Positive Rechallenge Research Articles

A rare occurrence of Vancomycin-induced gastrointestinal hemorrhage without thrombocytopenia: a case report and literature review

BackgroundVancomycin-induced bleeding has been reported, attributed to the mechanism of immune thrombocytopenia. A rare case of vancomycin-induced gastrointestinal hemorrhage in a young patient with no underlying disease, receiving intravenous vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infection, is presented. This occurrence occurred without thrombocytopenia. Relevant cases reported in the literature were also reviewed.Case presentationA 34-year-old male patient presented with maxillofacial multiple spaces infection accompanying left temporal abscess, bilateral lung abscesses. Culture results from both blood and secretion indicated that the infection was caused by MRSA. The patient received standard-dose vancomycin (1 g q12h intravenously guttae) for treatment. On the 5th day of therapy, he presented with bright red blood in his stool; however, vancomycin treatment was continued. By the 9th day, a decrease in hemoglobin level to 76 g/L and a platelet (PLT) count of 424 × 109/L raised concerns about gastrointestinal hemorrhage. The hemoglobin level decreased to 62 g/L on day 12. Due to the high tissue concentration of linezolid, administration of linezolid at a dose of 600 mg q12h intravenously guttae commenced on the 13th day as an alternative to vancomycin(D13-D17). Subsequently, on the 17th day, there was an improvement in hemoglobin level to 78 g/L. However, despite treatment with linezolid, the patient’s fever showed no significant improvement, prompting a switch back to vancomycin at a dosage of 1 g q12h intravenously guttae(D18-D22). On the 21st day, there was a recurrence of gastrointestinal hemorrhage, accompanied by a hemoglobin level of 42 g/L and a PLT count of 224 × 109/L. Gastroscopy revealed the presence of a gastroduodenal ulcer. The patient had no prior history of hemorrhoids, gastrointestinal ulcers, liver cirrhosis, or purpura. Prior to admission, he had not been administered non-steroidal anti-inflammatory drugs (NSAIDs) or steroids. During hospitalization, the only medications given were vancomycin, ambroxol and lidocaine. Additional tests ruled out immunological disorders as the cause of gastrointestinal ulcers, and a positive vancomycin rechallenge test indicated an association between vancomycin and bleeding. After discontinuation of vancomycin, no further bleeding occurred. This case highlights a rare occurrence of vancomycin-induced bleeding without thrombocytopenia, classified as “Certain” according to the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale for standardized case causality assessment.ConclusionThis case represents the first documented instance of vancomycin-induced bleeding without thrombocytopenia, as confirmed by a positive rechallenge test. This discovery will aid in the early detection of this rare adverse reaction in future cases.

Retinal vascular occlusion after COVID-19 vaccination: Analysis of the French pharmacovigilance database

Retinal vein occlusions and central retinal artery occlusions have been reported with coronavirus disease 2019 (COVID-19) vaccines. We aim to provide a descriptive analysis of cases reported in France until mid-2023, and recorded in the French pharmacovigilance database. An independent ophthalmologist reviewed all cases. We analyzed 290 cases (228 retinal vein occlusions, 58 central retinal artery occlusions, and four combinations). Retinal vein occlusions occurred with mRNA vaccines (68.0%) and adenovirus-vectored vaccines (32%), with an 11-day median onset delay. Almost half of the patients had retinal vein occlusion risk factors, mainly hypertension, and five had a positive rechallenge. Considering the lower adenovirus-vectored vaccines exposure in France, their proportion of retinal vein occlusions appears high. Among the 58 central retinal artery occlusion cases, most occurred with mRNA vaccines in patients with retinal artery occlusion risk factors (mainly hypertension), with a 17-day median onset delay. In conclusion, there was a temporal association in almost half of cases, but few cases with positive rechallenge, and many cases were confounded by risk factors (e.g., cardiovascular disorders, diabetes), which are also COVID-19 risk factors. Therefore, the risk of retinal vascular occlusion does not challenge the benefit-risk ratio of the vaccination, especially for mRNA vaccines.

