation [SD] US$17.18) and the cost of serious ADRs was US$521.29 (SD US$55.99). We estimated that the incremental costs of ADR management were US$380.17 annually per patient initiating MDR/RR-TB treatment. The incremental costs of ADR management for the public health sector in South Africa was US$4.76 million, 8.3% of the estimated cohort costs of MDR/RR-TB treatment ($57.55 million) for the 2015 cohort of 12 527 patients. Management of multiple ADRs and serious ADRs, which are common during the first 6 months of standard, long-course MDR/RR-TB treatment, substantially increases provider treatment costs. These results need to be taken into account when comparing regimen costs, and highlight the urgent need to identify drug regimens with improved safety profiles.

Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas' disease.

Up to half of patients with Chagas' disease under benznidazole treatment present adverse drug reactions (ADRs) and up to one-third do not complete standard treatment. To verify the incidence and possible factors associated with the suspension of benznidazole treatment in a large cohort of patients. We included 2075 patients treated with benznidazole during the projects managed by the medical humanitarian organization Doctors Without Borders (Médecins Sans Frontières) in Bolivia from 2009 to 2013. Benznidazole treatment was provided two or three times per day for ∼60 days at 5-7.5 mg/kg/day. A multiple logistic regression model was developed to evaluate the factors associated with permanent suspension of benznidazole treatment. Permanent benznidazole treatment suspension occurred in 211 patients (10.2%) and the average time until permanent treatment suspension was 23 days. Multifactorial analysis revealed that female sex (adjusted OR = 1.70), moderate ADRs (adjusted OR = 10.57), mild ADRs (adjusted OR = 1.69) and skin disorders (adjusted OR = 4.18) were significantly associated with the permanent suspension of benznidazole treatment. Women with mild or moderate skin ADRs presented a probability of treatment interruption of 18.6% and 59.0%, respectively. Benznidazole treatment was safe and a large proportion of patients were able to complete a full course of benznidazole treatment under close treatment surveillance. Female sex, skin disorders and mild and moderate ADRs were independently associated with the permanent suspension of benznidazole treatment. In particular, women with moderate skin ADRs had the highest risk of benznidazole treatment interruption.

Effect of prolonged-released oxycodone/naloxone in postoperative pain management after total knee replacement: a nonrandomized prospective trial

PurposeThe purpose of this study was to examine the effect of postoperative prolonged release oxycodone/naloxone (OXN) in comparison to other opioids (control group) on the early postoperative rehabilitation outcome after total knee replacement. MethodsIn a prospective, noninterventional, nonrandomized clinical trial, 80 patients were assigned to either the OXN group or a control group. Postoperative outcome and pain level at days 3, 6, 21, 35, and 6months were evaluated using the Bowel Function Index, Brief Pain Inventory Short Form questionnaire, the Hospital for Special Surgery score, modified Larson score, and the ability to attend physiotherapy. Medications were recorded and safety analysis was done. Both groups were compared using an analysis of covariance. ResultsThere were no significant differences between both groups regarding pain levels. OXN group patients reported better bowel function (median values of 0.0 for the OXN group and 20.0 for the control group). No effect of treatment group (P=.19) and no treatment-by-visit interaction on Hospital for Special Surgery final score (P=.67) could be detected, but Larson function score in the early postoperative phase was significantly better in the OXN group (P=.018). The proportion of OXN group patients who were able to attend without any restriction was 58.1%. The proportions of patients in the OXN group and control group who experienced mild or moderate adverse drug reactions were 23.3% and 37.8%, respectively. There were no serious adverse drug reactions. ConclusionIn conclusion, OXN provides an effective analgesia and offers several benefits such as higher ability to participate in physiotherapy and better functional results. Incidence and severity of constipation can be reduced by using prolonged-released OXN as compared with other opioids.

High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23

Objective: Iron isomaltoside (Monofer®) is a high-dose intravenous iron preparation with good tolerability and efficacy in inflammatory bowel disease (IBD) patients with iron deficiency anaemia (IDA). This trial evaluates the safety and efficacy, including effect on intact fibroblast growth factor 23 (iFGF23) of a high single dose and cumulative doses of iron isomaltoside in IBD patients with IDA.Materials and methods: The trial was a prospective, open-label, multi-centre trial conducted in IBD patients with IDA. Based upon haemoglobin (Hb) levels at baseline and weight, the patients received 1500, 2000, 2500 or 3000 mg of iron isomaltoside infused in single doses up to 2000 mg. The outcome measurements included adverse drug reactions (ADRs) and changes in haematology and biochemistry parameters.Results: Twenty-one IBD patients with IDA were enrolled, receiving 1500 (seven patients), 2000 (eight patients), 2500 mg (four patients) or 3000 (two patients) mg of iron. No serious ADRs were observed. Four patients experienced nine mild to moderate ADRs (hypersensitivity, pyrexia, vomiting, constipation, abdominal pain, dyspepsia (two events) and eye allergy (two events)). In total, 15 (75%) patients had an increase in Hb of ≥2.0 g/dL during the trial, with normalisation of ferritin. No changes in iFGF23 or clinically significant hypophosphataemia were found.Conclusion: Rapid infusions of high-dose iron isomaltoside, administered as single doses up to 2000 mg and cumulative doses up to 3000 mg, were without safety concerns and were efficacious in increasing Hb levels in IBD patients. Iron isomaltoside did not induce profound phosphate wasting via increased iFGF23 levels.

Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice.

Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319mg, 4.9mg/kg) and serum concentration (mean 387ng/ml) of clozapine was found with the variation in dose explaining 30% of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3ng/ml, P=0.018) and moderate ADRs (261.4 vs 416.3ng/ml, P=0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs.

Profile of rheumatology patients willing to report adverse drug reactions: bias from selective reporting.

BackgroundAdverse drug reactions (ADRs) have a significant impact on human health and health care costs. The aims of our study were to determine the profile of rheumatology patients willing to report ADRs and to identify bias in such a reporting system.MethodsSemi-intensive ADRs reporting system was used in our study. Patients willing to participate (N=261) completed the questionnaire designed for the purpose of the study at the hospital admission. They were subsequently classified into two groups according to their ability to identify whether they had experienced ADRs during the previous month. Group 1 included 214 out of 261 patients who were able to identify ADRs, and group 2 consisted of 43 out of 261 patients who were not able to identify ADRs in their recent medical history.ResultsGroup 1 patients were more significantly aware of their diagnosis than the patients from group 2. Marginal significance was found between rheumatology patients with and without neurological comorbidities regarding their awareness of ADRs. The majority of patients reported ADRs of cytotoxic drugs. The most reported ADRs were moderate gastrointestinal discomforts.ConclusionWe may draw a profile of rheumatological patients willing to report ADRs: 1) The majority of them suffer from systemic inflammatory diseases and are slightly more prone to neurological comorbidities. 2) They are predominantly aware of their diagnosis but less able to identify the drugs that may cause their ADRs. 3) They tend to report mainly moderate gastrointestinal ADRs; that is, other cohorts of patients and other types of ADRs remain mainly undetected in such a reporting, which could represent a bias. Counseling and education of patients as well as developing a network for online communication might improve patients’ reporting of potential ADRs.

The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic Considerations.

Vonoprazan fumarate (Takecab) is a first-in-class potassium-competitive acid blocker that has been available in the market in Japan since February 2015. Vonoprazan is administered orally at 20 mg once daily for the treatment of gastroduodenal ulcer, at 20 and 10 mg once daily for the treatment and secondary prevention of reflux esophagitis, respectively, at 10 mg once daily for the secondary prevention of low-dose aspirin- or non-steroidal anti-inflammatory drug-induced peptic ulcer, and at 20 mg twice daily in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori. It inhibits H(+),K(+)-ATPase activities in a reversible and potassium-competitive manner with a potency of inhibition approximately 350 times higher than the proton pump inhibitor, lansoprazole. Vonoprazan is absorbed rapidly and reaches maximum plasma concentration at 1.5-2.0 h after oral administration. Food has minimal effect on its intestinal absorption. Oral bioavailability in humans remains unknown. The plasma protein binding of vonoprazan is 80% in healthy subjects. It distributes extensively into tissues with a mean apparent volume of distribution of 1050 L. Being a base with pKa of 9.6 and with acid-resistant properties, vonoprazan is highly concentrated in the acidic canaliculi of the gastric parietal cells and elicited an acid suppression effect for longer than 24 h after the administration of 20 mg. The mean apparent terminal half-life of the drug is approximately 7.7 h in healthy adults. Vonoprazan is metabolized to inactive metabolites mainly by cytochrome P450 (CYP)3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1. A mass balance study showed that 59 and 8% of the orally administered radioactivity was recovered in urine as metabolites and in an unchanged form, respectively, indicating extensive metabolism. Genetic polymorphism of CYP2C19 may influence drug exposure but only to a clinically insignificant extent (15-29%), according to the population pharmacokinetic study performed in Japanese patients. When vonoprazan was co-administered with clarithromycin, the mean AUC from time 0 to time of the next dose (dosing interval) of vonoprazan and clarithromycin were increased by 1.8 and 1.5 times, respectively, compared with the corresponding control values, indicating mutual metabolic inhibition. The mean area under the curve from time zero to infinity obtained from patients with severe liver and renal dysfunction were elevated by 2.6 and 2.4 times, respectively, compared with healthy subjects, with no significant changes in plasma protein binding. Vonoprazan increases intragastric pH above 4.0 as early as 4 h after an oral dose of 20 mg, and the extensive anti-secretory effect is maintained up to 24 h post-dose. During repeated dosing of 20 mg once daily, the 24-h intragastric pH >4 holding time ratios were 63 and 83 % on days 1 and 7, respectively. Because vonoprazan elicited a more extensive gastric acid suppression than the proton pump inhibitor, lansoprazole, it also gave rise to two to three times greater serum gastrin concentrations as compared with lansoprazole. In pre-approval clinical studies for the treatment of acid-related disorders, mild to moderate adverse drug reactions (mostly constipation or diarrhea) occurred at frequencies of 8-17%. Neither severe liver toxicity nor neuroendocrine tumor has been reported in patients receiving vonoprazan.

