Risk of Neuroinflammatory Diseases Among New Recipients of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs

Using de-identified electronic health record (EHR) data in the US from TriNetX, Casey et al. conducted a retrospective, observational study to describe and compare the risk of neuroinflammatory disease among patients newly treated with TNF inhibitors compared to new users of other non-TNF DMARDs for the treatment of autoimmune disease (i.e., rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, or ulcerative colitis).

Neuroinflammatory disease was observed rarely among this cohort (1-2 events per 1,000 person-years). The authors observed no statistical difference in the relative hazard of neuroinflammatory events for patients treated with a TNF inhibitor compared to those treated with other non-TNF DMARDs.

Results from this study contrast those from other published studies; however, important methodologic differences may explain the disparate findings. The current study employed a “new-user” design (to mitigate immortal-time-bias), used an “active” comparator group (to mitigate confounding by indication), and accounted for important patient-level differences between treatments groups (to mitigate channeling bias).

While this study has substantially improved internal validity compared to previously conducted studies, it would be helpful to address potential censoring bias due to switching therapies or discontinuation of the initial therapy using more precisely defined treatment strategies and an emulated target trial design.

There appear to be no major conflicts of interest reported by the study authors. However, the funding source for this research initiative is not clearly evident.

Citation:

Casey M, Pannu S, Bajwa S, Duarte-García A, Putman M. Risk of Neuroinflammatory Diseases Among New Recipients of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs. Arthritis Care Res (Hoboken). 2024 Apr 3. doi: 10.1002/acr.25340. Epub ahead of print. PMID: 38570894.

https://pubmed.ncbi.nlm.nih.gov/38570894/

• Abstract

  Objective: Neuroinflammatory adverse events have been observed among new users of tumor necrosis factor (TNF) inhibitors. No studies to date have compared the real-world risk of TNFs with other new users of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). The objective of this study is to describe the risk of neuroinflammatory disease after initiation b/tsDMARDs.

  Methods: This new user comparative effectiveness cohort study used a large US-based electronic health records database to describe the unadjusted incidence of neuroinflammatory adverse events over a 3-year period. The cohort included patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, or ulcerative colitis initiating treatment with a TNF inhibitor (n = 93,661) or other b/tsDMARD (n = 38,354).

  Results: Among 132,015 patients included in the analysis, the most common first biologic agent was a TNF inhibitor; the unadjusted incidence of neuroinflammatory events was numerically lower among new users of TNF inhibitors (incidence 1.34 per 1,000 patient-years) as compared with the combined non-TNF group (1.69 per 1,000 patient-years). There was no significant association between TNF exposure and neuroinflammatory events as compared with the combined non-TNF b/tsDMARDs overall (hazard ratio 1.01; 95% confidence interval 0.75-1.36) and within each disease group.

  Conclusion: The overall risk of neuroinflammatory events among new users of TNF inhibitors did not differ substantially as compared with new users of other b/tsDMARDs. Meta-analyses of randomized trials should be conducted to corroborate these findings, which may be affected by channeling bias.

Post-marketing safety concerns with elagolix: a disproportionality analysis of the FDA adverse event reporting system

Using spontaneous reporting data from the FDA Adverse Event Reporting System (FAERS), Chang et al. analyzed adverse events (AEs) associated with elagolix - a medication indicated for the treatment of moderate-to-severe endometriosis pain (approved by the FDA in 2018).

Using several disproportionality signal analysis methods, the authors aimed to describe and analyze AEs associated with elagolix treatment in FAERS.

The authors detected several “known” or previously reported AE signals such as hot flushes, bone pain, suicidal ideation, depression, and increased liver enzymes. Additionally, several “unknown” (i.e., not reported in the elagolix prescribing information) potential safety signals were detected. These included cystitis interstitial, parosmia, and epiploic appendagitis. The median time to elagolix-associated AEs was 28.5 days.

While this study of spontaneous adverse event reports associated with elagolix reveals potential “known” and “unknown” safety signals, further research using a population-based data source and rigorous methodology is needed to fully elucidate the causal association. Importantly, comparisons to patients with endometriosis are needed to mitigate confounding by indication.

Citation:

Chang E, Shi YF, Liu JF, Wei W. Post-marketing safety concerns with elagolix: a disproportionality analysis of the FDA adverse event reporting system. Expert Opin Drug Saf. 2024 May 7:1-8. doi: 10.1080/14740338.2024.2351451. Epub ahead of print. PMID: 38700323.

https://pubmed.ncbi.nlm.nih.gov/38700323/

• Abstract

  Objective: Elagolix is approved for the treatment of moderate-to-severe pain associated with endometriosis. However, the long-term safety of elagolix in a large sample of real-world patients is unknown.

  Methods: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) reports were collected and analyzed from January 2019 to June 2023. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed in data mining to quantify the signals of elagolix-related adverse events (AEs).

  Results: After removing the non-drug-related AE signals, we detected several AE signals such as hot flushes, bone pain, suicidal ideation, depression, and increased liver enzymes, which were known during the clinical trial phase. In addition to this, we detected several unexpected important AEs that were not mentioned in the drug insert, including cystitis interstitial, parosmia, and epiploic appendagitis. The median onset time of elagolix-associated AEs was 28.5 days.

  Conclusion: Our study provides a comprehensive picture of the safety of elagolix in the post-marketing setting, while also identifying potential new AE signals. These findings emphasize the importance of continued monitoring of the potential risks of elagolix.

Novel anti-psoriasis agent-associated cardiotoxicity, analysis of the FDA adverse event reporting system (FAERS)

Using spontaneous reporting data from the FDA Adverse Event Reporting System (FAERS), Al-Yafeai et al. analyzed cardiovascular adverse events associated with newly approved agents for the treatment of psoriasis (i.e., secukinumab, ixekizumab, guselkumab, brodalumab, tildrakizumab, risankizumab-rzaa, deucravacitinib, spesolimab).

Using a disproportionality signal analysis approach, the authors aimed to estimate reporting odds ratios (RORs) of cardiovascular events with recently approved medications used to treat psoriasis compared to all medicines in FAERS.

The authors observed coronary artery disease (CAD), pericarditis, and atrial fibrillation (A-Fib) as the most prevalent cardiac complications associated with the newly approved psoriasis agents. Compared to reported cardiac events for all other pharmacotherapy in FAERS, an increased relative reporting odds of A-Fib and CAD was observed for risankizumab-rzaa. Ixekizumab and tildrakizumab were associated with an increased increased relative reporting odds of A-Fib. Secukinumab was associated with an increased increased relative reporting odds of pericarditis.

