Calcitonin gene-related peptide-targeting drugs and Raynaud's phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database.

BACKGROUND: Migraine is responsible for significant disability and societal burden. Recently, drugs targeting the calcitonin gene-related peptide (CGRP) pathway raised new hopes. CGRP, a potent vasodilator, plays a key role in the pathogenesis of migraine attacks. The deficiency of CGRP is involved in Raynaud's phenomenon, which consists of abnormal vasoconstriction of the digits. We aimed to assess the potential association of Raynaud's phenomenon with CGRP-targeting drugs, analyzing real-world data from the World Health Organization (VigiBase®). METHODS: We queried all reports of Raynaud's phenomenon involving a CGRP-targeting drug. We sought disproportionate reporting of Raynaud's phenomenon with these drugs. For this purpose, we relied on the calculation of the Information Component (IC). A positive lower end of the 95% confidence interval (CI) of the IC defines a statistically significant association. As migraine patients are prone to Raynaud's phenomenon, we also calculated the IC of Raynaud's phenomenon with CGRP-targeting drugs compared to 5HT1B/D agonists (triptans), and beta-blockers used in the treatment of migraine. RESULTS: Overall, 99 reports of Raynaud's phenomenon involving CGRP-targeting drugs have been yielded in VigiBase®. The most reported CGRP-targeting drug was erenumab, with 56 reports (56.6%). The median time to onset was 84 days. No fatality was notified, but one patient suffered from gangrene and extremity necrosis. As a whole, CGRP-targeting drugs were significantly associated with Raynaud's phenomenon, with an IC of 3.3 (95%CI: 3.0-3.5). There was a disproportionate reporting of Raynaud's phenomenon with CGRP-targeting drugs compared to triptans (IC 0.4; 95%CI: 0.1-0.6) and to beta-blockers (IC 0.5; 95%CI: 0.2-0.7) as well. CONCLUSIONS: There is a significant disproportionality signal of Raynaud's phenomenon with CGRP-targeting. This signal stands out when CGRP-targeting drugs are compared to other drugs used in patients with migraine. This study is limited by missing data in pharmacovigilance reports. CGRP-targeting drugs may be subject to Weber effect and reporting bias. Nonetheless, CGRP blockade might be the last straw that disrupts the physiological balance of vascular response in patients at-risk of Raynaud's phenomenon. Pending further data regarding vascular safety of CGRP-targeting drugs, caution is warranted in these patients.

Are current guidelines adapted for patient eligibility to PrEP? A case report.

BACKGROUND: Despite effective antiretroviral therapy developed over the last decade, HIV infection remains a major worldwide public health problem. Recently, a promising preventive treatment has been made available for HIV prophylaxis, PrEP for pre-ExPosure Prophylaxis. Indeed, it was shown to significantly reduce the risk of HIV infection in patients exposed to high risk of infection such as men having sex with men (MSM), heterosexuals and people who inject drugs. Several issues pertaining to PrEP remain uncertain including short and long-term adverse events, drug resistance, risk compensation and resurgence of other sexually transmitted infections. CASE PRESENTATION: We report a case of a 52-year-old MSM eligible for PrEP as he was exposed to a high risk of HIV infection, presented no clinical symptoms of HIV primary infection and was seronegative for HIV. PrEP therapy was then initiated with fixed association of emtricitabine-tenofovir disoproxil. One month later, HIV tests using two different assays were positive, despite perfect compliance reported by the patient and confirmed by plasma drug level. A retrospective search for plasma viral RNA in the blood sample before PrEP initiation turned out positive. Genotyping and treatment sensitivity performed on sample after one month of PrEP showed a virus resistance to lamivudine and emtricitabine. Similar cases in the literature and pivotal studies have reported HIV infections in patients initiating or undergoing PrEP. These patients where either infected but still seronegative, displaying no clinical symptoms upon enrollment, or became infected during PrEP. Reasons are mainly poor compliance to treatment, resistance to PrEP, and lack of diagnosis before PrEP. Guidelines advocate safe sex behavior before initiation, search for clinical signs of HIV primary infection and two different serologic tests performed with one-month interval. DISCUSSION AND CONCLUSIONS: Our patient newly HIV infected received PrEP as he was still seronegative. Current recommendations fail to screen recently HIV infected, but still seronegative patients who are initiating PrEP. This issue raises strong concerns regarding the lack of adequate selection for eligibility to PrEP and may contribute to exposing partners to HIV infection and select viral mutations. Infection risk could be minimized by search for plasma viral HIV RNA at pre-inclusion, at least for patients suspected of unsafe behaviors such as non-respect of the non-exposure period before PrEP initiation.

