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The Cochrane Database of Systematic... May 2022Ocrelizumab is a humanised anti-CD20 monoclonal antibody developed for the treatment of multiple sclerosis (MS). It was approved by the Food and Drug Administration... (Review)
Review
BACKGROUND
Ocrelizumab is a humanised anti-CD20 monoclonal antibody developed for the treatment of multiple sclerosis (MS). It was approved by the Food and Drug Administration (FDA) in March 2017 for using in adults with relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only disease-modifying therapy (DMT) approved for PPMS. In November 2017, the European Medicines Agency (EMA) also approved ocrelizumab as the first drug for people with early PPMS. Therefore, it is important to evaluate the benefits, harms, and tolerability of ocrelizumab in people with MS.
OBJECTIVES
To assess the benefits, harms, and tolerability of ocrelizumab in people with RRMS and PPMS.
SEARCH METHODS
We searched MEDLINE, Embase, CENTRAL, and two trials registers on 8 October 2021. We screened reference lists, contacted experts, and contacted the main authors of studies.
SELECTION CRITERIA
All randomised controlled trials (RCTs) involving adults diagnosed with RRMS or PPMS according to the McDonald criteria, comparing ocrelizumab alone or associated with other medications, at the approved dose of 600 mg every 24 weeks for any duration, versus placebo or any other active drug therapy.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
Four RCTs met our selection criteria. The overall population included 2551 participants; 1370 treated with ocrelizumab 600 mg and 1181 controls. Among the controls, 298 participants received placebo and 883 received interferon beta-1a. The treatment duration was 24 weeks in one study, 96 weeks in two studies, and at least 120 weeks in one study. One study was at high risk of allocation concealment and blinding of participants and personnel; all four studies were at high risk of bias for incomplete outcome data. For RRMS, compared with interferon beta-1a, ocrelizumab was associated with: 1. lower relapse rate (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.52 to 0.73; 2 studies, 1656 participants; moderate-certainty evidence); 2. a lower number of participants with disability progression (hazard ratio (HR) 0.60, 95% CI 0.43 to 0.84; 2 studies, 1656 participants; low-certainty evidence); 3. little to no difference in the number of participants with any adverse event (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 1651 participants; moderate-certainty evidence); 4. little to no difference in the number of participants with any serious adverse event (RR 0.79, 95% CI 0.57 to 1.11; 2 studies, 1651 participants; low-certainty evidence); 5. a lower number of participants experiencing treatment discontinuation caused by adverse events (RR 0.58, 95% CI 0.37 to 0.91; 2 studies, 1651 participants; low-certainty evidence); 6. a lower number of participants with gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) (RR 0.27, 95% CI 0.22 to 0.35; 2 studies, 1656 participants; low-certainty evidence); 7. a lower number of participants with new or enlarging T2-hyperintense lesions on MRI (RR 0.63, 95% CI 0.57 to 0.69; 2 studies, 1656 participants; low-certainty evidence) at 96 weeks. For PPMS, compared with placebo, ocrelizumab was associated with: 1. a lower number of participants with disability progression (HR 0.75, 95% CI 0.58 to 0.98; 1 study, 731 participants; low-certainty evidence); 2. a higher number of participants with any adverse events (RR 1.06, 95% CI 1.01 to 1.11; 1 study, 725 participants; moderate-certainty evidence); 3. little to no difference in the number of participants with any serious adverse event (RR 0.92, 95% CI 0.68 to 1.23; 1 study, 725 participants; low-certainty evidence); 4. little to no difference in the number of participants experiencing treatment discontinuation caused by adverse events (RR 1.23, 95% CI 0.55 to 2.75; 1 study, 725 participants; low-certainty evidence) for at least 120 weeks. There were no data for number of participants with gadolinium-enhancing T1 lesions on MRI and number of participants with new or enlarging T2-hyperintense lesions on MRI.
AUTHORS' CONCLUSIONS
For people with RRMS, ocrelizumab probably results in a large reduction in relapse rate and little to no difference in adverse events when compared with interferon beta-1a at 96 weeks (moderate-certainty evidence). Ocrelizumab may result in a large reduction in disability progression, treatment discontinuation caused by adverse events, number of participants with gadolinium-enhancing T1 lesions on MRI, and number of participants with new or enlarging T2-hyperintense lesions on MRI, and may result in little to no difference in serious adverse events (low-certainty evidence). For people with PPMS, ocrelizumab probably results in a higher rate of adverse events when compared with placebo for at least 120 weeks (moderate-certainty evidence). Ocrelizumab may result in a reduction in disability progression and little to no difference in serious adverse events and treatment discontinuation caused by adverse events (low-certainty evidence). Ocrelizumab was well tolerated clinically; the most common adverse events were infusion-related reactions and nasopharyngitis, and urinary tract and upper respiratory tract infections.