Omeprazole and Risk of Hypertension: Analysis of Existing Literature and the WHO Global Pharmacovigilance Database.

The association between omeprazole and hypertension is poorly documented. The summary of product characteristics of omeprazole approved by major regulators did not mention hypertension as an adverse drug event. Triggered by a locally reported case, this study was conducted to assess the possible causal relationship between omeprazole and hypertension. Globally reported cases of hypertension following use of omeprazole submitted to the World Health Organization global database, VigiBase, were retrieved on 5 March 2024 and analyzed descriptively. Besides this, a literature search was made to identify preclinical, clinical, and epidemiological information on the association between omeprazole and hypertension or increased blood pressure using different data sources. Relevant information, gathered from different data sources, was finally systematically organized into an Austin Bradford-Hill causality assessment framework to assess the causal relationship between omeprazole and hypertension. VigiBase indicated a total of 1043 cases of hypertension related to omeprazole from 36 different countries. In the global database, a statistical signal was triggered (IC025: 0.12) on association of omeprazole and hypertension. From the 1043 cases, 65.0% and 10.6% were reported as 'serious' and 'fatal', respectively. Hypertension resolved following withdrawal of omeprazole in 85 cases and recurred after re-introduction of the suspect drug in 14 cases. In 225 cases, omeprazole was the only suspected drug, while in 122 cases, omeprazole was the sole drug administered. When only these 122 cases were considered, 29 cases had positive dechallenge, four cases were with positive rechallenge and the median time-to-onset was 2 days. Literature search identified a possible biological mechanism and some experimental evidence that indicates omeprazole could possibly cause hypertension. Currently available totality of evidence suggests there is a possible causal relationship between omeprazole and hypertension. Hence, it is recommended to monitor and report any incidence of hypertension related to omeprazole, and further epidemiological studies are recommended to corroborate the suggested causal association.

Acetazolamide-induced pulmonary oedema: A disproportionality analysis from the EudraVigilance database.

To our knowledge, no prior study has analysed a possible association between acetazolamide and pulmonary oedema. The aim of this study was to use data from the EudraVigilance to detect a safety signal for acetazolamide-induced pulmonary oedema. We performed a disproportionality analysis (case-noncase method), calculating reporting odds ratios (RORs) up to 22 February 2024. Among 11 684 208 spontaneous cases of adverse reactions registered in EudraVigilance, 38 275 were pulmonary oedemas. Acetazolamide was involved in 31 cases. In more than half of those cases, the patients received a single dose of acetazolamide after undergoing cataract surgery: latency was 10-90 min. Remarkably, there were five cases of positive rechallenge and six cases resulted in death. The ROR for acetazolamide was 3.63 (95% CI 2.55-5.17). Disproportionality was also observed in VigiBase®: ROR 4.44 (95% CI 3.34-5.90). Our study confirms a signal that suggests a risk of serious pulmonary oedema associated with acetazolamide.

Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions

IntroductionData on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. MethodsCases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. ResultsOf 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. ConclusionsEpisodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Nifedipine-induced agranulocytosis: A rare case report and literature review

Rationale: Drug-induced agranulocytosis (DIAG) is a fatal idiosyncratic reaction characterized by a peripheral neutrophil count <0.5 × 109/L. Almost all classes of medications have been implicated with DIAG. However, agranulocytosis induced by antihypertensive drugs is rare worldwide. To the best of our knowledge, this is the first case of nifedipine-associated agranulocytosis with a positive rechallenge. Patient concerns: An 82-year-old man was admitted to our hospital due to uncontrolled fasting blood sugar. He had a history of hypertension and underwent treatment with nifedipine 6 years prior to admission. Blood tests showed white blood cell count of 2.30 × 109/L with a neutrophil count of 0.49 × 109/L. Diagnosis: Other malignancies that contributed to agranulocytosis were excluded, and the patient was diagnosed with DIAG. Interventions and outcomes: At first, gliclazide, rather than nifedipine, was considered as the culprit for DIAG and it was discontinued. Neutrophil count improved upon hematopoietic growth factors and traditional Chinese medicine. During the follow-up, the neutrophil count decreased again, and nifedipine was thought to be the offending agent for agranulocytosis. The neutrophil count increased to 0.91 × 109/L 2 months after nifedipine discontinuation. However, the patient was re-exposed to nifedipine and the neutrophil count decreased to 0.70 × 109/L. Lessons: Nifedipine-induced agranulocytosis is a rare but serious adverse drug reaction. For any patients with clinical suspicion or diagnosis of DIAG, a full drug history should be chronologically and completely taken in order to identify the suspected agents. Sometimes diagnosis of DIAG is challenging since some patients may be entirely asymptomatic. Management of DIAG starts with immediate discontinuation of the implicated drug. Empirical broad-spectrum antibiotics and hematopoietic growth factors may improve patient outcomes and reduce recovery time.