The Neuropsychiatric Safety Profile of Lasmiditan: A Comparative Disproportionality Analysis with Triptans.

Migraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT1B/1D receptor agonists, remain the first-line treatment, despite discouraged use in individuals at high cardiovascular risk. Lasmiditan, a selective lipophilic 5-HT1F agonist without vasoconstrictive effects, is an emerging option. We aimed to investigate the safety profile of lasmiditan in the WHO pharmacovigilance database (VigiBase®) using a comparative disproportionality analysis with triptans. VigiBase® was queried for all reports involving lasmiditan and triptans. Disproportionality analyses relied on the calculation of the information component (IC), for which 95% confidence interval (CI) lower bound positivity was required for signal detection. We obtained 826 reports involving lasmiditan. Overall, 10 adverse drug reaction classes were disproportionately reported with triptans, while only neurological (IC 1.6; 95% CI 1.5-1.7) and psychiatric (IC 1.5; 95% CI 1.3-1.7) disorders were disproportionately reported with lasmiditan. Sedation, serotonin syndrome, euphoric mood, and autoscopy had the strongest signals. When compared with triptans, 19 out of 22 neuropsychiatric signals persisted. The results of our analysis provide a more precise semiology of the neuropsychiatric effects of lasmiditan, with symptoms such as autoscopy and panic attacks. The cardiovascular adverse drug reaction risk with triptans was confirmed. In contrast, caution is warranted with lasmiditan use in patients with neurological or psychiatric comorbidities or serotonin syndrome risk. Our study was hindered by pharmacovigilance flaws, and further studies should help in validating these results. Our findings suggest that lasmiditan is a safe alternative for migraine treatment, especially when the neuropsychiatric risk is outweighed by the cardiovascular burden.

COVID-19 Vaccine-Associated Transient Global Amnesia: A Disproportionality Analysis of the WHO Safety Database.

Coronavirus disease 2019 (COVID-19) spread rapidly, resulting in a global pandemic for which vaccines were quickly developed. As their safety continues to be monitored, cases of transient global amnesia (TGA) following mRNA vaccination with elasomeran have been reported. TGA is characterized by sudden onset of anterograde amnesia with preservation of other cognitive functions and resolution within 24 h. We aimed to investigate the potential link of TGA with COVID-19 vaccines. We queried the World Health Organization VigiBase® for all reports of "Transient global amnesia", up to 6 December 2021. Disproportionality analysis relied on the Reporting Odds Ratio (ROR) with its 95% Confidence Interval (CI) and the Information Component (IC). A positive lower end of the 95% CI of the IC (IC025) is used to statistically detect a signal. Of all TGA cases, 289 were associated with a COVID-19 vaccine, representing the most frequent association. Tozinameran was mostly represented (147, 50.8%), followed by AZD1222 (69, 23,8%), elasomeran (60, 20.8%), and JNJ-78436735 (12, 4.2%). With an IC025 > 0, COVID-19 vaccines showed a significant ROR (5.1; 95%CI 4.4-6.0). Tozinameran reached the strongest ROR (4.6; 95%CI 3.9-5.0), followed by elasomeran (4.4; 95%CI 3.4-6.0), AZD1222 (3.8; 95%CI 3.0-5.0), and JNJ-78436735 (3.7; 95%CI 2.1-6.0). Our analysis of COVID-19 vaccines-related TGA reports shows significant disproportionality. Cerebrovascular, inflammatory, or migrainous mechanisms may underlie this association. Yet, numerous confounding factors cannot be tackled with this approach, and causality cannot be ascertained. The identification of this trigger of TGA may help the clinician in his etiological research.

Medications as a Trigger of Sleep-Related Eating Disorder: A Disproportionality Analysis.