Topics: Adult; Antibodies, Monoclonal, Humanized; Gadolinium; Humans; Interferon beta-1a; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence
PubMed: 35583174
DOI: 10.1002/14651858.CD013247.pub2 -
Frontiers in Pharmacology 2022Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor, has demonstrated efficacy in Parkinson's Disease (PD) patients with end-of-dose motor...
Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor, has demonstrated efficacy in Parkinson's Disease (PD) patients with end-of-dose motor fluctuations. This study aimed to compare the short-term (<6 months) and long-term (≥6 months) tolerability of opicapone adjuvant treatment in PD patients. Electronic databases including PubMed, Embase, Web of Science and Cochrane library were searched for randomized controlled trials (RCTs) and observational studies. The end points included any treatment-related adverse events (TEAEs), serious TEAEs (SAEs) and treatment discontinuation. A random-effects model was used to generate overall incidences of TEAE. Three RCTs, three RCT extension studies and three open-label studies involving 2177 PD patients were evaluated. In the short-term studies, there were reports of TEAEs with an incidence of ≥5% in individuals treated with opicapone 50 mg, including dyskinesia (14.1%), elevated blood creatine phosphokinase levels (8.0%) and urinary tract infection (6.0%). Any TEAEs, SAEs and treatment discontinuation all occurred at rates of 62.9%, 4.8% and 9.3%, respectively. TEAEs with opicapone 50 mg that were reported by more than 5% of patients in long-term studies included dyskinesia (16.1%), dry mouth (12.1%), medication effect decreased (12.1%), PD exacerbated (7.8%), blood creatine phosphokinase level raised (7.4%), nausea (6.1%) and insomnia (5.1%). The incidence of any TEAEs, SAEs and treatment discontinuation were, correspondingly, 73.2%, 8.7% and 8.4%. These studies demonstrated that opicapone was generally well-tolerated and had a low risk of adverse events, suggesting that it could be a valuable therapeutic choice for people with PD.
PubMed: 36506576
DOI: 10.3389/fphar.2022.1042992 -
Vaccine Oct 2015Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs).
OBJECTIVE
To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement.
METHODS
We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement.
RESULTS
Of 1205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity.
CONCLUSION
Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as new vaccines and drugs are evaluated.
Topics: Age Factors; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Humans; Infant; Infant, Newborn; Randomized Controlled Trials as Topic; Reproducibility of Results; Respiratory Sounds; Sensitivity and Specificity; Severity of Illness Index; Vaccines
PubMed: 26319071
DOI: 10.1016/j.vaccine.2015.08.060 -
BMC Infectious Diseases Oct 2023Approximately 10% of patients experience prolonged symptoms after Lyme disease. PTLDS (post treatment Lyme disease syndrome) is a controversial topic. It has been...
BACKGROUND
Approximately 10% of patients experience prolonged symptoms after Lyme disease. PTLDS (post treatment Lyme disease syndrome) is a controversial topic. It has been described as a source of overdiagnosis and off-label treatment. This review aims to describe the diagnostic errors and adverse events associated with the diagnosis and treatment of PTLDS.
METHODS
systematic review of the literature in the Medline and Cochrane Library databases, according to PRISMA criteria, including randomized clinical trials (RCT), observational studies, and case reports addressing diagnostic errors and adverse events published between January 2010 and November 2020 in English or French. Selection used a quadruple reading process on the basis of the titles and abstracts of the different articles, followed by a full reading.
RESULTS
17 studies were included: 1 RCT, 6 observational studies and 10 case reports. In the 6 observational studies, overdiagnosis rates were very high, ranging from 80 to 100%. The new diagnoses were often psychiatric, rheumatological and neurological. Disorders with somatic symptoms were often cited. Diagnostic delays were identified for cancers and frontoparietal dementia. In the RCT and observational studies, prolonged anti-infective treatments were also responsible for adverse events, with emergency room visits and/or hospitalization. The most common adverse events were diarrhea, sometimes with Clostridium difficile colitis, electrolyte abnormalities, sepsis, bacterial and fungal infections, and anaphylactic reactions.
CONCLUSION
This review highlights the risks of prolonged anti-infective treatments that have not been proven to be beneficial in PTLDS. It emphasizes the ethical imperative of the "primum non nocere" principle, which underscores the importance of not causing harm to patients. Physicians should exercise caution in diagnosing PTLDS and consider the potential risks associated with off-label treatments.
Topics: Humans; Enterocolitis, Pseudomembranous; Lyme Disease; Anti-Bacterial Agents; Sepsis
PubMed: 37784031
DOI: 10.1186/s12879-023-08618-w -
British Journal of Clinical Pharmacology Jul 2016Adverse drug events (ADEs) are harmful and unintended consequences of medications. Their reporting is essential for drug safety monitoring and research, but it has not... (Review)
Review
AIM
Adverse drug events (ADEs) are harmful and unintended consequences of medications. Their reporting is essential for drug safety monitoring and research, but it has not been standardized internationally. Our aim was to synthesize information about the type and variety of data collected within ADE reporting systems.
