Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

Clinical, economic and organizational impact of pharmacist interventions on injectable antineoplastic prescriptions: a prospective observational study.

BACKGROUND: Pharmacists play a key role in ensuring the safe use of injectable antineoplastics, which are considered as high-alert medications. Pharmaceutical analysis of injectable antineoplastic prescriptions aims to detect and prevent drug related problems by proposing pharmacist interventions (PI). The impact of this activity for patients, healthcare facilities and other health professionals is not completely known. This study aimed at describing the clinical, economic, and organizational impacts of PIs performed by pharmacists in a chemotherapy preparation unit. METHODS: A prospective 10-week study was conducted on PIs involving injectable antineoplastic prescriptions. Each PI was assessed by one of the four multidisciplinary expert committees using a multidimensional tool with three independent dimensions: clinical, economic and organizational. An ancillary quantitative evaluation of drug cost savings was conducted. RESULTS: Overall, 185 patients were included (mean age: 63.5 ± 13.7 years; 54.1% were male) and 237 PIs concerning 10.1% prescriptions were recorded. Twenty one PIs (8.9%) had major clinical impact (ie: prevented hospitalization or permanent disability), 49 PIs (20.7%) had moderate clinical impact (ie: prevented harm that would have required further monitoring/treatment), 62 PIs (26.2%) had minor clinical impact, 95 PIs (40.0%) had no clinical impact, and 9 PIs (3.8%) had a negative clinical impact. For one PI (0.4%) the clinical impact was not determined due to insufficient information. Regarding organizational impact, 67.5% PIs had a positive impact on patient management from the healthcare providers' perspective. A positive economic impact was observed for 105 PIs (44.3%), leading to a saving in direct drug costs of 15,096 €; 38 PIs (16.0%) had a negative economic impact, increasing the direct drug cost by 11,878 €. Overall cost saving was 3218€. CONCLUSIONS: PIs are associated with positive clinical, economic and organizational impacts. This study confirms the benefit of pharmacist analysis of injectable antineoplastic prescriptions for patient safety with an overall benefit to the healthcare system.

Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine?

Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.

Electronic Medication Regimen Complexity Index at admission and complications during hospitalization in medical wards: a tool to improve quality of care?

OBJECTIVE: Adverse events during hospitalization are a major worry considering their frequency and their burden. Many could be avoided by immediate identification of at-risk patients at admission and adapted prevention. The complexity of a patient's medication regimen immediately available at admission is a good indicator of the complexity of the patient's condition. This study aims to determine whether the electronic Medication Regimen Complexity Index (MRCI) at admission is associated with complications during hospitalization. DESIGN: We performed a multilevel logistic regression model, adjusted for age and sex. SETTING: Premier Perspective™ database, a clinical and financial information system from 417 US hospitals. PARTICIPANTS: Adults hospitalized for more than 3 days in a medical ward and included in Premier's Perspective™ database for 2006. INTERVENTION(S): Multilevel logistic regression. MAIN OUTCOME MEASURE: Association of the MRCI and complications during hospitalization, defined as in-hospital death, hospital-acquired infection, pressure ulcers; and need for highly technical healthcare, identified as the secondary introduction of catecholamines. RESULTS: In total, 1 592 383 admissions were included. The median MRCI at admission was 13 [interquartile range: 9-19]. The higher the MRCI, the higher the adjusted odds ratio of the following: in-hospital mortality, hospital-acquired infections, pressure ulcers and the secondary introduction of catecholamines. CONCLUSIONS: Our results suggested that the MRCI at admission was correlated with patient complexity, independent of age. Considering that patients with complex conditions pose a heavier workload for staff, measuring MRCI at admission could be used to allocate resources in medical wards at an institutional level. The MRCI might be a useful tool to assess the management of care.

[Cutaneous pigmentation related to intravenous iron extravasation: Analysis from the French pharmacovigilance database]. / Pigmentation cutanée liée à l'extravasation de fer injectable. Analyse de la base française de pharmacovigilance de 2000 à 2016.

INTRODUCTION: Intravenous iron infusion may be complicated by extravasation and lead to cutaneous pigmentation. METHODS: We queried the French pharmacovigilance database to assess the spontaneously reported cases over the 2000-2016 period. RESULTS: Fifty-one cases of cutaneous pigmentation related to intravenous iron extravasation were retrieved, none was associated to necrosis. Most of patients were women aged 20 to 49 years old. The pigmentation was mostly a brown coloration, persisting over one month in 19 cases (37.2%) and over 6 months in 9 cases (17.6%). The management of extravasation and pigmentation was heterogeneous and was rarely followed by a decrease of the coloration. CONCLUSION: Cutaneous pigmentation after intravenous iron extravasation can persist over time and create an aesthetic prejudice, particularly in young women. Standardized extravasation and iron-induced pigmentation management procedures appear necessary.