Drug-Induced Acute Pancreatitis in Adults: Focus on Antimicrobial and Antiviral Drugs, a Narrative Review.

Acute pancreatitis (AP) is an acute inflammation of the pancreas caused by the activation of digestive enzymes in the pancreatic tissue. The main causes of AP are cholelithiasis and alcohol abuse; less commonly, it can be caused by drugs, with a prevalence of up to 5%. Causal associations between drugs and pancreatitis are largely based on case reports or case series with limited evidence. We reviewed the available data on drug-induced AP, focusing on antimicrobial drugs and antivirals, and discussed the current evidence in relation to the classification systems available in the literature. We found 51 suspected associations between antimicrobial and antiviral drugs and AP. The drugs with the most evidence of correlation are didanosine, protease inhibitors, and metronidazole. In addition, other drugs have been described in case reports demonstrating positive rechallenge. However, there are major differences between the various classifications available, where the same drug being assigned to different probability classes. It is likely that the presence in multiple case reports of an association between acute pancreatitis and a drug should serve as a basis for conducting prospective randomized controlled trials to improve the quality of the evidence.

Safety Signal Generation for Sudden Sensorineural Hearing Loss Following Messenger RNA COVID-19 Vaccination: Postmarketing Surveillance Using the French Pharmacovigilance Spontaneous Reporting Database

The World Health Organization lately described sudden sensorineural hearing loss (SSNHL) as a possible adverse effect of COVID-19 vaccines. Recent discordant pharmacoepidemiologic studies invite robust clinical investigations of SSNHL after COVID mRNA vaccines. This post-marketing surveillance study, overseen by French public health authorities, is the first to clinically document post-vaccination SSNHL in terms of severity, duration, positive rechallenge cases and to examine the role of potential risk factors. This nationwide study aimed to assess the relationship between SSNHL and exposure to mRNA COVID-19 vaccines and to estimate the reporting rates (Rr) of SSNHL after mRNA vaccination per 1,000,000 doses (primary outcome). We performed a retrospective review of all suspected cases of SSNHL after mRNA COVID-19 vaccination spontaneously reported in France between January 2021 and February 2022, based on a comprehensive medical evaluation including patient medical history, side and range of hearing loss, hearing recovery outcomes after a minimum period of 3 months. Quantification of hearing loss and assessment of hearing recovery outcomes were performed according to a grading system modified from Siegel's criteria. A cutoff value of 21 days was used for the delay onset of SSNHL. The primary outcome was estimated using as a denominator the total number of doses of each vaccine administered over the study period in France. From an initial number of 400 extracted cases for both mRNA vaccines, 345 spontaneous reports were selected for further analysis. After detailed review of complementary medical data, 171 fully documented cases of SSNHL were found. Of these, 142 SSNHL cases occurred after tozinameran vaccination, with the following characteristics: Rr=1.45/1,000,000 injections; no difference between the first, second, and booster injection; complete recovery for 32 cases; median delay onset before day 21 = 4 days; median (range) age=51 (13-83) years; no sex effect. A total of 29 SSNHL cases were identified after elasomeran vaccination, with the following characteristics: Rr=1.67/1,000,000 injections; rank effect in favour of the first injection (p=0.036); complete recovery for 7 cases; median delay onset before day 21 = 8 days; median (range) age=47 (33-81) years; no sex effect. Autoimmune, cardiovascular, or audiovestibular risk factors were present in nearly 30% of cases. SSNHL was more often unilateral than bilateral for both mRNA vaccines (p<0.001 for tozinameran; p<0.003 for elasomeran), and the hearing loss degree was slight to moderately severe (Siegel's grade 1 to 3) on 74% of audiogram tests. There was 23 (13%) of profound hearing loss (Siegel's grade 5), among which 17 (74%) did not recover a serviceable ear. A positive rechallenge was documented for 8 cases, reinforcing the hypothesis of a causal relationship between mRNA COVID-19 vaccination and the occurrence of SSNHL. Episodes of SSNHL after COVID-19 mRNA vaccines are very rare adverse events that do not call into question the benefits of mRNA vaccines but deserve to be known given the potentially disabling impact of sudden deafness. It is, therefore, essential to properly characterize any post-injection SSNHL, especially in the case of a positive rechallenge, to provide appropriate individualized recommendations.

