Non-serious Adverse Drug Reactions Research Articles

Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study

In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127–0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage–antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. BT100 study, ClinicalTrials.gov registration: NCT05498363.

Assessing Treatment Efficacy and Determinants of Outcome in Isoniazid Mono-resistant Tuberculosis Patients: A Prospective Observational Study in Gujarat

Introduction: There is a high number of isoniazid-resistant tuberculosis (TB) in India; estimates imply that over 25% of TB patients there are isoniazid-resistant. Hence, the study aimed to evaluate the effectiveness of therapy for patients with isoniazid-mono-resistant TB and the negative effects of the H-mono-resistant TB Regime. Materials and Methods: It was a hospital-based prospective observational study from September 2021 to August 2022. Hence, 100 patients diagnosed with isoniazid mono-resistance TB enrolled in this study. After obtaining the prior informed consent of all patients willing to approve the collection and publication of their data, including extensive clinical history and radiological, microbiological, and biochemical investigations, this study included all diagnosed cases of isoniazid mono-resistant TB. A descriptive statistical analysis was done for continuous and categorical variables. Differences in characteristics between participants were tested with logistic regression and cross-tabulation. P <0.05 was considered significant. Results: Among 100 patients participated, their mean age was 50.8 ± 3.2 years. About 72 (72%) participants have successful treatment outcomes (cure). Only about 25 (25%) patients had minor adverse drug reactions. Body mass index (16.6 [3.6–74]), substance addiction history (9.5 [3.3–26.9]), previous history of TB (9 [3.3–24.0]), type of lesion (5.3 [1.6–17]), and extent of the lesion (2.6 [1.03–6.07]) in chest X-ray were associated statistically with the treatment outcome. Conclusion: The findings suggest that the H-mono-resistance regime is generally well-tolerated, with only a small percentage of patients experiencing nonserious adverse drug reactions, and the overall successful treatment outcome in H-mono patients was 72%. The study also highlights the importance of monitoring drug resistance patterns, particularly for levofloxacin and moxifloxacin, and the need for effective treatment regimens for isoniazid mono-resistant pulmonary TB.

Safety of subcutaneous and sublingual immunotherapy with allergoids in children: a real-life pharmacovigilance study.

Aims: Allergen-specific immunotherapy uses a sublingual (sublingual immunotherapy [SLIT]) or subcutaneous (subcutaneous immunotherapy [SCIT]) route. This pharmacovigilance study aimed to determine the number and type of adverse drug reactions (ADRs) for SLIT and SCIT using carbamylated monomeric allergoids (CMAs) in children. Materials & methods: This pharmacovigilance study analyzed real-world post-marketing reports collected from a safety database of Lais sublingual tablets and injective Lais-in, containing CMAs for over 10 years. Results & conclusion: From January 2009 to September 2022, 26,107 doses of Lais-in were administered in children; only two nonserious related ADRs (incidence: 0.000077%) were reported. Regarding SLIT, the results showed only 12 spontaneous nonserious ADR reports (incidence: 0.000004%). These data showed the excellent safety profile of both SLIT and SCIT CMAs.

Treatment of Immune Thrombocytopenia (ITP) with Eltrombopag - Results of the 5th Interim Analysis of the Study RISA, with Special Consideration of Treatment Discontinuations

