Antiretroviral Drug Exposure and Response in Obese and Morbidly Obese People With Human Immunodeficiency Virus (HIV): A Study Combining Modelling and Swiss HIV Cohort Data.

BACKGROUND: Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. METHODS: Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5 and 60 kg/m2. Therapeutic drug-monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. Subsequently, the model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and nonobese individuals. RESULTS: The PBPK model predicted an average reduction in ARV exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared with nonobese (BMI: 18.5-25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load than nonobese PWH. CONCLUSIONS: The concentrations of ARVs are modestly reduced in obese individuals, with no negative impact on the virological response. Our data provide reassurance that standard doses of ARVs are suitable in obese PWH, including those who gained substantial weight with some of the first-line ARVs.

Acute ischaemic stroke in active cancer versus non-cancer patients: stroke characteristics, mechanisms and clinical outcomes.

BACKGROUND AND PURPOSE: Demographics, clinical characteristics, stroke mechanisms and long-term outcomes were compared between acute ischaemic stroke (AIS) patients with active cancer (AC) versus non-cancer patients. METHODS: Using data from 2003 to 2021 in the Acute STroke Registry and Analysis of Lausanne, a retrospective cohort study was performed comparing patients with AC, including previously known and newly diagnosed cancers, with non-cancer patients. Patients with inactive cancer were excluded. Outcomes were the modified Rankin Scale (mRS) score at 3 months, death and cerebrovascular recurrences at 12 months before and after propensity score matching. RESULTS: Amongst 6686 patients with AIS, 1065 (15.9%) had a history of cancer. After excluding 700 (10.4%) patients with inactive cancer, there were 365 (5.5%) patients with AC and 5621 (84%) non-cancer AIS patients. Amongst AC patients, 154 (42.2%) strokes were classified as cancer related. In multivariable analysis, patients with AC were older (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00-1.03), had fewer vascular risk factors and were 48% less likely to receive reperfusion therapies (aOR 0.52, 95% CI 0.35-0.76). Three-month mRS scores were not different in AC patients (aOR 2.18, 95% CI 0.96-5.00). At 12 months, death (adjusted hazard ratio 1.91, 95% CI 1.50-2.43) and risk of cerebrovascular recurrence (sub-distribution hazard ratio 1.68, 95% CI 1.22-2.31) before and after propensity score matching were higher in AC patients. CONCLUSIONS: In a large institutional registry spanning nearly two decades, AIS patients with AC had less past cerebrovascular disease but a higher 1-year risk of subsequent death and cerebrovascular recurrence compared to non-cancer patients. Antithrombotic medications at discharge may reduce this risk in AC patients.

Clinically relevant bidirectional drug-drug interaction between midostaurin and voriconazole.

Midostaurin is often prescribed with azole antifungals in patients with leukaemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition, it inhibits and induces various CYPs at therapeutic concentrations. Thus, midostaurin is associated with a high potential for drug-drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49-year-old woman with acute myeloid leukaemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (Ctrough 10.3 mg L-1 , target Ctrough 1-5 mg L-1 ). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six-fold above the average expected level, but without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favourable, with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism, leading to increased exposure of both. This case highlights the knowledge gap regarding drug-drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases.

[Pharmacotherapy: New drugs and vaccines in 2022]. / Pharmacothérapie - Nouveaux médicaments et vaccins disponibles en 2022.

A selection of drugs and vaccines newly available in Switzerland is reviewed. Shingrix: recombinant shingles vaccine recommended for all patients ≥65 years and some immunosuppressed patients. Nirmaltrevir/ritonavir: oral treatment of SARS-CoV-2 with a high potential of drug-drug interactions. Tixagevimab/cilgavimab: antibody combination for pre-exposure prophylaxis of SARS-CoV-2 in subjects without vaccine response or contraindication to vaccine. Cabotegravir/rilpivirine: 1st long-acting injectable treatment for HIV. Imvanex: monkeypox vaccine for subjects most at risk. Tezepelumab: first-in-class treatment for severe asthma. Eptinezumab: another anti-CGRP antibody for the prevention of migraine. Ponesimod: multiple sclerosis treatment with the advantage of a shorter half-life than fingolimod or ozanimod.