While this study of spontaneous cardiovascular event reports reveals potential safety signal related to newly approved agents for the treatment of psoriasis, further research using a population-based data source and rigorous methodology is needed to fully elucidate the causal association. Further, comparisons to patients with psoriasis are needed to mitigate confounding by indication.

Citation:

Al-Yafeai Z, Sondhi M, Vadlamudi K, Vyas R, Nadeem D, Alawadi M, Carvajal-González A, Ghoweba M, Ananthaneni A. Novel anti-psoriasis agent-associated cardiotoxicity, analysis of the FDA adverse event reporting system (FAERS). Int J Cardiol. 2024 May 1;402:131819. doi: 10.1016/j.ijcard.2024.131819. Epub 2024 Jan 30. PMID: 38301830.

https://pubmed.ncbi.nlm.nih.gov/38301830/

• Abstract

  Introduction: Psoriasis is a chronic skin condition characterized by hyperproliferation of epidermal keratinocytes, resulting in erythematous and scaling lesions. The US Food and Drug Administration (FDA) has approved nine biologic agents to address the burden of psoriasis, but their cardiovascular risks remain poorly studied.

  Methods: This retrospective pharmacovigilance study utilized the FDA Adverse Event Reporting System (FAERS) database to analyze adverse events associated with newly approved therapeutic agents for psoriasis. We employed disproportionally signal analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval.

  Results: Among the vast FAERS database, which contained >25 million adverse events, a total of 334,399 events were associated with newly approved therapeutic agents for psoriasis. Cardiac adverse events accounted for 3852 cases, including pericarditis, atrial fibrillation, and coronary artery disease. Secukinumab had the highest number of reported adverse events, followed by brodalumab, while tildrakizumab had the lowest. Coronary artery disease was the most reported adverse event (1438 cases), followed by pericarditis (572 cases) and atrial fibrillation (384 cases). Secukinumab had the highest incidence of coronary artery disease, pericarditis, and atrial fibrillation. Risankizumab was significantly associated with an increased risk of coronary artery disease and atrial fibrillation, while tildrakizumab and Ixekizumab were associated with atrial fibrillation. Secukinumab was associated with an elevated risk of pericarditis.

  Conclusions: The study uncovers the cardiovascular adverse effects related to biologic agents used in psoriasis treatment. These findings emphasize the importance of monitoring and evaluating the cardiovascular safety profiles of biological agents used in psoriasis treatment.

Comparing the risk of deep vein thrombosis of two combined oral contraceptives: Norethindrone/ethinyl estradiol and drospirenone/ethinyl estradiol

Using spontaneous reporting data from the FDA Adverse Event Reporting System (FAERS), Stalas et al. compared the risk of deep vein thrombosis (DVT) for patients who recieved combined oral contraceptives (norethindrone/ethinyl estradiol (NET/EE) and drospirenone/ethinyl estradiol (DRSP/EE))

The study aimed to estimate the association of progestin and the risk of DVT among patients taking oral contraceptives for birth control. Since age was determined to be a confounder, analyses were stratified by age category.

The authors observed an increased risk of DVT for patients using DRSP/EE compared to patients using NET/EE for birth control. Additionally, the authors reported a possible drug-drug interaction with concomitant prednisone treatment.

While this study of spontaneous reports reveals a potential safety signal related to DRSP/EE, further research using a population-based data source and rigorous methodology is needed to fully elucidate the causal association.

Citation:

Stalas J, Morris R, Bu K, von Bargen K, Largmann R, Sanford K, Vandeventer J, Han W, Cheng F. Comparing the risk of deep vein thrombosis of two combined oral contraceptives: Norethindrone/ethinyl estradiol and drospirenone/ethinyl estradiol. Heliyon. 2024 Feb 18;10(5):e26462. doi: 10.1016/j.heliyon.2024.e26462. PMID: 38434341; PMCID: PMC10906292.

https://pubmed.ncbi.nlm.nih.gov/38434341/

• Abstract

  Background: Deep vein thrombosis (DVT) has been reported as an adverse event for patients receiving combined oral contraceptives. Norethindrone/ethinyl estradiol (NET/EE) and drospirenone/ethinyl estradiol (DRSP/EE) are two commonly prescribed combined hormonal oral contraceptive agents used in the United States, differing in their progestin component.

  Objective: The purpose of this study was to determine the association between the progestin component of a combined oral contraceptive and the risk of DVT in patients taking oral contraceptives for birth control using data derived from the FDA Adverse Event Reporting System (FAERS).

  Methods: The risk of DVT was compared between patients that had taken NET/EE with those that had taken the DRSP/EE COC formulation for birth control. In addition, age was assessed as a possible confounder and the outcome severity for those diagnosed with DVT were compared between the two groups. Finally, association rule mining was utilized to identify possible drug-drug interactions that result in elevated DVT risk.

  Results: DVT was the fourth most commonly adverse event reported for patients taking DRSP/EE accounting for 8558 cases and the seventeenth most commonly reported adverse event for NET/EE accounting for 298 cases. Age was found to be a significant confounder for users of DRSP/EE with regards to DVT risk across all age groups assessed: 20<Age ≤ 30 (ROR = 1.33, 95% CI 1.23-1.45), 30<Age ≤ 40 (ROR = 2.16, 95% CI 1.98-2.35), and Age>40 (ROR = 3.69, 95% CI 3.37-4.04) However, there was only a statistically significant elevated risk in patients over 40 years of age taking NET/EE (ROR = 1.98, 95% CI 1.36-2.88). Patients that had taken DRSP/EE and the corticosteroid prednisone simultaneously had an approximately 3-fold increase in DVT risk (ROR = 2.77, 95% CI 2.43-3.15) relative to individuals that had only taken DRSP/EE.

  Conclusion: Based on this analysis, there is a higher risk of developing DVT when taking DRSP/EE than when taking NET/EE as hormonal contraception. In addition, a possibly significant drug-drug interaction between different COC formulations and prednisone were identified. This interaction may result in elevated DVT risk due to a synergistic impairment of fibrinolysis and a decrease in plasmin production.

Adverse events of guselkumab in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system

Using spontaneous reporting data from the FDA Adverse Event Reporting System (FAERS), Xiang et al., conducted disproportionality analyses to characterize adverse events associated with guselkumab - an IL-23 inhibitor used to moderate to severe plaque psoriasis.

The disproportionality algorithms (PRR, ROR, BCPNN, and MGPS) identified unexpected adverse event signals associated with guselkumab. These included onychomadesis, malignant melanoma in situ, endometrial cancer, and erectile dysfunction.

While this study of spontaneous reports reveals potential new signals related to guselkumab, further research using a population-based data source and rigorous methodology is needed to fully elucidate the causal associations.