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia due to increased platelet clearance and decreased megakaryopoiesis. Eltrombopag (EPAG) is an oral thrombopoietin-receptor agonist, which is proved to be effective and safe in the treatment of ITP. Here we present data from the 5th interim analysis of the RISA study, specially considering the reasons for treatment discontinuation and possible links to the safety profile of EPAG. Methods: RISA is a prospective multicenter non-interventional study in Germany. It started in December 2015, and it will continue until December 2023. Statistical analysis is solely descriptive. Results: Data cutoff for this 5th interim analysis was 11th Feb 2022. 313 patients with persistent or chronic primary ITP (pITP) were enrolled. 302 of them received at least one dose of EPAG and completed at least one post baseline visit. Mean duration of participation was 74.1 months. Mean±SD age was 62.8±17.4 years. 54.8% of the patients were female. Mean±SD duration of ITP at baseline was 5.4±7.5 years. Comorbidity was present in 245 (81.1%) patients. Mean±SD number of concomitant diseases was 2.9±3.0. 99 (32.8%) patients completed the entire treatment period of 24 months, which includes all scheduled visits before data cutoff. Median treatment duration was 14 months (minimum 1 day, maximum 6.1 years). Treatment with EPAG was carried out at a median dosage of 50 mg daily. Median platelet counts increased from baseline 34.0x109/L (N=292) to 91.5x109/L (N=262) within one month. From then and until the end of the two-year observation period, platelet counts remained stable above 90x109/L. The proportion of patients whose platelet count was at least 50x109/L increased from 30.1% at baseline to 74.4% after one month and to 85.6% after twelve months. The number of bleeding events per patient-year decreased, from 1.35 at baseline to 0.59 and 0.16 after one and two years, respectively. 128 (42%) patients discontinued treatment, 51 (40%) of them before day 92. Reasons for discontinuation (multiple answers possible) were insufficient effectiveness in 55 (43%) cases, adverse events (AE) in 36 (28%) cases, death in 20 (16%) cases, non-compliance in 16 (13%) cases, lost to follow up in 10 (8%) cases, cessation of therapy due to complete response in 15 (12%) cases and other reasons in 10 (8%) cases. Across the data set, most frequent AE classified as non-serious adverse drug reactions (nsADR) were fatigue (5.3%), thrombocytopenia (3.3%), thrombocytosis (2.3%), diarrhea (3.0%) and dizziness (2.0%). The most common AE leading to discontinuation of treatment and classified as nsADR were thrombocytosis (1.3%), diarrhea (1.7%), fatigue (1.0%) and arthralgia (1.0%). The most frequent serious AE that led to treatment discontinuation and was rated as serious adverse drug reaction was pulmonary embolism, which occurred in 2 (0.7%) patients. Comorbidity was present in 109 (85.2%) of all patients who discontinued treatment. In this subgroup, the mean±SD number of concomitant diseases was 3.4±3.3. Conclusions: We were able to confirm that EPAG therapy in ITP effectively increases platelet counts and reduces the risk of bleeding. For methodological reasons, we were unable to calculate the actual overall response rate. However, based on the proportion of total patients who were shown to discontinue treatment due to insufficient effectiveness (18%), one could assume that all other patients responded to EPAG at least temporarily. This would result in an overall response rate of 82%. This seems to be consistent with the results of the open extension study EXTEND [Wong RSM et al. Blood 2017; 130: 2527-36], in which a similarly high overall response rate (86%) was found. In general, treatment with EPAG was well tolerated, with no new safety signals from our data set. In view of the high discontinuation rate, it should be borne in mind that about one in eight (12%) of these patients responded so well to EPAG therapy that this was taken as an opportunity for a discontinuation attempt. Other factors that may have contributed to treatment discontinuation included age and comorbidity of patients. Notably, the percentage and number of comorbidities in the discontinuation subgroup were even higher than in the overall study population. However, since this is a non-interventional observational study, results are descriptive and need to be interpreted with caution.

Interventions to address potentially inappropriate prescriptions and over-the-counter medication use among adults 65 years and older in primary care settings: protocol for a systematic review

PurposeTo inform recommendations by the Canadian Task Force on Preventive Health Care on potentially inappropriate prescribing and over-the-counter (OTC) medication use among adults aged 65 years and older in primary care settings. This protocol outlines the planned scope and methods for a systematic review of the benefits and harms and acceptability of interventions to reduce potentially inappropriate prescriptions and OTC medication use.MethodsDe novo systematic reviews will be conducted to synthesize the available evidence on (a) the benefits and harms of interventions to reduce potentially inappropriate prescriptions and OTC medications compared to no intervention, usual care, or non- or minimally active intervention among adults aged 65 years and older and (b) the acceptability of these interventions or attributes among patients. Outcomes of interest for the benefits and harms review are all-cause mortality, hospitalization, non-serious adverse drug reactions, quality of life, emergency department visits, injurious falls, medical visits, and the number of medications (and number of pills). Outcomes for the acceptability review are the preference for and relative importance of different interventions or their attributes. For the benefits and harms review, we will search MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for randomized controlled trials. For the acceptability review, we will search MEDLINE, Embase, PsycInfo, Cochrane Central Register of Controlled Trials, and the NHS Economic Evaluation Database for experimental and observational studies with a comparator. Websites of relevant organizations, other grey literature sources, and reference lists of included studies and reviews will be searched. Title and abstract screening will be completed by two independent reviewers using the liberal accelerated approach. Full-text review, data extraction, risk of bias assessments, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) will be completed independently by two reviewers, with any disagreements resolved by consensus or by consulting with a third reviewer. The GRADE approach will be used to assess the certainty of the evidence for outcomes.DiscussionThe results of this systematic review will be used by the Canadian Task Force on Preventive Health Care to inform their recommendation on potentially inappropriate prescribing and OTC medication use among adults aged 65 years and older.Systematic review registrationPROSPERO (KQ1: CRD42022302313; KQ2: CRD42022302324); Open Science Framework (https://osf.io/urj4b/).

Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients

IntroductionWhile pirfenidone and nintedanib have greatly influenced the treatment of idiopathic pulmonary fibrosis (IPF), both drugs have significant early adverse drug reactions (ADRs) and almost nothing is known of their rare and delayed ADRs. We collected and analyzed pirfenidone- or nintedanib-related ADRs identified in a French rare lung disease center, recorded their profiles and identified potential safety signals. MethodsWe analyzed the medical records of IPF patients treated with pirfenidone or nintedanib between January 2011 and January 2020 at the Rennes University Hospital to estimate the incidence of serious and non-serious ADRs cases due to each drug and the incidence of ADRs involving the cardiovascular, hepatobiliary, gastro-intestinal, dermatological, and metabolic/nutritional systems. ResultsThe 176 patients included 115 (65%) initially treated with pirfenidone and 61 (35%) given nintedanib. ADRs occurred in 78.3% of those given pirfenidone and in 70.5% of those given nintedanib. The incidence of first serious ADRs cases was about 33 per 100 person-years (100 PY) for both drugs; first non-serious pirfenidone ADRs cases were 102 per 100 PY and 130 per 100 PY for nintedanib. The incidence involving each organ system were quite similar, except for the gastro-intestinal and skin disorders. Cardiovascular disorders occurred in about 10 cases per 100 PY in both pirfenidone and nintedanib patients. DiscussionMost ADRs were consistent with the expected antifibrotic drug safety profiles. As arterial and venous thromboembolic events are rare, it is important to assess the risk associated with using antifibrotics by a dedicated pharmacoepidemiological study.

Quality of Spontaneous Reports of Adverse Drug Reactions Sent to a Regional Pharmacovigilance Unit.

Spontaneous reports (SRs) of adverse drug reactions (ADRs) remain the basis of pharmacovigilance systems. The main objective of this study was to evaluate the quality of SRs received by the Pharmacovigilance Unit of Beira Interior, in Central Portugal. The second objective was to identify factors associated with complete SRs. SRs received between 1 January 2017 and 31 October 2019 were analyzed. SR information was classified as “mandatory” or “recommended” criteria. SR were then grouped into three categories (well, slightly, and poorly documented). Association between “well documented” SR and confounding variables was estimated using a multiple logistic regression model. The results showed 22.4% of SRs are “well documented”, and 41.2% are “poorly documented”. Most of the complete SRs correspond to non-serious ADRs (55.8%), with a negative association between complete SRs and serious ADRs (OR = 0.595, [95% CI 0.362–0.977], p = 0.040). There is also a significant association between complete SRs and e-mail notification (OR = 1.876, [95% CI 1.060–3.321], p = 0.002). The results highlight the small amount of SR documentation sent to pharmacovigilance systems. There is an association between non-serious ADRs and complete SRs. These results reinforce the need for training for notification of ADRs and that these SRs include as much information as possible for an effective drug risk management.

Long-term real-world effectiveness and safety of fingolimod over 5 years in Germany

ObjectiveTo evaluate the 5-year real-world benefit–risk profile of fingolimod in patients with relapsing–remitting MS (RRMS) in Germany.MethodsPost-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) is a non-interventional real-world study to prospectively assess the effectiveness and safety of fingolimod in routine clinical practice in Germany. The follow-up period comprised 5 years. Patients were included if they had been diagnosed with RRMS and had been prescribed fingolimod as part of clinical routine. There were no exclusion criteria except the contraindications for fingolimod as defined in the European label. The effectiveness and safety analysis set comprised 4032 and 4067 RRMS patients, respectively.ResultsAt the time of the 5-year follow-up of PANGAEA, 66.57% of patients still continued fingolimod therapy. Annualized relapse rates decreased from baseline 1.5 ± 1.15 to 0.42 ± 0.734 at year 1 and 0.21 ± 0.483 at year 5, and the disability status remained stable, as demonstrated by the Expanded Disability Status Scale mean change from baseline (0.1 ± 2.51), the decrease of the Multiple Sclerosis Severity Score from 5.1 ± 2.59 at baseline to 3.9 ± 2.31 at the 60-months follow-up, and the percentage of patients with ‘no change’ in the Clinical Global Impression scale at the 60-months follow-up (78.11%). Adverse events (AE) occurring in 75.04% of patients were in line with the known safety profile of fingolimod and were mostly non-serious AE (33.62%) and non-serious adverse drug reactions (50.59%; serious AE 4.98%; serious ADR 10.82%).ConclusionsPANGAEA demonstrated the sustained beneficial effectiveness and safety of fingolimod in the long-term real-world treatment of patients with RRMS.