Une sélection de nouveaux médicaments et vaccins disponibles en Suisse est passée en revue. Shingrix : vaccin recombinant du zona recommandé chez les ≥ 65 ans et certains immunosupprimés. Nirmaltrevir/ritonavir : traitement oral du SARS-CoV-2 à haut potentiel d'interactions. Tixagévimab/cilgavimab : anticorps pour la prophylaxie préexposition du SARS-CoV-2 chez des sujets sans réponse vaccinale ou avec contre-indication au vaccin. Cabotégravir/rilpivirine : premier injectable à longue durée d'action contre le VIH. Imvanex : vaccin contre la variole du singe destiné aux sujets les plus à risque. Tézépélumab : premier traitement de sa classe pour l'asthme grave. Eptinézumab : un anticorps anti-CGRP de plus pour la prévention des migraines. Ponésimod : pour traiter la sclérose en plaques, avec l'avantage d'une plus courte demi-vie que le fingolimod ou l'ozanimod.

[Management of hyperuricemia in chronic kidney disease]. / Hyperuricémie et maladie rénale : prise en charge.

Hyperuricemia is often encountered as glomerular filtration rate decreased. It is associated with a more rapid decline of the renal function, but causality has not been demonstrated. Recent studies showed that treatment of hyperuricemia did not affect the progression in chronic kidney disease (CKD) patients. Thus, treatment with hypouricemic drugs of patients suffering of CKD and displaying asymptomatic hyperuricemia is not recommended. However, patients with CKD present often with acute flairs of gout, which might be difficult to treat. Therapeutic options are discussed in this article.

Une hyperuricémie apparaît précocement en cas de diminution de la filtration glomérulaire et de maladie rénale chronique. Elle est associée à un déclin plus rapide de la fonction rénale, mais un lien de causalité n'a pas été démontré. Plusieurs études récentes n'ont pas montré d'effet bénéfique d'un traitement hypo-uricémiant sur l'évolution de la fonction rénale. Ainsi, en cas d'hyper uricémie asymptomatique chez un patient souffrant de maladie rénale chronique, un traitement hypo-uricémiant n'est pas indiqué. Cependant, les patients souffrant de maladie rénale chronique font plus fréquemment des crises de goutte, et leur prise en charge est complexe car la maladie est à la fois plus résistante au traitement et les options thérapeutiques sont limitées. Celles-ci sont revues dans cet article.

[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.

Drugs Associated With Ischemic Stroke: A Review for Clinicians.

Certain drugs may increase the risk of ischemic stroke (IS). Our goal was to review associations between frequently used drugs and IS. We created an initial list of frequently used drugs to search Pubmed/MEDLINE from 1966 to 2020 and reviewed phase III and IV data, case series, and drug authorities' safety warnings to assess a potential association with IS. Drugs were grouped according to the World Health Organization Anatomical Therapeutic Chemical Classification System. Predefined criteria were applied to establish a level of evidence for an association, from A (high level of evidence of association) to E (high level of evidence of absence of association). In addition, we assessed relative risks and reviewed potential mechanisms of IS facilitation. We assessed 81 drugs or drug classes from 11 World Health Organization Anatomical Therapeutic Chemical Groups. We identified a high level of association for erythropoietin, combined contraceptives, oral estrogen replacement therapy, bevacizumab, tamoxifen, and antipsychotics and a moderate level for ponatinib, nilotinib, darunavir, and gonadotropin-releasing hormone agonists. Drug dose and treatment duration may modify the risk. For a substantial number of drugs, we found no association, and for others, there were insufficient data to categorize risk. We identified a high level of association of IS with a limited number of drugs, a potential association with some, and a lack of data for others. The summarized information may help clinicians to estimate the contribution of a drug to an IS, to better assess drug benefit-risk ratios, and to support decisions about using specific drugs.

Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity.

BACKGROUND: The extent of inappropriate prescribing observed in geriatric medicine has not been thoroughly evaluated in people ageing with HIV. We determined the prevalence of and risk factors for inappropriate prescribing in individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study. METHODS: Retrospective review of medical records was performed to gain more insights into non-HIV comorbidities. Inappropriate prescribing was screened using the Beers criteria, the STOPP/START criteria and the Liverpool drug-drug interactions (DDIs) database. RESULTS: For 175 included individuals, the median age was 78 years (IQR 76-81) and 71% were male. The median number of non-HIV comorbidities was 7 (IQR 5-10). The prevalence of polypharmacy and inappropriate prescribing was 66% and 67%, respectively. Overall, 40% of prescribing issues could have deleterious consequences. Prescribing issues occurred mainly with non-HIV drugs and included: incorrect dosage (26%); lack of indication (21%); prescription omission (drug not prescribed although indicated) (17%); drug not appropriate in elderly individuals (18%) and deleterious DDIs (17%). In the multivariable logistic regression, risk factors for prescribing issues were polypharmacy (OR: 2.5; 95% CI: 1.3-4.7), renal impairment (OR: 2.7; 95% CI: 1.4-5.1), treatment with CNS-active drugs (OR: 2.1; 95% CI: 1.1-3.8) and female sex (OR: 8.3; 95% CI: 2.4-28.1). CONCLUSIONS: Polypharmacy and inappropriate prescribing are highly prevalent in elderly people living with HIV. Women are at higher risk than men, partly explained by sex differences in the occurrence of non-HIV comorbidities and medical care. Medication reconciliation and periodic review of prescriptions by experienced physicians could help reduce polypharmacy and inappropriate prescribing in this vulnerable, growing population.

Pregnancy outcome following first-trimester exposure to fingolimod: A collaborative ENTIS study.

This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-ß-exposed pregnancies were compared. Rates of major congenital anomalies (MCA) were 4.8% (2/42) in the fingolimod group versus 2.3% (1/44) in the interferon-ß group (odds ratio, 2.2; 95% confidence interval, 0.2-24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-ß-exposed pregnancies was 0.6 (95% confidence interval, 0.2-1.8). Further studies are needed to definitely rule out a moderately increased MCA risk after fingolimod exposure during pregnancy.

[Pharmacovigilance update]. / Pharmacovigilance.

The main pharmacovigilance updates in 2020 are reviewed. Remdesivir in COVID-19: relatively safe but turns out to be less effective than expected. Hydroxychloroquine in COVID-19 : lack of efficacy and risk of arrhythmias. Cytokines storm in COVID-19: may impact pharmacokinetics. VEGF inhibitors: risk of aneurysm and artery dissection. Tofacitinib: dose-dependant risk of venous thromboembolic events. Ondansetron in the first trimester of pregnancy : a highly debated risk of orofacial cleft defects. Fingolimod : contraindicated during pregnancy due to suspected risk of congenital malformations. Ranitidine: global market withdrawal due to contamination with nitrosamines. Ulipristal for uterine fibroids : market withdrawal due to risk of severe liver injury. Ingenol mebutate : market withdrawal due to paradoxical risk of skin cancers.

Les principales actualités de pharmacovigilance 2020 sont passées en revue. Remdésivir et Covid-19 : moins efficace qu'attendu mais assez sûr. Hydroxychloroquine et Covid-19 : absence d'efficacité et risque d'arythmies. Orage cytokinique et Covid-19 : impact possible sur les paramètres pharmacocinétiques. Inhibiteurs du VEGF : risque d'anévrisme artériel et de dissection. Tofacitinib : risque d'événements thromboemboliques. Ondansétron au 1er trimestre de grossesse : risque controversé de fentes palatines. Fingolimod : contre-indiqué dans la grossesse pour possible risque malformatif. Ranitidine : retrait du marché mondial pour contamination par des nitrosamines. Ulipristal et fibromyomes utérins : retrait du marché pour risque d'atteinte hépatique grave. Mébutate d'ingénol : retrait du marché pour risque paradoxal de cancers cutanés.