Citation:

Xiang DC, Chen W, Fu ZW, Wu XH, Gao P, Wu Y. Adverse events of guselkumab in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system. Expert Opin Drug Saf. 2023 Jun 13:1-13. doi: 10.1080/14740338.2023.2223956. Epub ahead of print. PMID: 37294594.

https://pubmed.ncbi.nlm.nih.gov/37294594/

• Abstract

  Background: Guselkumab is an IL-23 inhibitor widely used for the treatment of moderate-to-severe plaque psoriasis. Our study aimed to characterize the profile of adverse events (AEs) associated with guselkumab from the FDA adverse event reporting system (FAERS).

  Methods: Disproportionality analysis including the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the Bayesian confidence propagation neural network (BCPNN), and the multiitem gamma Poisson shrinker (MGPS) algorithms were used to assess the signals of guselkumab related AE.

  Results: A total of 22,950,014 reports were collected from the FAERS database, of which 24,312 reports regarding guselkumab as the 'primary suspected (PS)' AEs were identified. AEs induced by guselkumab were distributed in 27 organ systems. In this study, 205 significant disproportionality preferred terms (PTs) that matched four algorithms simultaneously were obtained for analysis. Unexpected significant AEs such as onychomadesis, malignant melanoma in situ, endometrial cancer, and erectile dysfunction were observed.

  Conclusion: The clinical observed AEs, along with potential new AE signals associated with guselkumab were identified based on the analysis of FAERS data, which could provide valuable evidence for clinical monitoring, risk identification, and further safety studies of identification.

Assessment of Reported Adverse Events After Interchanging Between TNF-α Inhibitor Biosimilars in the WHO Pharmacovigilance Database

Using spontaneous reporting data from the World Health Organization (WHO) Pharmacovigilance Database, Pauline et al., aimed to analyze adverse event reports for patients switching from TNF inhibitor reference products to biosimilars and between biosimilars for the same reference product.

Injection-site reactions were the most reported adverse event (37.0%) followed by reduced effectiveness (23.9%). The proportion of injection-site reactions were higher for patients switching between biosimilars for the same reference product, but reduced effectiveness was more frequently reported when switching from a reference product to a biosimilar. The study authors also reported a disparity in reporting between healthcare professionals (HCPs) and non-HCPs. Injection-site reactions and infection-related symptoms were more likely reported by non-HCPs while adverse events related to effectiveness were more commonly reported by HCPs.

While this study of spontaneous reports reveals potential signals related to TNF reference product to biosimilar switching and biosimilar to biosimilar switching, further research using a population-based data source and rigorous methodology is needed to fully elucidate the causal association.

Citation:

Pauline O, Robert M, Bernardeau C, Hlavaty A, Fusaroli M, Roustit M, Cracowski JL, Khouri C. Assessment of Reported Adverse Events After Interchanging Between TNF-α Inhibitor Biosimilars in the WHO Pharmacovigilance Database. BioDrugs. 2023 Jun 6. doi: 10.1007/s40259-023-00603-8. Epub ahead of print. PMID: 37278971.

https://pubmed.ncbi.nlm.nih.gov/37278971/

• Abstract

  Background and objective: Observational studies have shown that a significant proportion of patients interchanging between tumor necrosis factor-α inhibitor biosimilars withdraws from the new treatment because of adverse effects. We aim to analyze adverse events related to interchanging from tumor necrosis factor-α (TNF-α) inhibitor reference products to biosimilars and between biosimilars reported in the World Health Organization pharmacovigilance database.

  Methods: We extracted all cases reporting the Medical Dictionary for Regulatory Activities term "Product substitution issue (PT)" for TNF-α inhibitors. Then, we analyzed and categorized all adverse events reported in more than 1% of cases. We compared the adverse events reported according to reporter qualification, type of switch, and type of TNF-α inhibitor using Chi2 tests. We conducted a network analysis coupled with a clustering approach to identify syndromes of co-reported adverse events.

  Results: In the World Health Organization pharmacovigilance database, 2543 cases and 6807 adverse events related to TNF-α inhibitor interchangeability have been reported up to October 2022. Injection-site reactions were the most reported adverse events with 940 cases (37.0%), followed by modifications in drug effect in 607 cases (23.9%). Musculoskeletal, cutaneous, and gastrointestinal disorders linked to the underlying disease were reported in 505 (20.0%), 145 (5.7%), and 207 (8.1%) cases, respectively. Adverse events non-related to the underlying disease were nonspecific (n = 458, 18.0%), neurologic (n = 224, 8.8%), respiratory (n = 132, 5.2%), and psychological disorders (n = 64, 2.5%). Injection-site reactions and infection-related symptoms (e.g., nasopharyngitis, urinary tract infection, lower respiratory tract infection) were more reported by non-healthcare professionals while adverse events related to reduced clinical efficacy (e.g., drug ineffective, arthralgia, psoriasis) were more reported by healthcare professionals. The proportions of injection-site reactions were higher when switching between biosimilars of the same reference product, but the proportions of adverse events related to reduced clinical efficacy (e.g., psoriasis, arthritis, psoriatic arthropathy) were more reported when switching from a reference product. The main differences in the proportions of reported cases between adalimumab, infliximab, and etanercept were driven by symptoms related to the underlying targeted diseases, except for a higher reporting rate of injection-site pain with adalimumab. Adverse events evocative of hypersensitivity reactions were reported in 192 (7.6%) cases. Most of the network clusters concerned non-specific adverse events or were related to reduced clinical efficacy.

  Conclusions: This analysis highlights the burden of patient-reported adverse events when interchanging between TNF-α inhibitor biosimilars, notably injection-site reactions, non-specific adverse events, and symptoms related to reduced clinical efficacy. Our study also highlights differences in reporting patterns between patients and healthcare professionals and depending on the type of switch. The results are limited by missing data, the lack of precision of the coded Medical Dictionary for Regulatory Activities terms, and by the variability of reporting rate of adverse events. Thus, incidence rates of adverse events cannot be inferred from these results.

Sodium-glucose cotransporter-2 inhibitors and cardiovascular safety profile: a pharmacovigilance analysis of the US food and drug administration adverse event reporting system

This analysis of spontaneous reports was conducted to assess the association between cardiac adverse events and exposure to SGLT2 inhibitors. The study period was 2013-2021. Disproportionality and Bayesian analyses were conducted using reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). The data source was FAERS.

While this study of spontaneous reports showed no association between cardiac adverse events and exposure to SGLT2 inhibitors, further research using a population-based data source and rigorous methodology are needed to fully elucidate the causal association.