Rapid Rate Intravenous Immunoglobulin Administration: Safety Outcomes in 11,334 Infusions

A national home infusion services provider (KabaFusion, LLC) traditionally administered intravenous immunoglobulin (IVIG) at conservative maximum infusion rates to minimize adverse drug reactions (ADRs). The objective of this retrospective observational study was to identify the impact of increased on-label infusion rates of a specific, high-purity product (Octagam) on patient safety. The study included all patients who received IVIG over a 10-year period. The study population was composed of both adult and pediatric patients, with neuroimmune, neuromuscular disorders, and primary immune deficiency diseases warranting IVIG treatment. Patients were divided into two randomized groups to provide an even distribution for analysis: those who received IVIG infusions at a rate of <110 mL/hr (Group 1) and those who received IVIG at ³110 mL/hr (Group 2). There were 489 patients identified for inclusion in Group 1 (n=245) and Group 2 (n=244). Demographics (gender, age) and exposure (number of infusions) were similar between both groups.
 
 The study data included 11,334 total IVIG infusions with a total of 392 ADRs (3.5%). ADRs in the high infusion rate group (Group 2) were significantly lower (5.1% vs.1.8%, p<0.0001). In addition, the incidence of non-serious ADRs in Group 2 (1.7%) vs. Group 1 (4.8%) were also significantly lower in the high infusion rate group (p<0.0001). The number of serious adverse drug reactions (SADRs) was lower in Group 2 but did not reach statistical significance (Group 1: 0.3% vs Group 2:0.1%, p=0.0741). Based on these results, infusion rates of specific high-purity IVIG products were associated with statistically and clinically significant lower non serious ADRs in both the adult and pediatric populations, in addition to having an association of clinical significance in both for SADRs. These results can be of great utility in clinical application if applied within the manufacturer’s recommended guidelines, to ease the burden of time required for patients undergoing IVIG infusions.

Safety and efficacy of hydroxychloroquine in 152 outpatients with confirmed COVID-19: A pilot observational study.

PurposeWe investigated the efficacy and safety of hydroxychloroquine for empirical treatment of outpatients with confirmed COVID-19.MethodsIn this prospective, single-center study, we enrolled ambulatory outpatients with COVID-19 confirmed by a molecular method who received hydroxychloroquine. The patients were divided into low- and moderate-risk groups based on the Tisdale risk score for drug-associated QT prolongation, and the QT interval was corrected for heart rate using the Bazett formula (QTc). The QTc interval was measured by electrocardiography both pretreatment (QTc1) and 4 h after the administration of hydroxychloroquine (QTc2). The difference between the QTc1 and QTc2 intervals was defined as the ΔQTc. The QTc1 and QTc2 intervals and ΔQTc values were compared between the two risk groups.ResultsThe median and interquartile range (IQR) age of the patients was 47.0 (36.2–62) years, and there were 78 men and 74 women. The median (IQR) QTc1 interval lengthened from 425.0 (407.2–425.0) to 430.0 (QTc2; 412.0–443.0) milliseconds (ms). However, this was not considered an increased risk of ventricular tachycardia associated with a prolonged QTc interval requiring drug discontinuation, because none of the patients had a ΔQTc of >60 ms or a QTc2 of >500 ms. Moreover, the median (quartiles; minimum-maximum) ΔQTc value was higher in patients in the moderate-risk group than those in the low-risk group (10.0 [−4.0–18.0; −75.0–51.0] vs. 7.0 [−10.5–23.5; −53.0–59.0 ms]) (p = 0.996). Clinical improvement was noted in 91.4% of the patients, the exceptions being 13 patients who presented with non-serious adverse drug reactions or who had severe COVID-19 and were hospitalized. Adverse effects related to hydroxychloroquine were non-serious and occurred in 52.8% (n = 80) of the patients.ConclusionsOur findings show that hydroxychloroquine is safe for COVID-19 and not associated with a risk of ventricular arrhythmia due to drug-induced QTc interval prolongation. Additionally, hydroxychloroquine was well tolerated, and there were no drug-related non-serious adverse events leading to treatment discontinuation in the majority of patients who were stable and did not require hospitalization.

Reporting of Safety Events during Anti-VEGF Treatment: Pharmacovigilance in a Noninterventional Trial.

