Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage-gated calcium channel ligand drugs.

AIMS: Gabapentin and pregabalin bind to α2-δ subunit of voltage-gated calcium channels (Cav ). Other drugs targeting Cav include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide and zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (oedema) and Cav -blocking anticonvulsants (suicide and ataxia). The objective of this study was to cluster the safety profile of different Cav -ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reaction (ADR) signature from cardiovascular CCBs and anticonvulsants. METHODS: We extracted all ADRs with at least one significant disproportionate reporting (reporting odds ratio) related to gabapentinoids, CCBs or anticonvulsants in VigiBase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Cav -ligand drugs that share a similar ADR signature. The robustness of the results was determined through four sensitivity analyses, varying on the dataset or the clustering method. RESULTS: A total of 16 drugs and 65 ADRs were included. Gabapentinoids were in Cluster #1, which included eight other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem and verapamil) and Cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses. CONCLUSIONS: The safety profile of gabapentinoids overlaps with those of some dihydropyridine CCBs and Cav -blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. METHODS: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. FINDINGS: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. INTERPRETATION: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.

Pregnancy outcome following in utero exposure to azathioprine: A French comparative observational study.

AIM OF THE STUDY: To evaluate whether azathioprine exposure during pregnancy increases the risk of birth defects and prematurity. METHOD: Prospective comparative observational study using the French pregnancy database TERAPPEL. To evaluate birth defects, outcomes of pregnancies exposed to azathioprine during the 1st trimester were prospectively assessed and compared to that of pregnancies exposed to another drug used for the same indications. Secondly, the rate of preterm births was compared between fetuses exposed to azathioprine at least during the third trimester and those exposed during the first trimester only. RESULTS: From 447 requests for a risk assessment for women receiving azathioprine during pregnancy, 193 pregnancies meet inclusion criteria. One hundred and twenty-four of them were exposed to azathioprine during the 1st trimester and were compared to that of 124 pregnancies exposed to another drug used for the same indication. Azathioprine use during the first trimester was not statistically associated with the risk of all birth defects ([7.3% vs. 5.4%]; [OR=1.36; 95%CI: 0.44-4.20]) nor with major birth defects (5.2% vs. 1.8% [OR=2.96; 95%CI: 0.56-15.64]). The rate of preterm births (22.5% vs. 27.3%, P=0.579) was similar regardless of the exposure period to azathioprine (at least during the third trimester or during the first trimester only). CONCLUSIONS: This study confirms that first trimester exposure to azathioprine is not associated with an elevated rate of birth defects and that the high rate of preterm births among women exposed to azathioprine is probably explained by the underlying maternal disease.

Adverse effect of Pneumocystis Jirovecii infection associated with rituximab therapy for autoimmune disease are more frequently reported in older vs. younger patient.

INTRODUCTION: Rituximab is a chimeric anti-CD20 antibody commonly used to treat patients with autoimmune diseases. Such diseases mainly affect young people, but older patients may also be concerned. So far, very little data exist concerning the safety of rituximab in older patients with autoimmune diseases. METHODS: This study was intended to describe the adverse reaction profile of rituximab in patients over 75 years of age treated for autoimmune diseases and to compare such profile to those observed in patients below 75 years of age. Adverse reactions related to rituximab were reported to the French Pharmacovigilance Network. From such reports, a descriptive analysis as well as a disproportionality analysis were performed to identify safety signals. RESULTS: 1096 reports of rituximab-related adverse reactions reported in France between 2006 and 2019, were included in the study, such as 127 in the older group (>75 years) and 969 in the younger group (<75 years). Infusion reactions were less frequently reported than other adverse drug reaction in older patients (11 vs. 27%, P<0.001). By contrast, a higher rate of opportunistic infection due to Pneumocystis jirovecii was reported in the older subject group (3.9 vs. 0.6%, P<0.001), along with neutropenia (22.8 vs. 9.3%, P<0.0001). These results were confirmed by the disproportionality analysis. CONCLUSION: Pneumocystis jirovecii infection was significatively more reported in older patients treated by Rituximab which probably reflects a higher incidence in this population. The use of anti-pneumocystis prophylaxis should be considered in this population.

Peripheral facial palsy post SARS-CoV-2 vaccine: A regional pharmacovigilance cases series.