Citation:

Zhang L, Pan C, Yang X, Jiang D, Cao M. Sodium-glucose cotransporter-2 inhibitors and cardiovascular safety profile: a pharmacovigilance analysis of the US food and drug administration adverse event reporting system. Expert Opin Drug Saf. 2023 May 26:1-8. doi: 10.1080/14740338.2023.2216453. Epub ahead of print. PMID: 37203199.

https://pubmed.ncbi.nlm.nih.gov/37203199/

• Abstract

  Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective in reducing the risk of heart failure (HF) in type 2 diabetic patients. We systematically examined the association between cardiac adverse events (CAEs) and SGLT2i.

  Research design and methods: We analyzed CAEs in the FDA Adverse Event Reporting System between January 2013 and March 2021. The CAEs were classified into four major groups according to their preferred terms. Disproportionality and Bayesian analyses were performed to detect signals using reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). Case seriousness was also described.

  Results: There were 2,330 CAEs associated with SGLT2i, and 81 were used for HFs. The SGLT2i were not associated with over-reporting frequencies of CAE based on ROR (ROR = 0.97, 95% confidence interval [CI]: 0.93, 1.01), PRR (PRR = 0.97, 95% CI: 0.94, 1.01), Bayesian confidence propagation neural network (IC = -0.04, IC025: N.A.), and multi-item gamma Poisson shrinker (EBGM = 0.97, EBGM05:0.94), unless further restricted to myocardial infarction (ROR = 2.03, 95% CI = 1.89, 2.17). Additionally, SGLT2i-associated CAEs are associated with 11.33% fatality and 51.25% hospitalization.

  Conclusions: SGLT2i present a favorable cardiac safety profile; however, concerns should be raised regarding their potential association with specific events.

Concomitant use of statins and sodium-glucose co-transporter 2 inhibitors and the risk of myotoxicity reporting: A disproportionality analysis

This research topic is near and dear to my heart. During my doctoral program, I spent five years studying the clinical importance of the drug interaction between statins and exposure to concomitant medications which inhibit statin metabolism.

This analysis of spontaneous reports was conducted to describe the risk of myotoxicity associated with concomitant exposure to SGLT2 inhibitors and statins. Similar to my dissertation research, the authors evaluated classic statin-related adverse events (i.e., myopathy and rhabdomyolysis). They also conducted sensitivity important analyses restricted to specific statin-SGLT2 inhibitor pairs with the highest interaction potential and accounted for stimulated reporting in the analyses.

In the disproportionality analyses, the authors observed no increased risk of myopathy or rhabdomyolysis with concomitant exposure to SGLT2 inhibitors and statins. The pairs with higher interaction potential produced potential signals for rhabdomyolysis; however, these signals disappeared after accounting for stimulated reporting.

While this study of spontaneous reports showed no increased risk of statin-related adverse events with concomitant exposure to statins with SGLT2 inhibitors, further research using a population-based data source and rigorous methodology are needed to fully elucidate the causal association.

Citation:

Gravel CA, Krewski D, Mattison DR, Momoli F, Douros A. Concomitant use of statins and sodium-glucose co-transporter 2 inhibitors and the risk of myotoxicity reporting: A disproportionality analysis. Br J Clin Pharmacol. 2023 Mar 13. doi: 10.1111/bcp.15711. Epub ahead of print. PMID: 36912450.

https://pubmed.ncbi.nlm.nih.gov/36912450/

• Details

  Aims: Recent case reports have suggested that sodium-glucose co-transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins.

  Methods: We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two-criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor-statin pairs with higher interaction potential (canagliflozin-rosuvastatin, empagliflozin-rosuvastatin) and accounted for stimulated reporting.

  Results: There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor-statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting.

  Conclusion: There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs

Ocular adverse events associated with BRAF and MEK inhibitor combination therapy: a pharmacovigilance disproportionality analysis of the FDA adverse event reporting system

This analysis of spontaneous reports was conducted to describe and compare ocular adverse events (oAEs) following combination therapy with BRAF plus MEK inhibitors (BRAFi+MEKi) using the FDA Adverse Event Reporting System (FAERS). The BRAFi+MEKi combination therapies, included vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B).

In the disproportionality analyses, the study authors found a number of positive oAE signals - many of which were not previously identified in clinical trials. The oAEs included: chorioretinopathy, detachment of retinal pigment epithelium, retinal detachment, serous retinal detachment, retinopathy, and serous retinopathy and were consistent for all BRAFi+MEKi combinations.

Further studies using population-based data sources and rigorous methodology are needed to fully elucidate the causal associations between BRAFi+MEKi combination therapies and oAEs. Additionally, future investigations may strive to better discriminate the risk of oAEs by each BRAFi+MEKi combination.

Citation:

Huang S, Guo Z, Wang M, She Y, Ye X, Zhai Q, Liu J, Du Q. Ocular adverse events associated with BRAF and MEK inhibitor combination therapy: a pharmacovigilance disproportionality analysis of the FDA adverse event reporting system. Expert Opin Drug Saf. 2023 Feb;22(2):175-181. doi: 10.1080/14740338.2023.2189235. Epub 2023 Mar 10. PMID: 36896641.

https://pubmed.ncbi.nlm.nih.gov/36896641/

• Details

  Background: BRAF and MEK inhibitor combination therapy have significantly improved the outcome of several BRAF-mutation tumors, but it also confers the risk of drug-induced ocular adverse events (oAEs). However, very few studies focused on this risk.

  Methods: The United States Food and Drug Administration Adverse Event Reporting System (FAERS) data from Quarter 1-2011 to Quarter 2-2022 were searched to detect signs of oAEs of three marketed BRAF and MEK inhibitor combination therapies: vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B). Disproportionality analyses were performed by calculating the proportional reporting ratio (PRR), χ2 (chi-square), and reporting odds ratios (RORs) with a 95% confidence interval (CI).

  Results: A series of oAEs were identified, including 42 preferred terms, which could be classified into 8 aspects. In addition to previously reported oAEs, several unexpected oAE signals were detected. Moreover, differences in oAE profiles were found among three combination therapies (V + C, D + T, and E + B).

  Conclusions: Our findings support an association between several oAEs and BRAF and MEK inhibitor combination therapies, including several new oAEs. In addition, oAEs profiles may vary across the treatment regimens. Further studies are needed to better quantify these oAEs.

Severe Hypersensitivity Reactions at Biosimilar versus Originator Rituximab Treatment Initiation, Switch and Over Time: A Cohort Study on the French National Health Data System

This rigorous population-based cohort study was conducted to estimate the association between hospitalized hypersensitivity reactions (i.e., anaphylactic shock or serum sickness) and biosimilar rituximab versus originator rituximab using the French National Health Data System (SNDS).