METHODS
We developed a systematic search strategy, applied it to four electronic databases, and completed an electronic grey literature search. Two authors reviewed titles and abstracts, and all eligible full-texts. We extracted data using a standardized form, and discussed disagreements until reaching consensus. We synthesized data by collapsing data elements, eliminating duplicate fields and identifying relationships between reporting concepts and data fields using visual analysis software.
RESULTS
We identified 108 ADE reporting systems containing 1782 unique data fields. We mapped them to 33 reporting concepts describing patient information, the ADE, concomitant and suspect drugs, and the reporter. While reporting concepts were fairly consistent, we found variability in data fields and corresponding response options. Few systems clarified the terminology used, and many used multiple drug and disease dictionaries such as the Medical Dictionary for Regulatory Activities (MedDRA).
CONCLUSION
We found substantial variability in the data fields used to report ADEs, limiting the comparability of ADE data collected using different reporting systems, and undermining efforts to aggregate data across cohorts. The development of a common standardized data set that can be evaluated with regard to data quality, comparability and reporting rates is likely to optimize ADE data and drug safety surveillance.
Topics: Adverse Drug Reaction Reporting Systems; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance
PubMed: 27016266
DOI: 10.1111/bcp.12944 -
Vaccines Apr 2022The Vaccine Adverse Event Reporting System database has been used to report adverse events following several vaccines. We studied the patient population predisposed to... (Review)
Review
The Vaccine Adverse Event Reporting System database has been used to report adverse events following several vaccines. We studied the patient population predisposed to such reactions and how these reactions differ with respect to the vaccine type. We searched the electronic databases PubMed, EMBASE, and Scopus up to 9 July 2021 for any study describing cardiac adverse events attributed to the vaccination. A total of 56 studies met the criteria comprising 340 patients. There were 20 studies describing cardiac adverse events following smallpox vaccination, 11 studies describing adverse events after influenza vaccination, and 18 studies describing adverse events after COVID-19 vaccination. There was a total of six studies describing cardiac adverse events after the pneumococcal vaccine, tetanus toxoid, cholera vaccine, and rabies vaccine. Adverse events following influenza vaccination occurred more commonly in older females within an average duration of four days from vaccination. Pericardial involvement was the most reported adverse event. Adverse events following COVID-19 vaccination happened at a mean age of 42.7 years, more commonly in males, and mostly after a second dose. Adverse events following smallpox vaccination occurred more commonly in younger males, with an average onset of symptoms from vaccination around 16.6 days. Adverse events were mostly myopericarditis; however, the acute coronary syndrome has been reported with some vaccines.
PubMed: 35632455
DOI: 10.3390/vaccines10050700 -
Drugs - Real World Outcomes Mar 2018Medication errors and adverse drug events are universal problems contributing to patient harm but the magnitude of these problems in Africa remains unclear. (Review)
Review
BACKGROUND
Medication errors and adverse drug events are universal problems contributing to patient harm but the magnitude of these problems in Africa remains unclear.
OBJECTIVE
The objective of this study was to systematically investigate the literature on the extent of medication errors and adverse drug events, and the factors contributing to medication errors in African hospitals.
METHODS
We searched PubMed, MEDLINE, EMBASE, Web of Science and Global Health databases from inception to 31 August, 2017 and hand searched the reference lists of included studies. Original research studies of any design published in English that investigated adverse drug events and/or medication errors in any patient population in the hospital setting in Africa were included. Descriptive statistics including median and interquartile range were presented.
RESULTS
Fifty-one studies were included; of these, 33 focused on medication errors, 15 on adverse drug events, and three studies focused on medication errors and adverse drug events. These studies were conducted in nine (of the 54) African countries. In any patient population, the median (interquartile range) percentage of patients reported to have experienced any suspected adverse drug event at hospital admission was 8.4% (4.5-20.1%), while adverse drug events causing admission were reported in 2.8% (0.7-6.4%) of patients but it was reported that a median of 43.5% (20.0-47.0%) of the adverse drug events were deemed preventable. Similarly, the median mortality rate attributed to adverse drug events was reported to be 0.1% (interquartile range 0.0-0.3%). The most commonly reported types of medication errors were prescribing errors, occurring in a median of 57.4% (interquartile range 22.8-72.8%) of all prescriptions and a median of 15.5% (interquartile range 7.5-50.6%) of the prescriptions evaluated had dosing problems. Major contributing factors for medication errors reported in these studies were individual practitioner factors (e.g. fatigue and inadequate knowledge/training) and environmental factors, such as workplace distraction and high workload.