Peripheral facial palsy (PFP) is a rare adverse reaction identified from clinical trials of coronavirus disease 2019 (COVID-19) vaccines (messenger ribonucleic acid [mRNA] and viral vector). Few data are available on their onset patterns and risk of recurrence after re-injection of a COVID-19 vaccine; the objective of this study was to describe PFP cases attributed to COVID-19 vaccines. All cases of facial paralysis reported to the Regional Pharmacovigilance Center of Centre-Val de Loire area between January and October 2021, in which the role of a COVID-19 vaccine was suspected, were selected. Based on initial data and following additional information requested, each case was reviewed and analyzed to include only confirmed cases of PFP for which the role of the vaccine could be retained. From the 38 cases reported, 23 were included (15 excluded because of diagnosis not retained). They occurred in 12 men and 11 women (median age of 51 years). The first clinical manifestations occurred with a median time of 9 days after COVID-19 vaccine injection, and the paralysis was homolateral to the vaccinated arm in 70%. The etiological workup, always negative, included brain imaging (48%), infectious serologies (74%) and Covid-19 PCR (52%). Corticosteroid therapy was prescribed for 20 (87%) patients, combined with aciclovir in 12 (52%). At 4-month follow-up, clinical manifestations had regressed completely or partially in 20 (87%) of the 23 patients (median time of 30 days). From them 12 (60%) received another dose of COVID-19 vaccine and none had a recurrence and the PFP regressed despite the second dose in 2 of the 3 patients not fully recovered at 4 months. The potential mechanism of PFP after COVID-19 vaccine, which don't have a specific profile, is probably the interferon-γ. Moreover, the risk of recurrence after a new injection appears to be very low, which makes it possible to continue the vaccination.

Rituximab-induced serum sickness is more frequent in autoimmune diseases as compared to hematological malignancies: A French nationwide study.

INTRODUCTION: Rituximab induced serum sickness (RISS) is a rare delayed hypersensitivity reaction. The aim of this study was to describe the epidemiological and clinical characteristics of the RISS cases reported in France. METHOD: Serum sickness cases involving rituximab were identified from the French PharmacoVigilance Database from 1998 to 2016. RESULTS: We analyzed 37 cases of RISS. Rituximab was prescribed for an autoimmune disease in 78% of cases. Serum sickness occurred mainly after the first injection (54%) with a median time to onset of 12 days. The most frequent manifestations were rheumatologic symptoms (92%), fever (87%), and skin lesions (78%). The incidence was significantly higher when rituximab was used for autoimmune diseases than for a hematological malignancies. Taking into account the existence of a Systemic Lupus Erythematosus (SLE) as the indication of rituximab or as a comorbidity, the incidence of RISS in patients with SLE was even higher. DISCUSSION: We report on the largest series of RISS studied to date and confirm that this reaction preferentially occurs in patients with autoimmune disease, especially SLE. This may be due to B-cell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, especially in patients with elevated autoantibody production. This could also explain why RISS often occurred after a single injection. CONCLUSION: Patients generally recovered from RISS rapidly without obvious benefit from corticosteroid therapy. The risk of recurrence should prompt clinicians to question the use of rituximab after an episode of RISS.

[Alitretinoin (Toctino®): A French follow-up study of harmacovigilance]. / Alitrétinoïne (Toctino®) : données françaises de pharmacovigilance.

INTRODUCTION: The adverse reaction profile of alitretinoin, a retinoid indicated in severe topical corticosteroid-refractory chronic hand eczema, is similar to that of other oral retinoids, especially isotretinoin. The objective of this study was to detect new adverse effects (not listed) of alitretinoin and to estimate the number of pregnancies exposed. MATERIAL AND METHODS: All cases of ADR reported in France with alitretinoin between October 1st, 2012 and February 29th, 2016 were analysed. RESULTS: During the 41 months of follow-up, 52 cases of serious adverse drug reaction (ADR) and 88 cases of non-serious and unexpected ADR were notified. The most frequent serious ADRs were psychiatric, neurological and dermatological. Psychiatric disorders, mainly depression and suicidal ideation represented 23% of serious ADRs. New adverse drug reactions were detected: myocardial infarction, pancreatitis and digestive haemorrhage. Three pregnancies exposed during the teratogenic risk period, were registered. DISCUSSION AND CONCLUSION: The safety profile of alitretinoin matches that of other retinoids. However, the rate of psychiatric disorders appears to be high. Otherwise, the risk of myocardial infarction in patients with cardiovascular risk factor should be considered as a safety concern. It could be explained by the hyperlipemic effects of alitretinoin and studies suggest a cardiovascular risk with retinoids through their effects on lipids (class effect), especially for patients with others cardiovascular risk factors. Pancreatitis and digestive hemorrhage are described with isotretinoin. The rate of reporting of pregnancy induced by a non-compliance with the Pregnancy Prevention Program is near the rate observed with isotretinoin. The high incidence of serious ADR and the non-application of pregnancy prevention program lead the French National Agency for Medicines to limit the first prescription of alitretinoin to dermatologists.