Using a variety of appropriate analytic methods and sensitivity analyses, the authors reported no increased risk of hospitalized hypersensitivity reactions for patients exposed to biosimilar rituximab versus originator rituximab.

The study findings are consistent with other published studies that also observed no difference in AE risk (e.g., immunogenicity) between biosimilar monoclonal antibodies or fusion proteins and originator products. That said, the incidence of the outcome event was relatively rare (<0.5%) which may have, impart, limited the precision to detect a true difference. To mitigate this limitation, researchers may consider including hypersensitivity reactions identified in the emergency department and death as part of the outcome definition.

Citation:

Jourdain H, Hoisnard L, Sbidian E, Zureik M. Severe Hypersensitivity Reactions at Biosimilar versus Originator Rituximab Treatment Initiation, Switch and Over Time: A Cohort Study on the French National Health Data System. BioDrugs. 2023 Mar 6. doi: 10.1007/s40259-023-00584-8. Epub ahead of print. PMID: 36877448.

https://pubmed.ncbi.nlm.nih.gov/36877448/

• Details

  Background: Biosimilar products of rituximab came to market in 2017. French pharmacovigilance centers have highlighted an excess of case reports of severe hypersensitivity reactions related to their use compared with the originator product.

  Objective: The aim of this study was to assess the real-world association between biosimilar versus originator rituximab injections and hypersensitivity reactions, among initiators and switchers, at first injection and over time.

  Methods: The French National Health Data System was used to identify all rituximab users between 2017 and 2021. A first cohort consisted of patients who initiated rituximab (originator or biosimilar), while a second cohort consisted of originator-to-biosimilar switchers, matched on age, sex, deliveries history, and pathology, with one or two patients still receiving the originator product. The event of interest was defined as a hospitalization for anaphylactic shock or serum sickness following a rituximab injection.

  Results: A total of 91,894 patients were included in the initiation cohort-17,605 (19%) with the originator product and 74,289 (81%) with a biosimilar. At initiation, 86/17,605 (0.49%) and 339/74,289 (0.46%) events occurred in the originator and biosimilar groups, respectively. The adjusted odds ratio of biosimilar exposure associated with the event was 1.04 (95% confidence interval [CI] 0.80-1.34), and the adjusted hazard ratio for biosimilar versus originator exposure was 1.15 (95% CI 0.93-1.42), showing no increased risk of event with biosimilar use at first injection, and over time. 17,123 switchers were matched to 24,659 non-switchers. No association was found between switch to biosimilars and occurrence of the event.

  Conclusion: Our study does not support any association between exposure to rituximab biosimilars versus originator and hospitalization for a hypersensitivity reaction, either at initiation, at switch, or over time.

Sodium-glucose co-transporter-2 inhibitor (SGLT2i) treatment and risk of osteomyelitis: A pharmacovigilance study of the FAERS database

This signal detection study was conducted to assess the risk of osteomyelitis and other known diabetes related adverse events following treatment with hypoglycemic medications including Sodium-glucose co-transporter-2 inhibitors (SGLT2i) as well as biguanides, dipeptidyl peptidase-4 (DPP4), glinides (GLN), glucagon-like peptide 1 (GLP-1), sulfonylureas (SUs), and thiazolidinediones (TZDs) using the US FDA Adverse Event Reporting System database (FAERS)

In the disproportionality, signal detection analyses, the authors reported moderate or strong adverse event signals of ketoacidosis, amputation, Fournier’s gangrene, UTI, skin ulcer, peripheral ischemia, acute kidney injury following treatment with SGLT2 inhibitors. However, the strongest adverse event signal for osteomyelitis was found to be unique to canagliflozin.

Given the substantial limitations of spontaneous reporting data, further research is warranted to evaluate the causal association between SGLT2 inhibitors, especially canagliflozin, and osteomyelitis using more robust research methodology and a population based data source.

Citation:

Zhao H, Li ZR, Zhang Q, Zhong MK, Yan MM, Qiu XY. Sodium-glucose co-transporter-2 inhibitor (SGLT2i) treatment and risk of osteomyelitis: A pharmacovigilance study of the FAERS database. Front Pharmacol. 2023 Feb 14;14:1110575. doi: 10.3389/fphar.2023.1110575. PMID: 36865915; PMCID: PMC9971937.

https://pubmed.ncbi.nlm.nih.gov/36865915/

• Details

  Background and purpose: Several clinical trials have indicated that the use of canagliflozin increases the risk of lower extremity amputation. Although the US Food and Drug Administration (FDA) has withdrawn its black box warning about amputation risk for canagliflozin, the risk still exists. We sought to estimate the association between hypoglycemic medications, especially sodium-glucose co-transporter-2 inhibitors (SGLT2is), and adverse events (AEs) before the irreversible outcome of amputation as a promising early warning, based on the FDA Adverse Event Reporting System (FAERS) data.

  Methods: Publicly available FAERS data were analyzed using a reporting odds ratio (ROR) method and validated by a Bayesian confidence propagation neural network (BCPNN) method. The developing trend of the ROR was investigated by a series of calculations based on the accumulation of data in the FAERS database quarter by quarter.

  Results: Ketoacidosis, infection, peripheral ischemia, renal impairment, and inflammation including osteomyelitis might be more likely to occur among users of SGLT2is, especially canagliflozin. Osteomyelitis and cellulitis are AEs unique to canagliflozin. Among 2,888 osteomyelitis-related reports referring to hypoglycemic medications, 2,333 cases were associated with SGLT2is, with canagliflozin accounting for 2,283 of these cases and generating an ROR value of 360.89 and a lower limit of information component (IC025) of 7.79. No BCPNN-positive signal could be generated for drugs other than insulin and canagliflozin. Reports suggesting that insulin could generate BCPNN-positive signals span from 2004 to 2021, whereas reports with BCPNN-positive signals emerged only since the second quarter (Q2) of 2017, 4 years since the approval of SGLT2is in Q2 of 2013, for canagliflozin and drug groups containing canagliflozin.

  Conclusion: This data-mining investigation revealed a strong association between canagliflozin treatment and developing osteomyelitis that might be a crucial forewarning to lower extremity amputation. Further studies with updated data are needed to better characterize the risk of osteomyelitis associated with SGLT2is.

COVID-19 Vaccination and the Incidence of De Novo or Recurrent Rheumatoid Arthritis: A French and International (VigiBase) Signal Detection Study

A descriptive study conducted using the French Pharmacovigilance Database (FPVD) to assess the risk of de novo RA and RA flares following COVID-19 vaccination (compared with the other nonlive vaccines) using the “case-nocase” method.