Chronic use of proton pump inhibitors, adverse events and potential biological mechanisms: A translational analysis.

Proton pump inhibitors (PPIs) are among the most frequently prescribed drugs. Even if PPI are usually considered as safe, there is a growing concern for a range of adverse effects of chronic PPI therapy often in the absence of appropriate indications. We propose, after a summary of renal, cardiovascular and neurological complications (dementia, chronic kidney disease, myocardial infarction and stroke), an integrative overview of the potential biological mechanisms involved. Eleven positive pharmacoepidemiological studies, mainly based on health insurance database linkage to hospital database, reported an increased risk of complications associated to PPI use and often a graded association suggesting also a possible dose-response relationship. Several mechanisms have been suggested through in vitro studies (endothelial dysfunction, endothelial senescence, hypomagnesemia, increase of chromogranin A levels, decrease of nitric oxide in endothelial cells) leading to the impairment of vascular homesostasis, paving the way to these complications. Evidence that PPIs may have off-targets and pleiotropic effects are mounting and may impose a cautious attitude in the prescription of PPI's, especially in elderly and/or in the context of chronic use.

[Pharmacokinetic drug interaction between miconazole mucoadhesive tablet and tacrolimus: About 3 case-reports in transplant patients]. / Interaction pharmacocinétique entre la forme mucoadhésive de miconazole et le tacrolimus : à propos de 3 observations cliniques chez des patients greffés.

Loramyc® is a mucoadhesive tablet of miconazole, indicated for the treatment of oropharyngeal candidiasis in immunocompromised patients. Miconazole, as others azole antifungals, is known for its potent inhibitory properties of cytochromes P450 enzymes and P-glycoprotein (P-gp). Inhibition of cytochromes P450 enzymes and P-gp can produce pharmacokinetic drug interaction. Immunosuppressive agents, such as calcineurin inhibitors (tacrolimus, cyclosporine) are substrates of cytochromes P450 3A4 and P-gp. Nevertheless, the impact of systemic absorption of miconazole mucoadhesive tablet has not been investigated by the laboratory before regulatory approval. No recommendation currently exists in case of co-prescription of Loramyc® and immunosuppressive agents which are counter-indicated as a matter of principle. Herein, we present 3 cases of transplanted patients, requiring miconazole mucoadhesive tablet, who presented a tacrolimus overdose. These cases illustrate that of therapeutic drug monitoring is feasible in order to prevent the occurrence of overdoses and adverse reactions related.

[Cyamemazine (Tercian®): Exploration of extrapyramidal syndrome cases contained in the French pharmacovigilance database]. / Cyamémazine (Tercian®) et syndromes extrapyramidaux : exploration des cas contenus dans la base nationale de pharmacovigilance.

PURPOSE: Cyamemazine (Tercian®) is currently the most widely prescribed neuroleptic in France. This widespread use is due to its anxiolytics properties and to a claimed good safety profile. Although, prescription of cyamemazine is not devoid of the risks associated with the use of neuroleptics: extrapyramidal syndromes. This study aims at describing extrapyramidal syndromes induced by cyamemazine registered in the French pharmacovigilance database. METHODS: All spontaneous reports of extrapyramidal syndromes in the French pharmacovigilance database between 1st January 1985 and 31th December 2015 were described and analyzed. RESULTS: During this period 132 cases following cyamemazine intake were reported in the French pharmacovigilance database. The extrapyramidal syndromes were considered as "serious" in 77% of cases. More than 80% of the cases were described with a dosage of cyamemazine under 100mg/day and no correlation between drug dose and seriousness of the cases were found. Thirty-six cases were described with a monotherapy of cyamemazine. CONCLUSION: We should keep in mind that despite its widespread use in various indications (e.g. anxiolytic) cyamemazine remains a neuroleptic and could induce extrapyramidal syndromes even with low dosage. Careful monitoring should be performed when introducing and with long-term use of cyamemazine, mostly in elderly patients or patient already being treated with neuroleptics.

[Surveillance system on drug abuse: Interest of the French national OPPIDUM program of French addictovigilance network]. / Dispositif pharmacoépidémiologique de surveillance des substances psychoactives : intérêts du programme national OPPIDUM du Réseau français d'addictovigilance.