Aim The prospective, noninterventional OCEAN study assessed the safety of intravitreal ranibizumab injections for treatment of neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion under real-world conditions in Germany. Methods Adults receiving ≥1 ranibizumab (0.5 mg) injections were recruited by 369 ophthalmologists and followed for 24 months. Information on adverse events (AEs) was reported by the treating physician or detected by the data management team. Collected information included observed AE, AE start and end date, intensity, causal relationship, outcome, severity, suspected drug, and actions taken. Results 2,687 AEs were reported for 1,176 of the 5,781 patients who had received a total of 32,621 injections: 27.4% nonserious AEs, 30.3% serious AEs, 27.3% nonserious adverse drug reactions (ADRs), and 15.0% serious ADRs. Most patients reported no AEs (79.7%) or only 1 AE (10.3%). AEs were most commonly reported in the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) Eye disorders (9.4% of patients) and General disorders and administration site conditions (5.8%). The most frequent AEs by MedDRA preferred term (PT) were visual acuity reduced (3.5% of patients), intraocular pressure increased (2.5%), and drug ineffective (2.1%). AEs occurred most frequently after 3 or 4 injections (1,129 of 2,687 AEs). The proportion of AEs in the SOC Eye disorders decreased slightly with increasing number of injections, from 39.8% of events after 1 or 2 injections to 29.1% after 5 or more injections. Rates of the most frequently reported PTs did not show any consistent increase with increasing number of injections. A decrease in overall AE rates was observed over the study course. Conclusions The results did not raise any new safety concerns for ranibizumab. The findings allow conclusions to be drawn on how pharmacovigilance data can be collected even more effectively in real-world studies to facilitate discussion on benefit-risk ratio.

Adverse drug reaction reporting in Canada: consumer versus physician reports

In Canada, adverse drug reaction (ADR) reporting was initiated in 1965. Since 2003, consumers have been able to report ADRs directly to Health Canada. This study compares consumer-reported ADRs with physician-reported ADRs based on seriousness, system organ class (SOC), and anatomical therapeutic chemical (ATC) classification. This retrospective observational study evaluated ADR reports received by the Canadian Vigilance ADR Reporting Database from January 2000 to December 2014. A total of 198,781 spontaneous ADR reports were analyzed in terms of who reported the ADR, the seriousness of the ADR, and category of ADR by SOC and ATC group. Chi-square tests for independence and odds ratios were used to detect statistically significant differences between reporters (consumers and physicians) based on seriousness, SOC, and ATC classification. Of 198,781 serious and non-serious ADR reports, 28.7% were from consumers, 26.6% from physicians, 22.9% from pharmacists, 21.4% from other healthcare professionals, and 0.5% from lawyers, with consumers reporting significantly more ADRs than physicians (p < 0.0001). Significant differences in ADR reporting were found between consumers and physicians, in terms of ADR seriousness, ATC classification, and SOC involved. ‘General disorders and administrative site conditions’ was the most common SOC in both consumer and physician reports of serious ADRs. This study, the first Canadian study to compare consumer and physician ADR reports, showed that consumers and physicians reported ADRs differently with regard to SOC and ATC classification. Consumer and physician reports should be included in post-marketing surveillance. Further research is required to investigate the extent to which additional information from consumer reports contribute to signal identification when assessing drug safety.

839 Response and Healthcare Resource Utilization in Inflammatory Bowel Disease Patients Treated With Either Infliximab or Vedolizumab

INTRODUCTION: Both infliximab (IFX) and vedolizumab (VDZ) are FDA-approved for treatment of inflammatory bowel disease (IBD) in adults. Much of the published data on clinical outcomes for either IFX or VDZ compare the biologic agent against more traditional therapies rather than alternative biologics. The aim of this study was to evaluate clinical response and healthcare resource utilization (HRU) in IBD patients (pts) treated with either IFX or VDZ for 12 months (mos). METHODS: We performed a review of adult Crohn’s disease (CD) and ulcerative colitis (UC) pts who initiated treatment with either IFX or VDZ from 2016-2018 at a large multicenter, gastroenterology private practice. Those who persisted on therapy for 12 mos were identified. Pts were case-matched 1:1 based on age, gender, diagnosis, and baseline disease severity scores using the partial Mayo (pMayo) for UC and the modified Harvey-Bradshaw Index (mHBI) for CD. Primary endpoints were changes in disease activity at 3, 6, and 12 mos compared to baseline, and IBD-related HRU, defined as emergency department (ED) visits, and hospitalizations during the 12 mos. Additionally, adverse drug reactions (ADR) and infections were assessed. RESULTS: Case-matching yielded 35 IFX (16 CD, 19 UC) and 35 VDZ (16 CD, 19 UC) pts for further assessment. Demographics were similar between groups: mean age 38 ± 20 vs 40 ± 15, male gender 54% vs 51%. Baseline scores were similar as noted in Figure 1. In the overall assessment of response between groups, both IFX and VDZ in CD were associated with a reduction in HBI score of &gt;60% at 3 mos. IFX and VDZ use in UC were associated with reductions in pMayo scores at 3 mos of 56% and 44%, respectively. These substantial reductions were sustained through 12 mos. IFX-treated pts had 4 IBD-related ED visits with 1 hospitalization, while VDZ-treated pts had 5 IBD-related ED visits and 4 hospitalizations. Infection rates were similar with 8 infections in IFX pts (23%) and 7 in VDZ pts (20%); 1 VDZ infection led to hospital admission. Thirteen (5 IFX, 8 VDZ) non-serious infusion-related ADRs were reported with no difference between treatment groups. CONCLUSION: The data demonstrate similarity in response and healthcare resource utilization over time with use of IFX or VDZ in the treatment of IBD patients. Although the number of case-matched patients in this study is limited and the population is restricted to responders, resource utilization was noticeably low. Additional study is warranted.