The authors found no increased risk of RA (de novo or flare) after COVID-19 vaccination compared with other nonlive vaccines.

Given the substantial limitations of spontaneous reporting data, further research is warranted to evaluate the causal association between COVID-19 vaccination and RA using more robust research methodology.

Citation:

Prontskus V, Fresse A, Yelehe-Okouma M, Facile A, Pietri T, Simon C, Le Souder C, Beurrier M, Gillet P; French network of Regional Pharmacovigilance Centres. COVID-19 Vaccination and the Incidence of De Novo or Recurrent Rheumatoid Arthritis: A French and International (VigiBase) Signal Detection Study. Clin Pharmacol Ther. 2023 Feb 8. doi: 10.1002/cpt.2866. Epub ahead of print. PMID: 36752604.

https://pubmed.ncbi.nlm.nih.gov/36752604/

• Details

  COVID-19 vaccination is critical in frequently immunocompromised patients with rheumatoid arthritis (RA). However, there is a question about the risk of RA flares following vaccination. Our study intended to find out about cases of new RA or flare-ups in people who already had RA that were reported in French and international pharmacovigilance databases after COVID-19 vaccination. We performed a "case-noncase" method in the international pharmacovigilance database VigiBase to identify the risk of RA following COVID-19 vaccination compared with other nonlive vaccines. Using the French Pharmacovigilance Database (FPVD), a descriptive analysis was carried out for RA cases after COVID-19 immunization and a multivariate logistic regression analysis was conducted to compare variables in the new-onset vs. flare-up groups. In 2021, 2,387 cases of RA were reported from 2,817,902 adverse drug reactions associated with COVID-19 vaccines recorded in VigiBase. The reporting odds ratio of RA onset with COVID-19 vaccines compared with the other nonlive vaccines was 0.66 (P < 0.0001). The FPVD reported 161 cases of RA with COVID-19 vaccines, including 77 new-onset RA and 84 cases of RA flare-up. In 88 cases (84.7%), RA occurred after the first dose. The mean time between vaccination and disease onset was 14 ± 21 days, and the delay was significantly shorter in the flare-up group. We do not show a higher risk of RA after COVID-19 vaccination compared with other nonlive vaccines in adults. De novo RA was more likely to happen quickly, be more severe, and have a worse outcome than flares in patients with RA.

Gastrointestinal perforation associated with novel antineoplastic agents: A real-world study based on the FDA Adverse Event Reporting System

The study authors used the FDAs spontaneous reporting system (FAERS) to assess safety signals of gastrointestinal perforation, a potentially fatal adverse event, following exposure to novel antineoplastic agents (e.g., anti-VEGF/VEGFR agents, anti-EGFR drugs, ICIs).

The authors found bevacizumab, cetuximab and lenvatinib had the most frequent and strongest safety signal for gastrointestinal perforation.

Given the substantial limitations of spontaneous reporting data, further research is warranted to evaluate the causal association between gastrointestinal perforation and novel antineoplastic agents using more robust research methodology.

Yu Z, Zhu H, Chen H, Zhu L, Liao X. Gastrointestinal perforation associated with novel antineoplastic agents: A real-world study based on the FDA Adverse Event Reporting System. J Pharm Pharm Sci. 2023 Feb 15;26:11235. doi: 10.3389/jpps.2023.11235. PMID: 36942297; PMCID: PMC9990630.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9990630/

• Details

  Purpose: Gastrointestinal perforation (GIP) is a fatal adverse event (AE). The AE of GIP induced by novel antineoplastic agents has attracted attention recently. We aimed to explore the AE signals of GIP related to novel antineoplastic agents comprehensively based on the FDA Adverse Event Reporting System (FAERS).

  Methods: The FAERS database containing 71 quarters of records was used for analysis. Reporting odds ratio (ROR), information component (IC), and empirical Bayesian geometric mean (EBGM) were utilized to evaluate the signals of GIP associated with novel antineoplastic drugs. Standardization of drug names was by employing MedEx-UIMA software and Python. Data analysis and visualization were performed using MySQL Workbench and R software.

  Results: After cleaning and handling the data, 5226 GIP cases were identified that were associated with new antineoplastic medications, where these agents were the main suspected contributors. A total of 37 novel antineoplastic drugs were detected with signals of GIP for ROR and IC. Only 22 drugs showed statistically significant signals for EBGM. We found the GIP signals of 22 novel antineoplastic drugs overlapped for the 3 indicators, including anti-vascular endothelial growth factor/vascular endothelial growth factor receptor, anti-endothelial growth factor receptor, immune checkpoint inhibitors, and so on.

  Conclusion: The potential risk of GIP associated with several novel antineoplastic agents was identified through data mining, which provided valuable information on the safety risks associated with GIP among these drugs. The potential threat of GIP should be recognized and managed properly when using these novel antineoplastic agents.

Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system

A hypothesis generating study used spontaneous reporting data (FAERS) to evaluate methotrexate related adverse events (interstitial lung disease, hepatotoxicity, myelosuppression and infection) with and without concomitant treatment with folic acid and TNF inhibitors.

The authors found the adverse event signals for hepatotoxicity and myelosuppression were diminished when methotrexate was co-administered with folic acid or TNF inhibitors.

Given the substantial limitations of spontaneous reporting data, further research is warranted to evaluate this relationship using more robust research methodology.

https://pubmed.ncbi.nlm.nih.gov/36909171/

Onda K, Honma T, Masuyama K. Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system. Front Pharmacol. 2023 Feb 22;14:1030832. doi: 10.3389/fphar.2023.1030832. PMID: 36909171; PMCID: PMC9992735.

• Details

  Methotrexate (MTX) is an essential anti-rheumatic drug used to treat rheumatoid arthritis (RA). Prevention or management of adverse reactions, including interstitial lung disease (ILD), hepatotoxicity, myelosuppression, and infection, remains fundamental for safe MTX therapy. Using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) (JAPIC AERS), we performed disproportionality analyses of adverse events related to MTX use and the impact of concomitant medications. Upon analyzing all reported cases in FAERS between 1997 and 2019, the crude reporting odds ratios (cRORs; 95% confidence intervals) for ILD, hepatotoxicity, myelosuppression, and tuberculosis (TB) in relation to MTX use were 4.00 (3.83-4.17), 1.99 (1.96-2.02), 3.66 (3.58-3.74), and 7.97 (7.65-8.3), respectively. Combining MTX with folic acid (FA) or tumor necrosis factor-alpha inhibitors (TNFis) tended to reduce cRORs for these adverse events (except for TB). Multiple logistic regression analysis in patients with RA was conducted to calculate adjusted reporting odds ratios (aRORs) for age, sex, and MTX treatment patterns (MTX alone and combined with FA and TNFi). Higher age (except for hepatotoxicity) and male sex were significantly associated with adverse events. Combining FA or TNFi with MTX reduced aRORs for MTX-related hepatotoxicity and myelosuppression; in contrast, the effect of FA was not obvious in ILD or TB. Although studies assessing spontaneous reporting systems have limitations such as reporting bias, data from our logistic regression analysis demonstrated that adding FA to MTX-based therapy could help reduce the dose-dependent adverse events of MTX, thereby providing clinical evidence that supports the beneficial effect of FA. This study also demonstrated the usefulness of FAERS in comparing adverse events based on treatment patterns.