Frequency of gastrointestinal manifestations among infants with cow’s milk protein allergy, Egypt

BackgroundCow’s milk is known to be the most frequent food allergen in infants in the first years of life. Eliminating cow milk protein from diets and reintroducing it with a challenge test are the main methods for sure diagnosis. Cow’s Milk-related Symptom Score (CoMiSS) has been developed for primary health care providers to improve their knowledge about CMPA.ObjectiveThis study was conducted to prescribe clinical presentation of cow’s milk allergy among infants.MethodsA cross-sectional study was conducted at Gastroenterology and Nutrition Unit, University Children Hospital, from the 1st of January 2020 to the 31st of December 2020. Forty infants, complaining of recurrent or persistent gastrointestinal manifestations, were included in our study (28 males and 12 females). Those infants were subjected to detailed medical and social patient history, comprehensive physical exam, and CoMiSS scoring as an awareness tool to suspect underlying cow milk allergy. Infants with a CoMiSS of more than 12 points and positive elimination rechallenge test were regarded as eligible to be part of our study.ResultsThis study showed that the most frequently occurring gastrointestinal manifestations associated with CMPA were regurgitation (92%), diarrhea (80%), colic (75%), vomiting (67.5%), and lastly constipation which represents only (5%).ConclusionRegurgitation and diarrhea are the commonest presentations for infants proved to have cow milk allergy with CoMiSS score and elimination rechallenge test, where constipation is the least common presentation for those infants.

COVID-19 Vaccination as a Trigger of IgA Vasculitis: A Global Pharmacovigilance Study.

IgA vasculitis (IgAV) can occur after vaccination. We aimed to assess a potential safety signal on the association between coronavirus disease 2019 (COVID-19) vaccines and IgAV. Cases of IgAV involving COVID-19 vaccines were retrieved in VigiBase. Disproportionate reporting was assessed using the Bayesian information component (IC) with all other drugs and vaccines as control groups. Three hundred thirty patients with de novo IgAV from 24 countries were included, mostly from the United States (193/330, 58%). Fifty percent (163/328) were female and median age was 32 years (IQR 15-59), of which 33% (84/254) were young (1-17 yrs). Median time to onset of IgAV was 7 days (IQR 2-16; n = 256) and 85% (280/330) of patients were vaccinated with mRNA vaccines. Seriousness was reported in 188/324 (58%) cases. Sixty-five percent (95/147) recovered and 1% (2/147) died. A positive rechallenge was reported for 3 of 4 patients (75%). A total of 996 cases of IgAV were identified with other vaccines. There was a small significant increase in IgAV reporting with COVID-19 vaccines compared with all other drugs (IC 0.22, 95% credible interval [CrI] 0.04 to 0.35). No disproportionality signal was found between COVID-19 vaccines and other vaccines (IC -1.42, 95% CrI -1.60 to -1.28). There was no significant difference between mRNA vaccines and viral vector COVID-19 vaccines. Men and children had a significant overreporting of IgAV compared with women and adults, respectively. This study provides reassuring results regarding the safety of COVID-19 vaccines in the occurrence of IgAV compared to other vaccines.