Alitrétinoïne (Toctino®) : données françaises de pharmacovigilance

The adverse reaction profile of alitretinoin, a retinoid indicated in severe topical corticosteroid-refractory chronic hand eczema, is similar to that of other oral retinoids, especially isotretinoin. The objective of this study was to detect new adverse effects (not listed) of alitretinoin and to estimate the number of pregnancies exposed. All cases of ADR reported in France with alitretinoin between October 1st, 2012 and February 29th, 2016 were analysed. During the 41 months of follow-up, 52 cases of serious adverse drug reaction (ADR) and 88 cases of non-serious and unexpected ADR were notified. The most frequent serious ADRs were psychiatric, neurological and dermatological. Psychiatric disorders, mainly depression and suicidal ideation represented 23% of serious ADRs. New adverse drug reactions were detected: myocardial infarction, pancreatitis and digestive haemorrhage. Three pregnancies exposed during the teratogenic risk period, were registered. The safety profile of alitretinoin matches that of other retinoids. However, the rate of psychiatric disorders appears to be high. Otherwise, the risk of myocardial infarction in patients with cardiovascular risk factor should be considered as a safety concern. It could be explained by the hyperlipemic effects of alitretinoin and studies suggest a cardiovascular risk with retinoids through their effects on lipids (class effect), especially for patients with others cardiovascular risk factors. Pancreatitis and digestive hemorrhage are described with isotretinoin. The rate of reporting of pregnancy induced by a non-compliance with the Pregnancy Prevention Program is near the rate observed with isotretinoin. The high incidence of serious ADR and the non-application of pregnancy prevention program lead the French National Agency for Medicines to limit the first prescription of alitretinoin to dermatologists.

Treatment of iron deficiency in patients with chronic kidney disease: A prospective observational study of iron isomaltoside (NIMO Scandinavia) .

Aims: Iron deficiency is common in patients with chronic kidney disease (CKD). Appropriate iron substitution is critical and intravenous iron is an established therapy for these patients. The objective of this study was to assess treatment routine, effectiveness, and safety of iron isomaltoside (Monofer®, Pharmacosmos A/S, Holbaek, Denmark) in CKD patients in clinical practice. Materials and methods: This was a prospective observational study conducted in predialysis CKD patients treated with iron isomaltoside according to the product label and to routine clinical care. Results: The study included 108 patients with predialysis CKD: 22 were in stage 2 – 3, 41 in stage 4, and 45 in stage 5. The mean (standard deviation) age was 67 (15) years, and 55% of patients were male. The majority of patients (65%) received one iron isomaltoside treatment. In patients with a baseline Hb < 10 g/dL, the mean dose of iron isomaltoside in the study was lower than the estimated total iron requirement (567 mg versus 921 mg). A treatment response of Hb ≥ 1 g/dL was achieved in 16/28 (57%) of patients, and the mean post-treatment Hb level was 10.5 g/dL. The probability of retreatment did not correlate with dose, but no dose administered was > 1,000 mg. There were no serious adverse drug reactions. One nonserious adverse drug reaction – injection site discoloration – was reported, and the patient had an uneventful recovery. Conclusion: Iron isomaltoside shows a good effectiveness and safety profile in predialysis CKD patients. However, some patients did not receive adequate iron doses to allow for optimal correction of their iron deficiency anemia.

Use and Safety of Anthroposophic Medicinal Products: An Analysis of 44,662 Patients from the EvaMed Pharmacovigilance Network.