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases

An interesting, hypothesis generating study that evaluated the risk of rhabdo with PPIs in two data sources (FAERS and MDV from Japan). They also assessed potential effect modification when the PPI was given concomitantly with a statin or fibrate - presumably because of a CYP3A4 drug-drug interaction. Histamine-2 blockers were used as the comparator.

They used statistical methods that seem too rigorous for spontaneous reporting data. That said, they found PPI exposure was associated with an increased risk of rhabdo in both data sets.

Given the substantial limitations of spontaneous reporting data, further research is warranted to evaluate this relationship.

https://pubmed.ncbi.nlm.nih.gov/36847276/

Mitsuboshi S, Hamano H, Kuniki Y, Niimura T, Chuma M, Ushio S, Lin TJ, Matsumoto J, Takeda T, Kajizono M, Zamami Y, Ishizawa K. Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases. Ann Pharmacother. 2023 Feb 27:10600280231156270. doi: 10.1177/10600280231156270. Epub ahead of print. PMID: 36847276.

• Details

  Background: It is unclear whether use of a proton pump inhibitors (PPIs) increases the risk of rhabdomyolysis.

  Objective: To clarify whether use of PPIs increases the risk of rhabdomyolysis.

  Methods: This cross-sectional study analyzed data entered into the Medical Data Vision (MDV) database in Japan and into the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). The MDV data were analyzed to evaluate the association between use of PPIs and rhabdomyolysis. Then, the FAERS data were analyzed to evaluate whether the risk of rhabdomyolysis was increased further when a statin or fibrate was used concomitantly with a PPI. In both analyses, histamine-2 receptor antagonist was set as a comparator because it is used to treat gastric disease. In the MDV analysis, Fisher's exact test and multiple logistic regression analysis were performed. In the FAERS analysis, a disproportionality analysis using Fisher's exact test and multiple logistic regression analysis were performed.

  Results: Multiple logistic regression analysis of both databases showed a significant association between use of PPIs and an increased risk of rhabdomyolysis (odds ratio [OR] = 1.74-1.95, P ≤ 0.01). However, use of a histamine-2 receptor antagonist was not significantly associated with increased risk of rhabdomyolysis. In the sub-analysis of the FAERS data, use of a PPI did not increase the risk of rhabdomyolysis in patients receiving a statin.

  Conclusion and relevance: The data in 2 separate databases consistently suggest that PPIs may increase the risk of rhabdomyolysis. The evidence for this association should be assessed in further drug safety studies.

Drugs That Interact With Colchicine Via Inhibition of Cytochrome P450 3A4 and P-Glycoprotein: A Signal Detection Analysis Using a Database of Spontaneously Reported Adverse Events (FAERS)

An important hypothesis generating study evaluating safety signals associated with colchicine and concomitant exposure to CYP3A4 and p-glycoprotein inhibitors.

Further research is warranted to fully elucidate this relationship.

https://pubmed.ncbi.nlm.nih.gov/36688283/

Gómez-Lumbreras A, Boyce RD, Villa-Zapata L, Tan MS, Hansten PD, Horn J, Malone DC. Drugs That Interact With Colchicine Via Inhibition of Cytochrome P450 3A4 and P-Glycoprotein: A Signal Detection Analysis Using a Database of Spontaneously Reported Adverse Events (FAERS). Ann Pharmacother. 2023 Jan 23:10600280221148031. doi: 10.1177/10600280221148031. Epub ahead of print. PMID: 36688283.

• Details

  Background: Colchicine has a narrow therapeutic index. Its toxicity can be increased due to concomitant exposure to drugs inhibiting its metabolic pathway; these are cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp).

  Objective: To examine clinical outcomes associated with colchicine drug interactions using the spontaneous reports of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).

  Methods: We conducted a disproportionality analysis using FAERS data from January 2004 through June 2020. The reporting odds ratio (ROR) and observed-to-expected ratio (O/E) with shrinkage for adverse events related to colchicine's toxicity (ie, rhabdomyolysis/myopathy, agranulocytosis, hemorrhage, acute renal failure, hepatic failure, arrhythmias, torsade de pointes/QT prolongation, and cardiac failure) were compared between FAERS reports.

  Results: A total of 787 reports included the combined mention of colchicine, an inhibitor of both CYP3A4 and P-gp drug, and an adverse event of interest. Among reports that indicated the severity, 61% mentioned hospitalization and 24% death. A total of 37 ROR and 34 O/E safety signals involving colchicine and a CYP3A4/P-gp inhibitor were identified. The strongest ROR signal was for colchicine + atazanavir and rhabdomyolysis/myopathy (ROR = 35.4, 95% CI: 12.8-97.6), and the strongest O/E signal was for colchicine + atazanavir and agranulocytosis (O/E = 3.79, 95% credibility interval: 3.44-4.03).

  Conclusion and relevance: This study identifies numerous safety signals for colchicine and CYP3A4/P-gp inhibitor drugs. Avoiding the interaction or monitoring for toxicity in patients when co-prescribing colchicine and these agents is highly recommended.

  https://pubmed.ncbi.nlm.nih.gov/36688283/

Patient-centered pharmacovigilance: priority actions from the inherited bleeding disorders community

Let’s not forget the patient when conducting pharmacovigilance…

• Details

  Pharmacovigilance, the science and practice of monitoring the effects of medicinals and their safety, is the responsibility of all stakeholders involved in the development, manufacture, regulation, distribution, prescription, and use of drugs and devices. The patient is the stakeholder most impacted by and the greatest source of information on safety issues. It is rare, however, for the patient to take a central role and exert leadership in the design and execution of pharmacovigilance. Patient organizations in the inherited bleeding disorders community are among the most established and empowered, particularly in the rare disorders. In this review, two of the largest bleeding disorders patient organizations, Hemophilia Federation of America (HFA) and National Hemophilia Foundation (NHF), offer insights into the priority actions required of all stakeholders to improve pharmacovigilance. The recent and ongoing increase in incidents raising safety concerns and a therapeutic landscape on the cusp of unprecedented expansion heighten the urgency of a recommitment to the primacy of patient safety and well-being in drug development and distribution.

  https://pubmed.ncbi.nlm.nih.gov/36861041/

What Factors Make EU Regulators Want to Communicate Drug Safety Issues Related to SGLT2 Inhibitors? An Online Survey Study

An interesting study to better understand how drug safety regulators view the need to communicate safety issues related to sodium-glucose cotransporter-2 (SGLT2) inhibitors

• Details

  Introduction: Previous studies have found differences in the communication of safety issues among medicines regulatory agencies.