[Medicines, sex and gender]. / Médicaments, sexe et genre.

Sex-related differences affecting pharmacokinetic and pharmacodynamic processes result mostly from sex dimorphisms in body composition, and liver and kidney function, in addition to hormonal regulation of enzymes, transporters and drug receptors. Gender biases have long compromised the identification of these differences in clinical trials. They also modulate prescription patterns and therapeutic benefits. Men and women would benefit from different standard dosages of some anti-infectives, anticancer agents and other treatments requiring precise dosage adjustment. This would alleviate the well-documented excess of adverse reactions affecting women. However, the variability of pharmacological responses within each sex exceeds the average male-female difference, highlighting the importance of other criteria for therapeutic individualisation.

Les processus pharmacocinétiques et pharmacodynamiques reflètent les dimorphismes sexuels affectant la composition corporelle, les fonctions rénale, hépatique et la régulation des enzymes, transporteurs et récepteurs de médicaments. Des biais liés au genre ont longtemps compromis l'identification de ces différences dans les essais cliniques. Ils modulent aussi la prescription et le bénéfice thérapeutique. Des posologies standard différentes entre hommes et femmes mériteraient d'être proposées pour certains anti-infectieux, anticancéreux et autres traitements requérant un ajustement posologique précis. Cela atténuerait le surcroît démontré d'effets indésirables touchant les femmes. La variabilité des réponses pharmacologiques dans chaque sexe excède la différence moyenne hommes-femmes, rappelant l'importance d'autres critères d'individualisation thérapeutique.

Real-life management of drug-drug interactions between antiretrovirals and statins.

BACKGROUND: PIs cause drug-drug interactions (DDIs) with most statins due to inhibition of drug-metabolizing enzymes and/or the hepatic uptake transporter OATP1B1, which may alter the pharmacodynamic (PD) effect of statins. OBJECTIVES: To assess the management of DDIs between antiretrovirals (ARVs) and statins in people living with HIV (PLWH) considering statin plasma concentrations, compliance with dosing recommendations and achievement of lipid targets. METHODS: PLWH of the Swiss HIV Cohort Study were eligible if they received a statin concomitantly with ARVs. HDL, total cholesterol (TC) and statin plasma concentration were measured during follow-up visits. Individual non-HDL and TC target values were set using the Framingham score and the 2018 European AIDS Clinical Society recommendations. RESULTS: Data were analysed for rosuvastatin (n = 99), atorvastatin (n = 92), pravastatin (n = 46) and pitavastatin (n = 21). Rosuvastatin and atorvastatin underdosing frequently led to suboptimal PD response. Insufficient lipid control was observed with PIs despite high atorvastatin concentrations, likely explained by inhibition of OATP1B1 resulting in less statin uptake in the liver. Target lipid values were more often achieved with unboosted integrase inhibitors due to both their favourable DDI profiles and neutral effect on lipids. Insufficient lipid control was common with pravastatin and pitavastatin regardless of co-administered ARVs and despite using maximal recommended statin doses. The latter suggests lower efficacy compared with rosuvastatin or atorvastatin. CONCLUSIONS: Suboptimal management of DDIs with statin underdosing was observed in 29% of prescriptions. Integrase inhibitor-based regimens and/or treatment with rosuvastatin or atorvastatin should be favoured in patients with refractory dyslipidaemia.

[Drugs that aggravate the course of COVID-19†: really†?] / Traitements aggravant une infection par le COVID-19†: vraiment†?