BackgroundThere is a need for data on the clinical safety of anthroposophic medicinal products (AMPs).ObjectivesThe main objective of this analysis was to determine the frequency of adverse drug reactions (ADRs) to AMPs, relative to the number of AMP prescriptions.MethodsEvaMed (Evaluation of Anthroposophic Medicine) was a prospective pharmacovigilance study with the patients of 38 physicians in outpatient care in Germany. Diagnoses and prescriptions were extracted from the electronic medical records. All physicians documented ADRs of Grades III–IV and serious ADRs, seven ‘prescriber physicians’ also documented non-serious ADRs of any intensity. Patients were eligible for this analysis if they had one or more AMP prescription in the years 2001–2010, followed by one or more physician visit.ResultsA total of 44,662 patients with 311,731 AMP prescriptions, comprising 1722 different AMPs, were included. One hundred ADRs to AMPs occurred, caused by 83 different AMPs. ADR intensity was mild, moderate, and severe in 50% (n = 50/100), 43%, and 7% of cases, respectively; one ADR was serious. Among patients of prescriber physicians, ADRs of any intensity occurred in 0.071% (n = 67/94,734) of AMP prescriptions and in 0.502% (n = 65/12,956) of patients prescribed AMPs. In subgroup analyses according to age, specific AMPs or AMP groups, dosage forms, and concentrations (altogether 11 groups), the highest ADR frequency was 0.290% of prescriptions (for one specific AMP). Among all patients, serious ADRs occurred in 0.0003% (n = 1/311,731) of prescriptions and 0.0022% (n = 1/44,662) of patients.ConclusionIn this analysis from a large sample, ADRs to AMP therapy in outpatient care were rare; ADRs of high intensity as well as serious ADRs were very rare.Electronic supplementary materialThe online version of this article (doi:10.1007/s40801-017-0118-5) contains supplementary material, which is available to authorized users.

Effectiveness of an add-on treatment with the homeopathic medication SilAtro-5-90 in recurrent tonsillitis: An international, pragmatic, randomized, controlled clinical trial

ObjectiveTo investigate the effectiveness and safety of the homeopathic product SilAtro-5-90 in recurrent tonsillitis. MethodsIn this international, pragmatic, controlled clinical trial, 256 patients (6–60 years) with moderate recurrent tonsillitis were randomized to receive either SilAtro-5-90 in addition to standard symptomatic treatment, or to receive standard treatment only. The primary outcome was the mean time period between consecutive acute throat infections (ATI) within 1 year (analyzed via repeated events analysis). ResultsDuring the evaluation year, the risk of getting an ATI was significantly lower (hazard ratio: 0.45, proportional means model, p = 0.0002, ITT) with SilAtro-5-90 compared to control. Tonsillitis-specific symptoms were significantly reduced (p < 0.0001, ITT) and the need of antibiotics to treat acute throat infections (p = 0.0008; ITT) decreased. 3 non-serious adverse drug reactions were reported for SilAtro-5-90. ConclusionsAn integrative treatment approach where SilAtro-5-90 is given alongside mainstream symptomatic treatment may bring therapeutic benefit to patients suffering from recurrent tonsillitis.Trial registration: ISRCTN registry: Registration number ISRCTN19016626, registered 23 January 2013.

Effectiveness and safety of lactulose retention enema in cirrhotic patients with grade 3 or grade 4 hepatic encephalopathy

Background: Hepatic encephalopathy (HE) is a complex, reversible neuropsychiatric syndrome. The present study evaluated the clinical effectiveness and safety of lactulose retention enema for the treatment of Grade 3 or 4 HE (West Haven Criteria, WHC) in Indian patients.Methods: This retrospective, open-label, uncontrolled cohort study was conducted at three study centers in India. Patients of either gender (18-65 years) admitted to the hospital with liver cirrhosis having Grade 3 or 4 HE were included. The primary endpoint was to evaluate complete reversal of Grade 3 and 4 HE after 24 h and 48h. The secondary endpoints were grade shift at 24 and 48 h before and after administration of lactulose enema, time to complete reversal of Grade 3 or 4 HE, and mortality. Safety was also evaluated.Results: Overall, retrospective records of 50 patients were evaluated. Complete reversal of Grade 3 or 4 HE was observed in a statistically significant (p&lt;0.0001) proportion (95% confidence interval) of patients at 24 h (n=40, 80% [66. 3%-90.0%]) and 48 h (n=45, 90% [78. 2%-96.7%]) after treatment. After 24 h of treatment, majority of the patients were noted with Grade 2 (78%) HE. Further improvement was noted after 48 h of treatment with majority of the patients having Grade 2 (40%) and Grade 1 (48%) HE. Mean (SD) time for complete reversal of Grade 3 or 4 HE was 25.39±8.85 h after treatment. All death cases observed (n=6, 12.0%) were assessed as unrelated to the treatment by the investigator, but rather related to the underlying disease and/or precipitating factors. Four non-serious adverse drug reactions in two patients and one rectal device-associated complication in one patient were noted during the patient record reviews.Conclusions: Lactulose retention enema was clinically effective and resulted in complete reversal of Grade 3 or 4 HE in the majority of patients. It was overall well-tolerated.