  Objectives: To explore (1) to what extent regulators' opinions regarding the need to communicate safety issues related to sodium-glucose cotransporter-2 (SGLT2) inhibitors might be influenced by their concern about the safety issue, and (2) whether regulators' concerns might be influenced by certain characteristics of the safety issue or by the demographic and professional characteristics and attitudes of the regulators.

  Methods: An online cross-sectional survey study with a rating-based conjoint analysis among clinical and pharmacovigilance assessors from the EU regulatory network was performed between April and June 2021. Regulators were invited by email, and participants were asked about their level of concern and their opinion regarding the need to communicate about 12 scenarios defined by four characteristics: adverse drug reaction, source of information, causality, and frequency. The outcomes for the first objective were to update the summary of product characteristics (SmPC; yes/no) and to send direct healthcare professional communications (DHPC; yes/no). The determinant was regulators' level of concern (range 0-100%). The outcome of the second objective was regulators' level of concern, and the determinants were the characteristics of the safety issue, demographic and professional characteristics, and attitudes of the regulators (beliefs about medicines and risk perception).

  Results: A total of 222 regulators completed the survey (64% women; mean age 46 ± 10 years). Depending on the scenario, 54-94% and 25-74% of the participants would update the SmPC or send a DHPC, respectively. The participants' level of concern influenced their opinions regarding the need to update the SmPC and send a DHPC (odds ratio (OR) 13.0; 95% confidence interval (CI) 7.8-21.7 and OR 13.6; 95% CI 9.5-19.2, respectively, for every 10% increase in the level of concern). All characteristics of the safety issue influenced the level of concern. Younger participants, women, and those working for Eastern European agencies had a higher level of concern than older participants, men, and those working in other regions. Beliefs about medicines and general risk perception also influenced their concern.

  Conclusions: The opinion regarding the need to communicate safety issues was influenced by the concern of regulators. Regulators' concern was influenced by the characteristics of the safety issue, demographic characteristics, and attitudes. Diverse groups of experts regarding such factors would ensure that various views are incorporated in risk communication decisions.

  https://pubmed.ncbi.nlm.nih.gov/36790560/

Hepatitis B virus reactivation associated with Janus kinase (JAK) inhibitors: a retrospective study of pharmacovigilance databases and review of the literature

An important hypothesis generating study regarding the potential risk of hepatitis B virus reactivation associated with Janus kinase (JAK) inhibitors

• Details

  Background: Recently, there have been clinical reports of hepatitis B virus reactivation (HBVr) related with Janus kinase (JAK) inhibitors. However, there were no studies to investigate the association between HBVr and different JAK inhibitors.

  Research design and methods: This study was a retrospective review utilizing the FAERS pharmacovigilance database and a systematic literature search for all cases of HBVr reported with JAK inhibitors. Disproportionality analysis and Bayesian analysis were used in data detection to screen the suspected HBVr after the administration of different JAK inhibitors, based on based on the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database from Q4 2011 to Q1 2022.

  Results: There was a total number of 2097 (0.02%) reports of HBVr in FAERS, of which 41 (1.96%) were associated with JAK inhibitors. Baricitinib appeared to have the strongest signal among four JAK inhibitors, based on the highest reporting odds ratio (ROR=4.45, 95% confidence interval [CI] 1.67-11.89). Ruxolitinib also showed signals, whereas no signals were detected among Tofacitinib and Upadacitinib. In addition, 23 cases developed JAK inhibitors associated HBVr in 11 independent studies were also summarized.

  Conclusion: While there may be an association between JAK inhibitors and HBVr, it appears to be a numerically uncommon occurrence. Further studies are needed to optimize the safety profiles of JAK inhibitors.

  https://pubmed.ncbi.nlm.nih.gov/36794347/

Myopericarditis Associated with the Novavax COVID-19 Vaccine (NVX-CoV2373): A Retrospective Analysis of Individual Case Safety Reports from VigiBase

An important hypothesis generating study regarding the potential risk of Myopericarditis following treatment with Novavax (NVX-CoV2373)

• Details

  Background: Myocarditis and pericarditis have been associated most notably with mRNA vaccines, but the association with a recently authorized adjuvated vaccine (NVX-CoV2373) is controversial.

  Objective: The aim was to analyze the cases of myocarditis and pericarditis in association with NVX-CoV2373 reported to the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase), applying disproportionality analyses.

  Patients and methods: The main characteristics of the ICSRs reporting myopericarditis with NVX-CoV2373 have been summarized. Reporting odds ratios (RORs) as a measure of disproportionality for reported myopericarditis (November 1967-August 2022) have been calculated for NVX-CoV2373; mRNA and adenoviral vector-based vaccines were also included as a reference.

  Results: In total, 61 ICSRs included NVX-CoV2373. Most of the reports originated in Australia (50; 82.0%); 24 (39.3%) were considered serious. None of them were fatal. The median age of individuals was 35.5 years old, and most were males (38; 62.3%). Chest pain was the most common co-reported event 43 (70.5%). The median induction period was 3 days after immunization. Increased disproportionality for myopericarditis was found for NVX-CoV2373 (ROR 14.47, 95% confidence interval [CI] 11.22-18.67) and mRNA vaccines: BNT162b2 (ROR 17.15, 95% CI 16.88-17.42) and mRNA-1273 (ROR 6.92, 95% CI 6.77-7.08). Higher values were found in males. The adenoviral vector-based vaccine Ad26.COV2.S showed slightly increased disproportionality (ROR 1.83, 95% CI 1.70-1.98), whereas no increased disproportionality was found for ChAdOx1.

  Conclusions: NVX-CoV2373 vaccine showed a similar increased disproportionality as mRNA vaccines. More evidence from controlled studies is necessary; however, a precautionary approach is warranted. Healthcare professionals should be aware of the potential occurrence of myopericarditis with this new vaccine.

  https://pubmed.ncbi.nlm.nih.gov/35987197/