[Pharmacovigilance. Withdrawal and rebound effects: not just with psychotropic drugs]. / Pharmacovigilance. Sevrage et effet rebond: pas seulement avec les psychotropes.

The list of drugs whose abrupt discontinuation is likely to induce withdrawal symptoms or a rebound in the pathology being treated is not limited to psychotropic drugs. It includes a number of somatic drugs (e.g. proton pump inhibitors, opioids, triptans, fingolimod, corticosteroids, antiepileptics, nootropics, antiparkinsonians, denosumab, beta-blockers, laxatives, nasal vasoconstrictors, etc.). This type of unintended effect, often underestimated, generally results from a drug-induced homeostatic imbalance that persists after the drug has been discontinued. Taking this risk into account right from the initial prescription should make it possible to prevent such complications, by encouraging intermittent use of the drug, or by applying a very gradual reduction in dosage when a regular treatment is stopped.

La liste des médicaments dont l'arrêt brusque est susceptible d'entraîner des symptômes de sevrage ou un rebond de la pathologie traitée ne se limite pas aux psychotropes, mais inclut un certain nombre de médicaments somatiques (inhibiteurs de la pompe à protons, opioïdes, triptans, fingolimod, corticostéroïdes, antiépileptiques, nootropes, antiparkinsoniens, dénosumab, bêtabloquants, laxatifs, vasoconstricteurs nasaux, etc.). Ce type d'effet indésirable, souvent méconnu, résulte en général d'un déséquilibre homéostatique causé par le médicament, persistant après son interruption. La prise en compte de ce risque dès la prescription initiale devrait permettre de prévenir ces complications, en privilégiant un recours intermittent au médicament ou en prévoyant une diminution très progressive des posologies au moment de mettre un terme à un traitement continu.

[Metabolism and therapeutic monitoring of azathioprine in gastroenterology and hepatology]. / Métabolisme et suivi thérapeutique de l'azathioprine en gastroentérologie et hépatologie.

Azathioprine keeps an important place in the treatment of inflammatory bowel disease and autoimmune hepatitis. This molecule has a narrow therapeutic margin, associated with a risk of toxicity, particularly hematological and hepatic. Its complex metabolism is subject to genetic polymorphisms that are reflected in the inter-individual variability observed in the response to treatment and its tolerance profile. Hence, its use requires a good knowledge of this molecule. Treatment is initiated after a preliminary workup, followed by a progressive titration of the dosage while closely monitoring possible toxicities. Monitoring of blood levels of metabolites (including active ones) helps guide personalized dose adjustment.

L'azathioprine garde actuellement une place importante dans le traitement des maladies inflammatoires chroniques de l'intestin et de l'hépatite autoimmune. Il s'agit d'une molécule à marge thérapeutique étroite, associée à un risque de toxicité, notamment hématologique et hépatique. Son métabolisme complexe est influencé par des polymorphismes génétiques qui sont reflétés dans la variabilité interindividuelle observée dans la réponse au traitement et le profil de tolérance. Son utilisation nécessite donc une bonne connaissance de cette molécule. L'instauration du traitement se fait après un bilan préalable, puis une titration progressive des posologies, tout en surveillant étroitement les éventuelles toxicités. Le monitoring des concentrations sanguines des métabolites (notamment actifs) permet de guider l'adaptation personnalisée des posologies.

[Pharmacovigilance - mRNA COVID-19 vaccines : current state of knowledge on their adverse effects]. / Pharmacovigilance - Vaccins à ARNm contre le Covid-19 : le point sur les effets indésirables.

The COVID-19 pandemic has stimulated the rapid development and large-scale use of technologically innovative vaccines, such as the mRNA vaccines Spikevax (Moderna) and Comirnaty (Pfizer-BioNTech). This unprecedented deployment has challenged pharmacovigilance, requiring combined skills in safety monitoring, prompt data analysis and continuous dissemination of knowledge. Main recognised adverse events of these vaccines are moderate and transient, linked to their significant reactogenicity. Active post-marketing surveillance has identified rare adverse events such as myopericarditis and a variety of skin reactions. A number of potential rare adverse events are being evaluated and could be retained at the individual level, but do not question the overall safety of these vaccines.

La pandémie de Covid-19 a conduit au développement rapide de vaccins à la technologie innovante, utilisés à large échelle, dont les vaccins à ARNm Spikevax (Moderna) et Comirnaty (Pfizer-BioNTech). Ce déploiement sans précédent défie la pharmacovigilance, nécessitant d'allier un suivi attentif de la sécurité, une analyse rapide des données et une diffusion continue des connaissances. Les principaux effets indésirables reconnus pour ces vaccins sont modérés et transitoires, liés à leur importante réactogénicité. Une pharmacovigilance active a permis d'identifier des effets indésirables rares, tels que des myopéricardites et diverses réactions cutanées. Un certain nombre d'effets indésirables rares potentiels sont en cours d'évaluation et pourraient être retenus à l'échelle individuelle, mais ne remettent pas en cause la sécurité vaccinale globale.