Rechallenge after anti-tuberculosis drug-induced liver injury in a high HIV prevalence cohort.

BackgroundThere are limited data on the outcomes of rechallenge with anti-tuberculosis therapy (ATT) following anti-tuberculosis drug-induced liver injury (AT-DILI) in a high HIV prevalence setting.ObjectivesTo describe the outcomes of rechallenge with first-line ATT.MethodHospitalised participants with AT-DILI who were enrolled into a randomised controlled trial of N-acetylcysteine in Cape Town, South Africa, were followed up until completion of ATT rechallenge. We described rechallenge outcomes, and identified associations with recurrence of liver injury on rechallenge (positive rechallenge).ResultsSeventy-nine participants were rechallenged of whom 41 (52%) were female. Mean age was 37 years (standard deviation [s.d.] ±10). Sixty-eight (86%) were HIV-positive, of whom 34 (50%) were on antiretroviral therapy (ART) at time of AT-DILI presentation. Five participants had serious adverse reactions to an aminoglycoside included in the alternate ATT regimen given after first-line ATT interruption: acute kidney injury in three and hearing loss in two. The median time from first-line ATT interruption to start of first-line ATT rechallenge was 13 days (interquartile range [IQR]: 8–18 days). Antiretroviral therapy was interrupted for a median of 32 days (IQR: 17–58) among HIV-positive participants on ART before AT-DILI. Fourteen participants had positive rechallenge (18%). Positive rechallenge was associated with pyrazinamide rechallenge (P = 0.005), female sex (P = 0.039) and first episode of tuberculosis (TB) (P = 0.032).ConclusionRechallenge was successful in most of our cohort. Pyrazinamide rechallenge should be carefully considered.

O-28 DRUG-INDUCED LIVER INJURY IN LATINAMERICA: First ten years’ experience of the ongoing LATINDILI Network

In 2011, the Latin-American DILI-Network (LATINDILIN) set up under the guidance of the Spanish DILI Registry a network of hepatologists to prospectively identify and characterize DILI patients. To evaluate the drugs more frequently associated with DILI in LA, clinical phenotype and outcome. Demographics, clinical and biochemical parameters of all cases included in the LATINDILI Network were analysed according to the type of liver injury (hepatocellular, Hep; cholestatic, Chol and mixed, Mix). 404 DILI cases were included. Anti-infectives (31%), musculoskeletal system drugs (13%) and herbal products (9.2%) were the main causative therapeutic drug classes. Mean age was 49 years (female sex, 61%). Hep injury predominated (62%) whereas Chol and Mix patterns were 24% and 15% of cases, respectively. Chol patients (mean age 56y) were older than Hep and Mix cases (47 and 50, p<0.05). Jaundice was more prevalent in Chol and Mix injury than in Hep cases (65% vs 75% vs 58%, respectively, p=0.062), though no differences in hospitalization rates were observed (Hep 43%, Chol and Mix 46%, p=0.867). Of note, 12 cases, mostly Hep, had a positive rechallenge. Positive autoantibodies were more common in Hep cases (25% vs Chol 9.1% vs Mix 19%, p=0.010), with nitrofurantoin/herbal products as the most common causative agents. Hep cases showed a higher risk of severe/fatal injury (18% vs 6.0% and 1.8% in Chol and Mix cases, respectively, p<0.001). The new Hy's law performed as expected, with 14% of ALF/Tx cases. Hep cases more frequently died from liver-related death (3.5%) compared with Chol (1.1%) and Mix (0) cases. In Latin-American DILI cases with Hep pattern predominated, showing a higher severity and most frequent inadvertent re-exposition. The LATINDILI Network is proving as an important tool for the characterization of DILI singularities in this world region, and improvement of Public Health. AEMPS, FEDER (PI18/01804). COST Action CA-17112.

Possible Association Between Apremilast Therapy and Increased Tearing.