Clinical observation of the adverse drug reactions caused by non-ionic iodinated contrast media: results from 109,255 cases who underwent enhanced CT examination in Chongqing, China.

To analyse the pattern and factors that influence the incidence of adverse drug reactions (ADRs) induced by non-ionic iodinated contrast media and to evaluate their safety profiles. Data from 109,255 cases who underwent enhanced CT examination from 1 January 2008 to 31 August 2013 were analysed. ADRs were classified according to the criteria issued by the American College of Radiology and the Chinese Society of Radiology. A total of 375 (0.34%) patients had ADRs, including 281 mild (0.26%); 80 moderate (0.07%); and 14 severe (0.01%) ADRs; no death was found. 302 (80.53%) of the ADRs occurred within 15 min after examination. Patients aged 40-49 years (204 cases, 0.43%; p < 0.01) or who underwent coronary CT angiography (93 cases, 0.61%; p < 0.01) were at a higher risk of ADRs. Female patients (180 cases, 0.40%; p < 0.01) or outpatients had significantly higher incidence rates of ADRs. The symptoms and signs of most of the ADRs were resolved spontaneously within 24 h after appropriate treatment without sequelae. The occurrence of ADRs is caused by the combined effects of multiple factors. The ADRs induced by non-ionic iodinated contrast media are mainly mild ones, while moderate or severe ADRs are relatively rare, suggesting that enhanced CT examination with non-ionic iodinated contrast media is highly safe, and severe adverse events will seldom occur under appropriate care. The study included 109,255 patients enrolled in various types of enhanced CT examinations, which could reflect ADR conditions and regulations in Chinese population accurately and reliably.

Pattern of Adverse Drug Reactions in Children Attending the Department of Pediatrics in a Tertiary Care Center: A Prospective Observational Study.

AIMTo study the pattern of various adverse drug reactions (ADRs) occurring in children attending the Department of Pediatrics, SMGS Hospital, Jammu over 1 year.SUBJECTS AND METHODSThis was a prospective study, with study population of patients attending Department of Pediatrics over a period of 1 year. A structured format was used to enroll the participants. A pilot study was conducted to test the suitability of the format and feasibility of the study. The study was carried out to review various pattern of ADRs by using the Naranjo probability scale, and severity was assessed by using the Hartwig severity scale. ADRs were classified according to the classification used by the Adverse Drug Reaction Monitoring Center, Central Drugs Standard Control Organization, New Delhi, India.RESULTSIn the present study, 104 patients were found to have developed acute drug reactions. Among these, 83.6% were type B, 14.42% type A, and 1.92% were type U. Furthermore, 25.96% ADRs were due to anticonvulsants, followed by antibiotics (22.11%), antipyretics (11.53%), vaccination (8.65%), steroids (6.73%), decongestants (5.67%), snake antivenom and antiemetics (3.84%), and fluids, insulin, and antacids (1.92%). The patients’ dermatological system was involved in 67.30%, followed by the central nervous system (CNS) in 11.53% patients. Renal system was involved in 6.73% patients. Cardiac, musculoskeletal, metabolic, and other systems were involved in 4.80%, 3.84%, 2.88%, and 0.96%, respectively. According to the Hartwig severity scale of ADRs, 64.4% patients had moderate ADRs, 29.8% patients had severe ADRs, and 5.76% had mild ADRs. In the present study, 64.4% patients expressed moderate severity, whereas 29.8% expressed high severity and 5.76% expressed mild ADRs.CONCLUSIONADRs were seen in 71% of the patients between 1 and 5 years of age, 26% in the age group of 5–10 years, and 3% were more than 10 years old. Anticonvulsants (25.96%) and antibiotics (22.11%) were responsible for majority of ADRs. Rash (55.76%) was the most common presentation of ADR. Owing to the high number of ADRs, the present study points to the need for rigid adverse drug monitoring among pediatric patients to ensure the safety of drug therapy.