Spontaneous Partial Remission in a Child With B-Lineage Acute Lymphoblastic Leukemia and Chickenpox: A Role For Acyclovir?

A 2.5-year-old boy presented to his pediatrician with progressive pallor, asthenia, fever, splenomegaly, and hematomas. Leukemia was suspected, and a bone marrow aspirate confirmed acute lymphoblastic leukemia. Before chemotherapy induction, the child developed a vesicular rash and was diagnosed clinically with chickenpox. Acyclovir treatment was initiated immediately, whereas induction chemotherapy was postponed by 10 days. At the time of chickenpox resolution, a spontaneous partial recovery of his blood counts and a 50% decrease of blastic bone marrow infiltration were noted. After a brief nonsystematic review, we discuss the potential beneficial effect of acyclovir and chickenpox infection in children with leukemia.

Sofosbuvir add-on to ribavirin for chronic hepatitis E in a cirrhotic liver transplant recipient: a case report.

BACKGROUND: Chronic hepatitis E represents an emerging challenge in organ transplantation, as there are currently no established treatment options for patients who fail to clear hepatitis E virus (HEV) following reduction of immunosuppressive therapy and/or treatment with ribavirin. Sofosbuvir has shown antiviral activity against HEV in vitro but clinical utility in vivo is unknown. CASE PRESENTATION: We describe a 57-year-old liver transplant recipient with decompensated graft cirrhosis due to chronic hepatitis E. Reduction of immunosuppressive treatment as well ribavirin alone for 4 months did not result in viral clearance. Add-on of sofosbuvir for 6 months was associated with HEV RNA becoming undetectable in plasma. However, sustained viral clearance could not be achieved. CONCLUSIONS: Sofosbuvir may have some antiviral activity against HEV when added to ribavirin. However, this did not suffice to yield sustained viral clearance. Our well-characterized observation emphasizes the need for new treatment options to cure chronic hepatitis E in the setting of organ transplantation.

Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports.

BACKGROUND: The use of immune checkpoint inhibitor (ICI) therapy is becoming a standard of care for several cancers. Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) cause a broad spectrum of autoimmune adverse events. ICI-induced type 1 diabetes mellitus (T1DM) is extremely rare (< 1%) but potentially life-threatening. It appears to be more common with PD-1 blockade (or combination immunotherapy) than with anti-CTLA-4 therapy, often during the first three to six months of therapy. CASES PRESENTATION: We report an acute onset T1DM with severe inaugural diabetic ketoacidosis (DKA) and remarkably elevated Glutamic Acid Decarboxylase antibody (GADA) titres following a single administration of combined ICI therapy with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in two adult patients with advanced metastatic melanoma. In these cases, the time to diabetes onset was remarkably short (two and five weeks), and one presented with fulminous T1DM in a previous long-standing type 2 diabetes mellitus. CONCLUSIONS: Oncological patients treated with combination therapy of anti-PD-1 and anti-CTLA-4 can develop a particular pattern of T1DM, with very rapid onset within a few weeks after starting ICI therapy, even in the presence of an existing type 2 diabetes. ICI-induced T1DM is a medical emergency in presence of severe inaugural DKA and requires a collaboration between specialists and primary care physicians, as well as patient education, for early diagnosis and supportive care.

[Challenges in managing diabetes in chronic hemodialysis]. / Défis dans la prise en charge du diabète en hémodialyse chronique.

Hemodialysis (HD) centers are facing an increasing number of patients with diabetes. These cases require an intensive multidisciplinary approach of the consequences of renal failure, glycemic control and nutrition and the management of frequent co-morbidities, in particular the diabetic foot. A major challenge is to decrease glycemic variability and the risk of hypoglycemia. Because of increased risk of hypoglycemia-associated mortality, the HbA1C target is loosened in the majority of HD patients. Continuous glucose monitoring technology has identified important glycemic fluctuations during and after dialysis. However, their reliability in HD needs to be improved. New therapeutic pathways that decrease glucose excursions and hypoglycemia, such as GLP1 receptor agonists and sensor-coupled insulin pumps, have yet to be validated in HD.

