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.

Spontaneous adverse event notifications by patients subsequent to the marketing of a new formulation of Levothyrox® amidst a drug media crisis: atypical profile as compared with other drugs.

Since patients may report spontaneously adverse events associated with their medications, such notifications are constantly on the rise. In 2017, an unexpected rise of notifications associated with the marketing of a new formula of Levothyrox, differing from the 30-year-old drug only by minor elements, occurred in France amidst widespread media coverage. Not much, if any, scientific or pharmacological rationale was identified to explain that signal. This led us to focus on the profile and the clinical characteristics of these notifications and compare them to those associated with other drugs. We gathered all the spontaneous drug adverse event notifications associated with either Levothyrox® or other drugs, that we received from patients in 2017, in the sanitary territory of ~2.3 M people we surveyed. Each notification was assessed by a multidisciplinary team. We compared the number of notifications, the number of symptoms described and their clinical characteristics. A total of 1 544 patient notifications were evaluated: 1 372 cases totaling 7 342 adverse events concerned Levothyrox® new formula, as compared with 172 cases reporting 528 adverse events for all other drugs. The number of symptoms reported per notification was significantly higher for Levothyrox® (5.4) than for other drugs (3.1, P < 0.001). Symptoms associated with Levothyrox® belonged to more System Organ Classes and were often unrelated to the disease or treatment, as compared with those associated with other drugs. The distribution of the cases according to the number of symptoms described was starkly different, the Levothyrox® distribution being unimodal. Health authorities must address this issue as such large atypical reporting disproportionally affects the European pharmacovigilance database.