CONCLUSION
Medication errors in the African healthcare setting are relatively common, and the impact of adverse drug events is substantial but many are preventable. This review supports the design and implementation of preventative strategies targeting the most likely contributing factors.
PubMed: 29138993
DOI: 10.1007/s40801-017-0125-6 -
Drugs & Aging Nov 2023The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia.
OBJECTIVES
While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined.
METHODS
We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia.
RESULTS
A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine.
CONCLUSIONS
Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia.
CLINICAL TRIAL REGISTRATION
The study was pre-registered on PROSPERO (CRD42021258376).
Topics: Humans; Acetylcholinesterase; Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Donepezil; Galantamine; Parkinson Disease; Phenylcarbamates; Randomized Controlled Trials as Topic; Rivastigmine; Sleep Initiation and Maintenance Disorders
PubMed: 37682445
DOI: 10.1007/s40266-023-01065-x -
Alimentary Pharmacology & Therapeutics Jan 2009Screening colonoscopy exposes healthy patients to the risk of serious adverse events associated with bowel preparation. Randomized controlled trials are not an effective... (Review)
Review
BACKGROUND
Screening colonoscopy exposes healthy patients to the risk of serious adverse events associated with bowel preparation. Randomized controlled trials are not an effective method for evaluating this risk.
AIM
To search published literature in order to characterize the risk of adverse events associated with oral polyethylene glycol (PEG) or sodium phosphate (NaP).
METHODS
A systematic review identified case reports of any serious events associated with PEG or NaP. Reports to the Food and Drug Administration (FDA) were also examined.
RESULTS
Fifty-eight publications of significant events in 109 patients using NaP and 22 patients using PEG were identified. As the total number of prescriptions issued is unknown, rates for the two agents cannot be directly compared. Most commonly reported were electrolyte disturbances, renal failure and colonic ulceration for NaP and Mallory-Weiss tear, electrolyte disturbances and allergic reactions for PEG between January 2006 and December 2007; there were 171 cases of renal failure reported to the FDA following use of NaP and 10 following PEG.
CONCLUSIONS
Adverse events following bowel preparation are uncommon, but potentially serious. Given that many of these patients are healthy individuals undergoing screening, the benefit/risk ratio must be carefully considered when deciding which preparation to prescribe in individual patients.
Topics: Administration, Oral; Cathartics; Colonoscopy; Humans; Phosphates; Polyethylene Glycols; Surface-Active Agents
PubMed: 18729847
DOI: 10.1111/j.1365-2036.2008.03837.x -
Therapeutic Advances in Gastroenterology 2023Vonoprazan, a novel acid-suppressive drug, is non-inferior to proton pump inhibitors (PPIs) for the management of gastric acid-related diseases. However, the safety of...
BACKGROUND
Vonoprazan, a novel acid-suppressive drug, is non-inferior to proton pump inhibitors (PPIs) for the management of gastric acid-related diseases. However, the safety of vonoprazan has not been systematically evaluated yet.
OBJECTIVES
To elucidate the incidence and type of adverse events (AEs) in patients taking vonoprazan.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES AND METHODS
PubMed, EMBASE, and Cochrane Library databases were searched for all studies reporting the safety of vonoprazan. The incidences of any AEs, drug-related AEs, serious AEs, AEs leading to drug discontinuation, and common AEs were pooled. Odds ratios (ORs) were calculated to compare the incidence of AEs between patients taking vonoprazan and PPIs.
RESULTS
Seventy-seven studies were included. The pooled incidences of any AEs, drug-related AEs, serious AEs, and AEs leading to drug discontinuation were 20, 7, 1, and 1%, respectively. The incidences of any AEs (OR = 0.96, = 0.66), drug-related AEs (OR = 1.10, = 0.44), serious AEs (OR = 1.14, = 0.36), and AEs leading to drug discontinuation (OR = 1.09, = 0.55) were not significantly different between patients taking vonoprazan and PPIs. In subgroup analyses, patients with peptic ulcer disease (PUD) had higher incidences of any AEs, serious AEs, and AEs leading to drug discontinuation than those with gastroesophageal reflux disease (GERD), () infection, and artificial ulcer after gastric endoscopic submucosal dissection (ESD), but patients with infection had a higher incidence of drug-related AEs than those with PUD, GERD, and artificial ulcer after gastric ESD. The incidence of AEs was higher in patients taking long-term use of vonoprazan than those taking short-term use of vonoprazan.
CONCLUSION
Vonoprazan is well tolerated and shows similar safety compared to PPIs. The safety of vonoprazan may be primarily influenced by its indications and duration.
REGISTRATION
PROSPERO CRD42022314982.
PubMed: 37113190
DOI: 10.1177/17562848231167858