The safety of NSAIDs, corticosteroids and renin-angiotensin inhibitors in COVID-19 is challenged. NSAIDs may interfere with the defense process against viral infection and are best avoided. Systemic corticosteroids have not shown benefit in viral infection, including other coronavirus; thus they should be avoided, unless prescribed for another indication. The benefit-risk ratio is however clearly in favor of continuing inhaled corticosteroids in patients with asthma or COPD. ACE inhibitors and sartans upregulate the expression of angiotensin-converting enzyme 2 (ACE2), the pulmonary receptor for SARS-CoV-2. Any possible clinical impact of these treatments on COVID-19 infection remains to be clarified; in the meantime, they should be continued.

La sécurité des AINS, corticoïdes et antihypertenseurs agissant sur le système rénine-angiotensine lors d'infection à COVID-19 est mise en question. Les AINS pourraient interférer avec le processus de défense face à une infection virale ; ils sont donc plutôt à éviter. Les corticoïdes systémiques n'ont pas montré de bénéfice lors d'infections virales, y compris à d'autres coronavirus ; ils sont à éviter, sauf si prescrits pour une autre indication. Le rapport bénéfice/risque est en revanche clairement en faveur de la poursuite des corticostéroïdes inhalés chez les asthmatiques ou BPCO. Les IEC et les sartans modulent l'expression de l'enzyme de conversion de l'angiotensine 2 (ACE2), récepteur pulmonaire du SARS-CoV-2. L'impact clinique de ces traitements sur l'infection à COVID-19 reste à préciser ; en attendant, ils sont à poursuivre.

[Pharmacovigilance update]. / Pharmacovigilance.

The main pharmacovigilance updates in 2018 are reviewed. Quinolones : no longer recommended for mild or moderately severe infections. Denosumab in cancer patients: increased risk of new primary malignancies. Cyproterone : increased risk of meningioma at high dose. Saccharomyces boulardii : risk of fungemia in frail patients. Ulipristal : risk of hepatotoxicity. Daclizumab : early withdrawal from the market as risks clearly outweigh benefits. Interactions between boosted antiretrovirals and anti-P2Y12 : prasugrel appears as the best option. Neural tube defects in babies born to women treated with dolutegravir : a signal to investigate. Cobicistat-boosted antiretrovirals exposure is decreased during pregnancy. Fourth generation pills containing drospirenone : a greater propensity to prolong the QT interval than 2nd generation pills.

Les actualités de pharmacovigilance 2018 sont passées en revue. Quinolones : pas en première intention pour les infections simples. Dénosumab : risque accru de second cancer. Cyprotérone : à dose élevée, risque accru de méningiome. Saccharomyces boulardii : risque de fongémie chez les patients débilités. Ulipristal : risque d'hépatotoxicité. Daclizumab : retrait du marché en raison d'un rapport bénéfice-risque inacceptable. Interactions antirétroviraux boostés et anti-P2Y12 : le prasugrel apparaît comme la meilleure option. Exposition précoce au dolutégravir in utero et non-fermeture du tube neural : un signal à investiguer. Antirétroviraux boostés par cobicistat : des concentrations trop basses chez les femmes enceintes. Pilules de 4e génération avec drospirénone : une plus grande propension à allonger l'intervalle QT que les pilules de 2e génération.

[Pharmacovigilance update]. / Pharmacovigilance.

The main pharmacovigilance updates in 2017 are reviewed. Denosumab : rebound-associated multiple vertebral fractures after discontinuation. Canagliflozine: increased risk of foot/leg amputations. Biologic and targeted cancer therapies, direct-acting antivirals for chronic hepatitis C: risk of hepatitis B reactivation. Checkpoint inhibitors : immune-related adverse events and graft rejection. Fingolimod : rebound-associated reactivation of MS following withdrawal. Daclizumab: risk of severe liver injury leading to restricted use in MS patients. Posaconazole: risk of overexposure when switching from oral suspension to tablets. Voriconazole: cutaneous squamous cell carcinoma under long-term therapy. Proton pump inhibitors : early exposure might increase fracture risk in young children.