Results of a prospective multicenter non-interventional study in adult outpatients with acute sinusitis treated with Flemoclav Solutab® in routine clinical practice in Russia (FlemENT)

Background. According to Russian clinical guidelines, amoxicillin/clavulanic acid is an antibiotic of the 1st choice in treatment of adult outpatients with acute sinusitis with suspected or confirmed bacterial etiology. The growth of bacterial resistance causes reasonable concern of otorhinolaryngologists about the efficacy of commonly used antibiotics in the routine clinical practice. Objective. The objective of this study was to evaluate the clinical success rate and tolerability of acute sinusitis treatment with Flemoclav Solutab® as initial antibiotic treatment in adult outpatients with acute sinusitis in routine clinical practice. Methods. A prospective multi-center study. The study covered adult outpatients with acute sinusitis with suspected or confirmed bacterial etiology treated with Flemoclav Solutab® and included the assessment of effectiveness and tolerability of Flemoclav Solutab® in the patients with acute sinusitis. Besides, the clinical effectiveness of treatment with this antibiotic in the subgroups of patients aged 65 years or older, smokers and non-smokers was assessed. Clinical success was determined as the complete resolution of all the symptoms and clinical signs of acute bacterial sinusitis that did not require supplementary of alternative antimicrobial therapy. In period of October 2015 to February 2016 eighty otorhinolaryngologists from various regions of Russia examined 893 adult outpatients (346 men and 547 women) with acute sinusitis treated with the antibiotic Flemoclav Solutab®. Clinical recovery confirmed by the data of all the examinations was achieved in 97.2% [(868/893), 95% CI 96.1 – 98.3%]. In the subgroup of patients aged 65 years or older the clinical success rate was 98.5% [(128/130), 95% CI 96.3 – 100%], in the subgroup of non-smokers clinical success was 97.3% [(690/709), 95% CI 96.1 – 98.5], in the subgroup of smokers clinical success was 96.7% [(178/186), 95% CI 94.2–99.3%]. Twenty five cases of adverse drug reactions (ADR) were recorded in 20 (2.2%) patients, of them 22 non-serious ADRs were in 17 (1.9%) patients and 3 serious ADRs were in 3 (0.3%) patients. Conclusion. The study proved high clinical success of acute sinusitis treatment with Flemoclav Solutab® in adult outpatients, including the patients aged 65 years or older, smokers and non-smokers. Antimicrobial treatment with Flemoclav Solutab® was well tolerated.

Low-dose modified-release prednisone in axial spondyloarthritis: 3-month efficacy and tolerability.

BackgroundOral glucocorticoids (GCs) have been shown to be effective in reducing the inflammatory symptoms of rheumatoid arthritis, but their use is not supported by evidence in spondyloarthritis (SpA). Modified-release (MR) oral prednisone taken at bedtime has been shown to be more effective than immediate-release prednisone taken in the morning. The efficacy of low-dose MR prednisolone in patients with SpA is unknown.Patients and methodsThis single-center cohort study retrospectively assessed the effectiveness and safety of 12-week low-dose MR prednisone (5 mg daily, bedtime administration) in GC-naïve adult patients with symptomatic axial SpA. A 50% improvement of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or a final BASDAI score of <4 according to disease activity at baseline was chosen as the primary outcome parameter after MR prednisone.ResultsFifty-seven patients were evaluated; of them, 41 had an active disease (BASDAI score of ≥4) at baseline. MR prednisone significantly reduced BASDAI (from 5.5±2.6 to 3.0±2.8, P<0.001) as well as inflammatory symptoms, pain, fatigue and morning stiffness. The overall response rate after MR prednisone was 52.6% (53.7% in patients with active SpA and 50.0% in patients with low-active disease; nonsignificant). At multivariable analysis, none of the considered clinical findings independently predicted the response to MR prednisone in subjects with active SpA. Overall, seven patients (11.8%) had nonserious adverse drug reactions after MR prednisone.ConclusionIn patients with symptomatic SpA and naïve to GCs, low-dose MR prednisone reduced the symptoms and clinical indexes of disease activity and showed a positive safety profile.