Les centres d'hémodialyse (HD) sont confrontés à un nombre croissant de patients diabétiques. Leur prise en charge multidisciplinaire tient compte de l'insuffisance rénale, du contrôle glycémique, de la nutrition et des comorbidités fréquentes, en particulier le pied diabétique. La réduction de la variabilité glycémique et des hypoglycémies qui sont associées à une mortalité accrue reste un défi. La cible de l'HbA1C est assouplie chez la majorité des patients. L'usage du contrôle en continu de la glycémie permet d'identifier les fluctuations glycémiques per et interdialytiques importantes. Sa fiabilité doit cependant être améliorée en HD. Les nouvelles voies thérapeutiques qui diminuent les excursions glycémiques et le risque d'hypoglycémie comme les GLP1 agonistes et les pompes à insuline couplées aux sensors restent à valider en HD.

[Pharmacovigilance update]. / Pharmacovigilance.

The main pharmacovigilance updates in 2015are reviewed. Sofosbuvir amiodarone interaction: risk of severe bradycardia. Dasabuvir clopidogrel interaction: increased dasabuvir concentrations and potential risk of QTprolongation. SGLT2 inhibitors: risks of diabetic acidocetosis and bone fracture. Dabigatran: therapeutic drug monitoring may improve benefit-risk ratio. Ibuprofen: at higher dosage, vascular risks are comparable to coxibs. Pregabaline, gabapentine: potential for abuse and addiction. Varenicline: potentiates alcohol's effects. Codeine: contra-indicated as cough medicine under the age of twelve. Valproate: strengthened warnings on the risks of valproate use in pregnancy. Dimethylfumarate: rare observations of progressive multifocal leucoencephalopathy. Ustekinumab: rare observations of erythrodermia.

Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report.

BACKGROUND: Recurrent hepatitis C virus infection after liver transplantation is associated with reduced graft and patient survival. Re-transplantation for graft failure due to recurrent hepatitis C is controversial and not performed in all centers. CASE PRESENTATION: We describe a 54-year-old patient with hepatitis C virus genotype 1b infection and a null response to pegylated interferon-α and ribavirin who developed decompensated graft cirrhosis 6 years after a first liver transplantation. Treatment with sofosbuvir and ribavirin allowed for rapid negativation of serum HCV RNA and was well tolerated despite advanced liver and moderate renal dysfunction. Therapeutic drug monitoring did not reveal any clinically significant drug-drug interactions. Despite virological response, the patient remained severely decompensated and re-transplantation was performed after 46 days of undetectable serum HCV RNA. The patient is doing well 12 months after his second liver transplantation and remains free of hepatitis C virus. CONCLUSIONS: The use of directly acting antivirals may allow for successful liver re-transplantation for recipients who remain decompensated despite virological response and is likely to improve the outcome of liver re-transplantation for end-stage recurrent hepatitis C.

[Pharmacovigilance update]. / Pharmacovigilance.

The main pharmacovigilance updates in 2014 are reviewed. Ivabradine: increased risk of cardiovascular death and myocardial infarction in patients with symptomatic angina treated with high dosages. Clopidogrel: rare observations of acquired hemophilia. Orlistat: may reduce the absorption of HIV antiretrovirals. Ponatinib: increased risk of arteriopathy and thrombosis. Axitinib: significant risk of heart failure (class effect). Tocilizumab: possible causal relationship with the emergence or aggravation of psoriasis. Lithium: hypercalcemia and hyperparathyroidism commonly observed. Sildenalfil: suspected causal association with melanoma, so far not proven, Methylphenidate: rare observations of priapism. St John's wort (Hypericum): reduced effectiveness of hormonal contraceptives, including implants.

[New hepatitis C treatments: pharmacological considerations and potential for drug interactions]. / Nouveaux traitements de l'hépatite C: aspects pharmacologiques et potentiel d'interaction.

Progress in the understanding of the hepatitis C virus life cycle allowed the development of new, very promising antiviral therapies. Although these new drugs have a favourable profile in terms of efficacy, tolerance and interaction potential, their prescription in the setting of comedication and impaired renal or hepatic function remains a challenge. Here, we provide a summary of pharmacological considerations, focusing on sofosbuvir, simeprevir and daclatasvir. A better understanding of their metabolic pathways and transporters may help the prescriber to identify and manage drug interactions especially in patients under immunosuppressive or anti-HIV therapy. Recommendations for the prescription of these drugs in specific situations are also discussed.

Population Pharmacokinetics of Trametinib and Impact of Nonadherence on Drug Exposure in Oncology Patients as Part of the Optimizing Oral Targeted Anticancer Therapies Study.

Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients' drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient's journey to address patients' needs regarding trametinib and support medication adherence.