Les actualités de pharmacovigilance 2017 sont passées en revue. Dénosumab : fractures vertébrales multiples à l'arrêt (rebond). Canagliflozine : augmentation du risque d'amputation des membres inférieurs. Biologiques, anticancéreux ciblés et nouveaux traitements de l'hépatite C : possible réactivation du virus de l'hépatite B. Checkpoint inhibitors : atteintes auto-immunes diverses et rejet de greffe. Fingolimod : aggravation de sclérose en plaques (SEP) à l'arrêt (rebond). Daclizumab : restriction d'utilisation dans la SEP en raison de l'hépatotoxicité. Posaconazole : risque de surexposition lors de switch de la suspension orale aux comprimés. Voriconazole : carcinome cutané spinocellulaire sous traitement au long cours. Inhibiteurs de la pompe à protons : fractures lors d'exposition précoce chez les enfants.

[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.

[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.

[Pharmacovigilance update]. / Pharmacovigilance.

The main pharmacovigilance updates in 2013 are reviewed. Nitrofurantoin: lower efficacy and an increased risk of adverse events when creatinine clearance is below 60 ml/min. Dabigatran: contraindicated in patients with mechanical heart valves. Azithromycin: QT prolongation and increased risk of death. Zolpidem: towards a lower dosage. Roflumilast: avoid in patients known or at risk for mood disorders. Retigabine: indication restricted to last-line use and new monitoring requirements after reports of pigment changes in retina and other tissues. Telaprevir and rituximab: severe mucocutaneous reactions. Fingolimod: rare cases of progressive multifocal leucoencephalopathy. Tolvaptan: potential for hepatotoxicity. Nicotinic acid/laropiprant: suspension of marketing authorization as benefits no longer outweigh risks.

[Drug-induced adverse events in the elderly: a traveler's guide]. / Guide pratique des effets indésirables médicamenteux chez les seniors.

Elderly people are prone to drug-induced adverse events (AEs), which often manifest as an atypical clinical picture. The differential diagnosis of any new symptom or alteration in the general state of health in the elderly must, therefore, include AEs. This article offers a practical tool designed to help clinicians to rapidly identify which drugs may induce which kind of frequent symptoms or syndromes.

Joint fluid concentrations of amphotericin B after local application with calcium sulphate-report of 2 cases.

Fungal periprosthetic joint infections (PJI) are difficult to treat, due to important biofilm formation and limited local penetration of systemically administered antifungals. Calcium sulphate (CaSO4 ) might be a promising carrier to increase local concentration of antifungals. We hypothesized that local amphotericin B release from CaSO4 is high enough to significantly contribute to treatment of fungal PJI. We report joint fluid and serum concentrations of amphotericin B after local application with CaSO4 as an implanted resorbable carrier material as adjunct to standard surgical and systemic antifungal treatment in two cases of PJI with Candida spp. Maximal joint fluid amphotericin B concentration was 14.01 mg/L 5 days after the second local administration of liposomal amphotericin in Case One and 25.77 mg/L 14 days after the second local administration in Case Two. Concentrations higher than minimal inhibitory concentrations (MIC) could be measured for 21 days and 17 days after local administration in Case One and Two, respectively. In Case Two, serum concentration of amphotericin B was <0.01 mg/L 3 days after local administration of 450 mg liposomal amphotericin B. No local or systemic adverse reaction was observed. Fungal PJI was successfully eradicated in both cases with a follow-up of 12 months in Case One and 20 months in Case Two. Application of amphotericin B-loaded CaSO4 was associated with joint fluid concentrations higher than minimal inhibitory concentrations for Candida spp. for approximately 3 weeks, with the advantage that the carrier material dissolves spontaneously and does not require secondary removal. Relapse of fungal infections did not occur in these two patients.