Sleep-related eating disorder (SRED) is a parasomnia with recurrent, involuntary, amnestic eating episodes during sleep. There is growing evidence of the association between SRED and medications. Therefore, we aimed to rank drugs showing the strongest association. VigiBase® (WHO pharmacovigilance database) was queried for all reports of "Sleep-related eating disorder". Disproportionality analysis relied on the Reporting Odds Ratio, with its 95% Confidence Interval (CI), and the Information Component. Our VigiBase® query yielded 676 cases of drug-associated SRED. Reports mostly involved zolpidem (243, 35.9%), sodium oxybate (185, 27.4%), and quetiapine (97, 14.3%). Significant disproportionality was found for 35 medications, including zolpidem (387.6; 95%CI 331.2−453.7), sodium oxybate (204.2; 95%CI 172.4−241.8), suvorexant (67.3; 95%CI 38.0−119.2), quetiapine (53.3; 95%CI 43.0−66.1), and several psychostimulants and serotonin-norepinephrine reuptake inhibitors (SNRIs). Patients treated with nonbenzodiazepines or SNRIs were significantly older (mean age: 49.0 vs. 37.5; p < 0.001) and their SRED were more likely to be serious (62.6% vs. 51.4%; p = 0.014) than patients treated with sodium oxybate or psychostimulants. Psychotropic drugs are involved in almost all reports. In patients with SRED, an iatrogenic trigger should be searched for.

Spontaneous reporting of adverse drug reactions as an outlet for patient dismay? The case of Levothyrox® change of excipients.

Following minor changes of excipients of Levothyrox®, the French Pharmacovigilance Database was overwhelmed by patients' spontaneous reports of adverse drug reactions associated with the new formula. After noticing that most of these reports differed from those related to other drugs, we aimed to characterize their features and compared them with spontaneous reports associated with other chronic treatments as comparators. We randomly sampled patient reports associated with either Levothyrox® new formula (n = 200) or comparator drugs (n = 200) from March 2017 till March 2018 from the National Pharmacovigilance Database. We evaluated the number of incriminated drugs and adverse drug reactions per report and verified whether they were "expected" or not according to the Summary of Product Characteristics. Levothyrox®-associated reports included, on average, more adverse drug reactions (8 ± 4) than comparators (2 ± 2, P < 0.01) and mentioned mostly one drug (98.5% of reports), whereas comparators mentioned two at least (P < 0.001). The quantitative distribution of adverse drug reactions per report differed quite significantly, appearing almost Gaussian for Levothyrox® whereas Poisson-like for comparators (P < 0.0001). Age did not differ significantly in the two groups (54.2 vs. 49.7, NS), but female predominated in Levothyrox® group (94.5%) as compared with comparators (60.8%, P < 0.001). A mere third of the Levothyrox®-associated adverse drug reactions were deemed "expected," versus two thirds for comparators (P < 0.001). The pattern of spontaneous reports associated with Levothyrox®, whether fueled by media or influenced by social networks, appears atypical, as compared with that of comparators. Such reports, by their abundance, may impair the automatic detection of relevant concomitant signals.

Major bleeding events in octagenarians associated with drug interactions between dabigatran and P-gp inhibitors.

BACKGROUND: The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring. Yet, concerns about possible drug interactions susceptible to increase its inherent bleeding risk, especially in very elderly patients, have been raised recently. The aim of our study was to evaluate to what extent the co-prescription of P-gp inhibitors with dabigatran may increase its plasma levels and lead to bleeding complications, in usual conditions of care of the very elderly. METHODS: Fifty-eight patients over 85 years old with non valvular atrial fibrillation receiving dabigatran were included in a prospective cohort. Prescriptions were screened for the presence of P-gp inhibitors (Group A) or not (Group B). RESULTS: Patients from Group A had increased dabigatran mean plasma concentrations as compared with patients from Group B (A vs. B: 182.2 ± 147.3 vs. 93.7 ± 64.9 ng/mL). One third of the patients from Group A had dabigatran concentrations that were deemed "out of range" versus none in Group B (P = 0.05). This was associated with more frequent bleeding complications in Group A (A: 30.4%, B: 8.6%, P = 0.04). CONCLUSION: In our cohort of very elderly patients, at least, the co-prescription of dabigatran with P-gp inhibitors in usual conditions of care resulted in higher dabigatran plasma concentrations and more frequent bleeding occurrences.