To evaluate a possible association between apremilast and increased tearing. A retrospective observational case series in which reports from VigiBase, the World Health Organization global database of Individual Case Safety Reports, and the literature involving apremilast were evaluated by the National Registry of Drug-Induced Ocular Side Effects for possible increased tearing. A total of 45 cases of possible apremilast-induced increased tearing were identified. All patients were on the standard dose of 30 mg BID. There was no sex difference and ages ranged from 28 to 77 years with an average of 56 years ± 12. Time to onset of the increased tearing ranged from a few days to many months. There were 10 cases of positive dechallenge, 3 cases of positive rechallenge, and 1 case with double-positive rechallenge. In the cases with positive dechallenge and rechallenge, the increased tearing resolved as early as within 2 days after stopping the drug. Most cleared within 2 weeks. One case required 3 months for tearing to return to normal. Based on patterns and positive dechallenge and rechallenge data, apremilast possibly causes increased tearing on rare occasions.

Factors Influencing Regulatory Decision-Making in Signal Management: Analysis Based on the Signals Identified from the FAERS.

This study aimed to identify factors that influence the decision to take safety regulatory actions in routine signal management based on spontaneous reports. For this purpose, we analyzed the safety signals identified from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and related information. From the signals that the FDA identified in the FAERS between 2008 1Q and 2014 4Q, we selected 216 signals for which regulatory action was or was not taken. Characteristics of the signals were extracted from the FAERS quarterly reports that give information about what signals were identified from the FAERS and what actions were taken for them, and the FAERS data released in the same quarter when the signal was published. Univariate and multivariable logistic regression analysis was used to assess the relationship between the characteristics of each of the signals and the decision on regulatory action. As a result of the univariate logistic regression analysis, we selected 5 factors (positive rechallenge, number of cases accumulated in the last one-year period before the signal indication, previous awareness, serious outcome, risk for special populations) to include in the multivariable logistic regression model (p < 0.2). The multivariate logistic regression analysis showed that the number of cases accumulated in the last one-year period before the signal indication and previous awareness were associated with the regulatory action (p < 0.05). The present study showed that number of cases accumulated in the last one-year period before the signal indication and previous awareness potentially associated with the United States regulatory action. When assessing safety signals, we should be careful of the adverse events with a large number of cases accumulated rapidly in a short period. In addition, we should pay attention to new information on not only unknown risks but also previously identified and potential risks.

Postmarketing safety surveillance of quadrivalent recombinant influenza vaccine: Reports to the vaccine adverse event reporting system

On October 7, 2016, the Food and Drug Administration approved recombinant hemagglutinin quadrivalent influenza vaccine (RIV4) (Spodoptera frugiperda cell line; Flublok Quadrivalent) for active immunization for the prevention of influenza disease in individuals 18 years of age and older. Clinical trials did not reveal any major differences in adverse events or serious adverse events following Flublok Quadrivalent versus standard-dose quadrivalent inactivated influenza vaccine. To improve our understanding of the safety profile of this vaccine, we reviewed and summarized adverse event reports after Flublok Quadrivalent administration to the Vaccine Adverse Event Reporting System (VAERS). Through June 30, 2020, VAERS received 849 reports after RIV4 vaccination. The vast majority (810; 95%) were non-serious. Among serious events, there were 10 cases of Guillain-Barré syndrome, including 5 people who required mechanical ventilation and 2 people who died. Many allergic reactions were reported as non-serious, but required interventions to treat a life-threatening event, e.g., epinephrine, nebulizers, albuterol, glucocorticoids, and supplemental oxygen. Two people experienced a positive rechallenge (i.e., allergic reactions after repeated vaccination with RIV4), including a person who—despite premedication with antihistamines—developed respiratory difficulties, required epinephrine, and was transported to the emergency department. The occurrence of anaphylaxis and other allergic reactions in some individuals may reflect an underlying predisposition to atopy that may manifest itself after an exposure to any drug or vaccine, and does not necessarily suggest that Flublok Quadrivalent is particularly allergenic. Postmarketing safety surveillance will continue to be vital for understanding the benefits and risks of quadrivalent recombinant influenza vaccine.

Suspected adverse reactions to performance enhancing dietary supplements: Spontaneous reports from the Italian phytovigilance system.