It is important to assess drug abuse liability in 'real life' using different surveillance systems. OPPIDUM ('Observation of illegal drugs and misuse of psychotropic medications') surveillance system anonymously collects information on drug abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. The aim of this article is to demonstrate the utility of OPPIDUM system using 2015 data. OPPIDUM is a cross-sectional survey repeated each year since 1995. In 2015, 5003 patients described the modality of use of 10,159 psychoactive drugs. Among them, 77% received an opiate maintenance treatment: 68% methadone (half of them consumed capsule form) and 27% buprenorphine (39% consumed generic form). Brand-name buprenorphine is more often injected than generic buprenorphine (10% vs. 2%) and among methadone consumers 7% of methadone capsule consumers have illegally obtained methadone (vs. 9% for syrup form). The proportion of medications among psychoactive drugs injected is important (42%), with morphine representing 21% of the total psychoactive drugs injected and buprenorphine, 16%. OPPIDUM highlighted emergent behaviors of abuse with some analgesic opioids (like tramadol, oxycodone or fentanyl), pregabalin, or quetiapine. OPPIDUM highlighted variations of drugs use regarding geographic approaches or by drug dependence care centers (like in harm reduction centers). OPPIDUM clearly demonstrated that collection of valid and useful data on drug abuse is possible, these data have an interest at regional, national and international levels.

[The current aspects of the use of ecstasy/MDMA in France]. / Les aspects actuels de l'usage de l'ecstasy/MDMA en France.

Methylenedioxymethamphetamine (MDMA), the active compound of ecstasy, has been used for several years, especially by young adults to benefit of psychostimulant properties. By raising the level of neuromodulators in the synapsis, MDMA can cause psychiatric and physical injuries. After reduced supplies in 2009 (number of ecstasy seizures equal to 10 percent of those recorded in 2002), judicial authorities now observed an increased availability (a half more part of seizures in 2012 than 2010). From its "Spontaneous Notifications" data base and "deaths in connection with the abuse of medicine and substances (DRAMES)", "observation of illegal drugs and misuse of psychotropic medications" (OPPIDUM), and "observation of drug dependencies in ambulatory medicine" (OPEMA) national inquiries, the French Addictovigilance network (CEIP-A) highlighted the increasing consumption of MDMA. The way of use appeared quite unchanged: users were mainly young men between 25 and 30 years; they favored an occasional use but mainly combined other products such as alcohol, cannabis and other stimulants. Severity of the clinical cases, based on hospital care and forensic data, could be consistent with the higher amounts of MDMA measured in pills.

Vaccines and Bell's palsy: A narrative review.

The association between vaccines and peripheral facial palsy (PFP), an issue that has been the subject of debate for many years, has been raised again following results of clinical trials assessing mRNA based COVID-19 vaccines. To review the available literature on this topic, PubMed was searched from inception until February 25, 2022. Inclusion criteria were case reports with documented rechallenge and comparative epidemiological studies. Cases of COVID-19 vaccine-induced PFP with available data on vaccine rechallenge were also identified from Vigibase until December 31, 2021. Of the 347 articles retrieved, 32 comparative epidemiological studies, 1 meta-analysis and 4 case reports met our criteria, of which 13 involved COVID-19 vaccines. Eight studies found an association between at least one vaccine and the occurrence of PFP, whereas 24 did not. Positive studies involved seasonal or pandemic H1N1 influenza vaccines administered parenterally (4 studies) or intranasally (1 study with a toxin-adjuvanted vaccine), BNT162b2, a mRNA COVID-19 vaccine (1 disproportionality analysis and 1 observed-to-expected analysis) and an inactivated virus COVID-19 vaccine (CoronaVac®) (1 study combining a case-control and an observed-to-expected approach). Strong evidence was found only for the intranasal influenza vaccine while other positive studies detected only a marginal association between PFP and vaccination. Of the four case reports with documented rechallenge, only two were positive and involved an influenza vaccine and tozinameran in one case each. In Vigibase, rechallenge was documented in 49 reports with 29 (59.2%) cases being negative and 20 (40.8%) positive. The available data did not confirm an excess risk of PFP after vaccination in most studies. Moreover, of the eight epidemiological studies suggesting a possible excess risk of PFP after any vaccine, three were disproportionality analyses and two observed-to excepted analyses, suggesting great caution should be taken when interpreting these results.

[COVID-19 and adenovirus vaccines: French experience of enhanced pharmacovigilance]. / COVID-19 et vaccins à adénovirus : expérience française de suivi renforcé de pharmacovigilance.

As part of the COVID-19 vaccination campaign, the National Agency for the Safety of Medicines and Health Products and all 31 regional pharmacovigilance centers were mobilized in an exceptional reinforced vaccine pharmacovigilance surveillance system. Concerning adenovirus vaccines, Vaxzévria® and Jcovden®, this national system, based on the daily analysis of notified cases of adverse events, has allowed the early identification of safety signals, some of which have been validated, others still under analysis, common to mRNA vaccines or more specific of adenovirus vaccines such as Vaccine Induced Immune Thrombocytopenia. Complementing european and international actions, this follow-up has contributed to a better definition of the safety profile of these vaccines and has led to redefine the vaccine strategy in our country. Although today these two vaccines have no longer place in the national vaccine strategy, they are still used in other countries, where the experience acquired could be useful and will contribute to fuel the reflection on future therapies involving viral vectors.