Novel Patient-Friendly Orodispersible Formulation of Ivermectin is Associated With Enhanced Palatability, Controlled Absorption, and Less Variability: High Potential for Pediatric Use.

Ivermectin has been used since the 1980s as an anthelmintic and antiectoparasite agent worldwide. Currently, the only available oral formulation is tablets designed for adult patients. A patient-friendly orodispersible tablet formulation designed for pediatric use (CHILD-IVITAB) has been developed and is entering early phase clinical trials. To inform the pediatric program of CHILD-IVITAB, 16 healthy adults were enrolled in a phase I, single-center, open-label, randomized, 2-period, crossover, single-dose trial which aimed to compare palatability, tolerability, and bioavailability and pharmacokinetics of CHILD-IVITAB and their variability against the marketed ivermectin tablets (STROMECTOL) at a single dose of 12 mg in a fasting state. Palatability with CHILD-IVITAB was considerably enhanced as compared to STROMECTOL. Both ivermectin formulations were well tolerated and safe. Relative bioavailability of CHILD-IVITAB compared to STROMECTOL was estimated as the ratios of geometric means for Cmax, AUC 0-∞, and AUC0-last, which were 1.52 [90% CI: 1.13-2.04], 1.27 [0.99-1.62], and 1.29 [1.00-1.66], respectively. Maximum drug concentrations occurred earlier with the CHILD-IVITAB formulation, with a median Tmax at 3.0 h [range 2.0-4.0 h] versus 4.0 h [range 2.0-5.0 h] with STROMECTOL (P = .004). With CHILD-IVITAB, variability in exposure was cut in half (coefficient of variation: 37% vs 70%) compared to STROMECTOL. Consistent with a more controlled absorption process, CHILD-IVITAB was associated with reduced variability in drug exposure as compared to STROMECTOL. Together with a favorable palatability and tolerability profile, these findings motivate for further clinical studies to evaluate benefits of such a patient-friendly ODT formulation in pediatric patients with a parasitic disease, including infants and young children <15 kg.

Comparison of cannabinoid concentrations in oral fluid and whole blood between occasional and regular cannabis smokers prior to and after smoking a cannabis joint.

A cross-over controlled administration study of smoked cannabis was carried out on occasional and heavy smokers. The participants smoked a joint (11% Δ9-tetrahydrocannabinol (THC)) or a matching placebo on two different occasions. Whole blood (WB) and oral fluid (OF) samples were collected before and up to 3.5 h after smoking the joints. Pharmacokinetic analyses were obtained from these data. Questionnaires assessing the subjective effects were administered to the subjects during each session before and after the smoking time period. THC, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) were analyzed in the blood by gas chromatography or liquid chromatography (LC)-tandem mass spectrometry (MS/MS). The determination of THC, THCCOOH, cannabinol (CBN), and Δ9-tetrahydrocannabinolic acid A (THC-A) was carried out on OF only using LC-MS/MS. In line with the widely accepted assumption that cannabis smoking results in a strong contamination of the oral cavity, we found that THC, and also THC-A, shows a sharp, high concentration peak just after smoking, with a rapid decrease in these levels within 3 h. No obvious differences were found between both groups concerning THC median maximum concentrations measured either in blood or in OF; these levels were equal to 1,338 and 1,041 µg/L in OF and to 82 and 94 µg/L in WB for occasional and heavy smokers, respectively. The initial WB THCCOOH concentration was much higher in regular smokers than in occasional users. Compared with the occasional smokers, the sensation of confusion felt by the regular smokers was much less while the feeling of intoxication remained almost unchanged.

5-Fluorouracil-associated severe hypertriglyceridaemia with positive rechallenge.

Chemotherapy-induced hypertriglyceridaemia (HTG) is a potential serious adverse event. Severe HTG with triglycerides (TG) >11.3 mmol/L (1000 mg/dL) can cause acute pancreatitis in addition to cardiovascular diseases such as coronary artery disease. While the association of capecitabine (5-fluorouracil (5-FU) prodrug) with clinically relevant HTG is a well-known adverse reaction, 5-FU is not typically associated with HTG. We here report the case of a patient who developed 5-FU-associated grade 4 HTG with TG level raising up to 37.1 mmol/L (3286 mg/dL) occurring after the ninth cycle of adjuvant FOLFOX (Fluorouracil and Oxaliplatin) chemotherapy. Fenofibrate treatment and diet were started. Chemotherapy was postponed and then resumed for two additional cycles. However, severe HTG recurred shortly after. Chemotherapy was therefore permanently stopped. Approximately 8 weeks after chemotherapy discontinuation, TG fell back to range at 2.1 mmol/L (189 mg/dL) allowing interruption of fenofibrate without HTG recurrence at 3 months.