Herbal tonic and adaptogens are often used to improve overall well-being. However, few clinical evidence supports their use and their safety is not known before marketing. In this context, the aim of our study was to analyze the spontaneous reports of suspected adverse reactions (ARs) to performance enhancing herbal dietary supplements collected by the Italian Phytovigilance System. Between March 2002 and September 2020, 110 spontaneous reports were collected, 58 of which related to products containing botanicals, alone or in association. Twenty-three serious reactions were reported, 21 of which required hospitalization, one was life-threatening and another caused disability. Dermatological and cardiovascular reactions were the most frequent. Hepatic ARs were the most serious (9 out of 10). A positive dechallenge was indicated in 69% of cases, while a positive rechallenge occurred in 15%. Concomitant use of other products was present in 18 reports (31%), while predisposing conditions were indicated in 17 (29%). Present data highlight safety concerns on herbal dietary supplements used as cognitive and physical performance enhancers, mainly due to their quality and use without expert supervision. Considering that postmarketing surveillance is not required for these products, spontaneous reports represent the only tool to point out risks related to food supplements.

A Drug-Induced Acute Pancreatitis Retrospective Study.

Background and Aims Drugs are considered a relatively rare and understudied cause of acute pancreatitis (AP). The lack of convincing and conclusive data on drug-induced AP (DIAP) complicates the diagnosis as well as the identification of the causative drug. The aim of this study is to document causes of DIAP cases that occurred in the Saguenay-Lac-Saint-Jean (SLSJ) population. Methods We have conducted a retrospective and descriptive population-based study of DIAP cases that occurred between 2006 and 2014 in the six hospitals serving the entire SLSJ population. Cases were selected from the Quebec Ministry of Health hospitalizations registry (MED-ECHO) administrative public database. A medical chart review was performed in an attempt to characterize DIAP hospitalizations and to identify the imputable drugs. Results During the studied period, 75 cases (30.7% male, 69.3% female) were included totaling 90 hospitalizations for DIAP. Among them, 50 causative drugs were identified and were distributed in 17 different drug classes. Recurrent DIAPs were documented in 13 cases, and among them, 6 cases have experimented a positive rechallenge. Six drugs (5-fluorouracil, atorvastatin, bortezomib, nilotinib, rosuvastatin, and triamcinolone) were associated with the highest degree of evidence. The most common causative drugs of DIAP hospitalization were azathioprine (n = 7), followed by atorvastatin (n = 6), hydrochlorothiazide (n = 5), rosuvastatin (n = 4), and codeine (n = 4). Conclusions This study has added new evidences about potentially pancreatitis-associated drugs in literature. This is the first study to report definite 5-fluorouracil- and triamcinolone-induced AP. An updated version of the evidence-based literature review is needed to support the clinicians in the identification of the causative drugs.

Complementary Use of U.S. FDA's Adverse Event Reporting System and Sentinel System to Characterize Direct Oral Anticoagulants-Associated Cutaneous Small Vessel Vasculitis.

Cutaneous small vessel vasculitis (CSVV) has been reported after exposure to direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban. We used the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to describe clinical characteristics associated with CSVV among DOAC-exposed patients. Furthermore, we characterized this signal in the Sentinel System to relate the clinical data from the individual FAERS cases to population-based electronic healthcare data. We queried FAERS for all cases of CSVV associated with DOACs from U.S. approval date of each DOAC through March 16, 2018. Within the Sentinel System, we identified incident CSVV cases using ICD-9 and ICD-10 diagnosis codes among adults aged≥30years who received a DOAC in the prior 90days between January 1, 2010, and June 30, 2018. We excluded patients with evidence of select autoimmune diagnoses in the 183days prior to their CSVV diagnoses and reported patient characteristics in the 183-day period prior to CSVV diagnoses. In FAERS, we identified 50 cases of CSVV reported with rivaroxaban (n=26), apixaban (n=14), dabigatran (n=9), and edoxaban (n=1). Approximately 50% of the cases reported time to onset within 10days after DOAC exposure. When specified, the predominant type of CSVV reported was leukocytoclastic vasculitis (n=31), followed by Henoch-Schonlein purpura (n=4). Hospitalization occurred in most of the cases (n=37). Switching of the offending agent after the development of CSVV was reported (n=26). Three rivaroxaban (n=3) cases and one dabigatran case (n=1) reported positive rechallenge. In the Sentinel system, we identified 3659 CSVV cases with prior DOAC exposure, with 85% of events occurring within 10days. The assessment of FAERS cases, combined with the temporal clustering of the Sentinel System cases suggest a possible causal relationship of DOACs and CSVV. Future efforts should characterize the risk of CSVV among the various DOAC users.

A271 ETIOLOGICAL CHARACTERIZATION OF DRUG-INDUCED ACUTE PANCREATITIS

Abstract Background Drugs are considered a relatively rare and understudied cause of acute pancreatitis (AP). The lack of convincing and conclusive data on drug-induced AP (DIAP) complicates the diagnosis as well as the identification of the causative drug. Aims We hypothesized that documenting the causes of DIAP in the Saguenay-Lac-Saint-Jean (SLSJ) will add new evidence to the current literature and will provide a comprehensive picture of this health condition in the region. The aim of this study is to document causes of DIAP cases that occurred in the SLSJ population. Methods We have conducted a retrospective and descriptive population-based study of DIAP cases that occurred between 2006 and 2014 in the six hospitals deserving the SLSJ entire population. Cases were selected from the Quebec Ministry of Health hospitalizations registry (MED-ECHO) administrative public database. Medical chart review was performed in attempt to characterize DIAP hospitalizations and to identify the imputable drugs. Results During the studied period, 75 cases (30.7% male, 69.3% female) were included totalling 90 hospitalizations for DIAP. Among them, 51 causative drugs were identified and were distributed in 17 different drug classes. Recurrent DIAP were documented in 13 cases and among them, 6 cases have experimented positive rechallenge. Six drugs (5-fluorouracil, atorvastatin, bortezomib, nilotinib, rosuvastatin and triamcinolone) were associated with the highest degree of evidence. The most common causative drugs of DIAP hospitalization were azathioprine (n = 7), followed by atorvastatin (n =6), hydrochlorothiazide (n = 5), rosuvastatin (n = 4) and codeine (n = 4). Conclusions This study has added new evidences about potentially pancreatitis-associated drugs in literature. This is the first study to report definite 5-fluorouracil and triamcinolone-induced AP. An updated version of the evidence-based literature review is needed to support the clinicians in the identification of the causative drugs. Funding Agencies None

Contribution of Causality Assessment for an Automated Detection of Safety Signals: An Example Using the French Pharmacovigilance Database.

Qualitative approaches based on drug causality assessment estimate the causal link between a drug and the occurrence of an adverse event from individual case safety reports. Quantitative approaches based on disproportionality analyses were developed subsequently to allow automated statistical signal detection from pharmacovigilance databases. This study assessed the potential value of causality assessment for automated safety signal detection. All drug-serious adverse event pairs with a positive rechallenge and a semiology suggestive of drug causality were identified in the French pharmacovigilance database (BNPV) from 2011 to 2017. The results were compared with those obtained from automated disproportionality analyses of the BNPV/World Health Organization (WHO) VigiBase®, complemented by the list of signals validated by the WHO-UMC (Uppsala Monitoring Centre). Summary of Product Characteristics (SmPCs), Martindale®, Meyler's® and MedLINE® were used as other sources of information for the purpose of comparison. Of the 155 pairs of interest, 115 (74.2%) were also identified by another source of information. Since the individual case reporting in the BNPV, 23 (14.8%) of the adverse events (AEs) have been added to the SmPC, seven of which were not identified by disproportionality. Finally, 40 pairs were not identified by any other source of information, 13 of which were considered as potential new safety signals after analysis of case reports by pharmacovigilance experts. The signals identified by causality assessment involved antineoplastic and immunomodulatory drugs especially, in comparison with signals identified by WHO-UMC or by disproportionality within the BNPV. The approach therefore appears useful as an additional tool for safety signal detection, especially for antineoplastic and immunomodulating agents.