Farid Kheloufi

Informativeness of patient initial reports of adverse drug reactions. Can it be improved by a pharmacovigilance centre

SummaryPurposeLittle is known about the informativeness of initial patient reports before they are reviewed by a pharmacovigilance centre (PVC). We aim to describe the patterns of patient adverse drug reaction (ADR) reporting in France and estimate the contribution of a review by a PVC assessor on the informativeness of these reports.MethodsA retrospective study was conducted on patient reports between July 2011 and July 2015. Informativeness of 16 key elements of information (including drug start and end date, duration of treatment, time to onset and duration of the ADR, outcome, medical history and concomitant medication) was assessed in initial reports before and after review by a pharmacovigilance assessor.ResultsOverall, 240 reports concerning 522 ADR and involving 278 drugs were reported over this 4-year period. Mean number of available key elements of information in initial reports was increased from 11/16 to 15/16 after review of reports by the PVC. Time to onset and duration of the ADR were respectively available in only 51 and 58% of the reports before review compared to 83 and 90% after review. Medical history and concomitant medication were missing in 75% of the initial reports compared to less than 30% of the reports after review. Contacting the reporter enabled an increase of informativeness of most elements of information for more than 90% of the reports.ConclusionPatient reports often need to be completed on key elements of information that are required to assess reports. Both upstream education of patients and downstream intervention of a pharmacovigilance assessor to complete missing information could help to enhance the informativeness of such reports.

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 PPIs, especially in elderly and/or in the context of chronic use.

Comment on “Patient Reporting in the EU: Analysis of EudraVigilance Data”

We read with interest the work by Banovac et al. [1] describing the evolution of patient reporting before and after the latest European pharmacovigilance regulation became operational in 2012. For the first time in the European Union (EU), and over a 6-year period, they compare patient and healthcare professional (HCP) reports according to different types of data such as adverse drug reaction (ADR) type, reported substances, indication, and demographic characteristics of patients. They confirm that patient reports complement those performed by HCPs in terms of reported System Organ Class (SOC) and reported substances. They also give a real overview of patient reporting in the EU, which is very welcomed. Patient reporting of ADRs has become one of the challenges of 21st century pharmacovigilance [2]. Indeed, patients are increasingly involved in pharmacovigilance reporting systems worldwide and patient voice is given more and more consideration by health authorities and marketing authorization holders (MAHs). Additionally, growing initiatives from consumer organizations are being recognized as potential valuable sources of information [3]. Given an increase in patient reporting in the EU, the results of this study raise a major issue, which is the role of patient reporting and the quality of reported information. The authors acknowledge that measuring the completeness of reports (level of population of all relevant fields in an individual case safety report [ICSR]) was not in the scope of their study. As mentioned, it is a subject for future research and its impact on signal detection should be further investigated. The value of the reports as a signal is directly dependent on the amount of clinically relevant information they include in addition to the fact that an ADR report requires a thorough examination of the potential drug–ADR association. Some studies revealed no major qualitative difference between patient and HCP reports but did not study the intrinsic quality of the reports [4]. Indeed, published data concerning patient reports and the availability of important elements of information such as time to onset of the ADR, concomitant medication, medical history, or outcome are scarce [5–7]. In a 5-year study conducted on patient reports received after French legislation legally authorized patient reporting in June 2011, we recently reported that several elements of information needed for a proper assessment of ADR are not always provided in patient reports. Completeness of 16 key elements of information (including drug start and end date, duration of treatment, time to onset and duration of the ADR, outcome, medical history, and concomitant medication) was assessed in initial patient reports. The mean number of available key elements of information in initial reports was 11 of 16. Time to onset and duration of the ADR were respectively available in only 51 and 58% of the reports. Medical history and concomitant medication were This comment refers to the article available at doi:10.1007/s40264017-0534-1.

Perampanel-associated self-harm ideation after dosage increase

Perampanel (Fycompa®) is an AMPA receptor antagonist used to treat epilepsy that has recently raised concerns about suicidal ideation and associated behavior [1, 2]. We describe the case of Mr. A, a 35-year-old man without any history of psychiatric disorders, treated with perampanel for a pharmacoresistant focal epilepsy, who subsequently experienced self-harm ideation without suicidal intention after dosage increase. In March 2015, oxcarbazepine 450 mg was prescribed to be taken twice daily by Mr. A due to a focal tonic-clonic seizure with a secondarily generalized seizure identified as a right temporal epilepsy. Mr. A had not experienced any epilepsy for several months until he developed two clustered seizures over a period of 1 month. Oxcarbazepine dosage was increased to 900 mg twice daily. Perampanel was added at a dose of 2 mg daily over a 2-week period and he was advised by his neurologist about the potential risk of behavioral disorders occurring during perampanel therapy. No adverse drug reaction (ADR) occurred on perampanel 2 mg daily. Perampanel and oxcarbazepine were the only medication taken by Mr. A. After 15 days, perampanel was increased to 4 mg daily. Less than 1 week after the dose was increased to 4 mg daily, Mr. A developed self-harm ideation in the form of wristcutting ideation, every time he saw a knife or a blade. Mr. A. continued his treatment for 48 h and compulsive self-mutilation ideation persisted. Perampanel was stopped and oxcarbazepine was continued. Ideas of self-injury disappeared within the week following the discontinuation of perampanel and Mr. A. did not cut his wrists. He confirmed to his neurologist that he only had the compulsion to do harm to himself and did not want to commit suicide or die. No other neuropsychiatric event occurred in the following months. To our knowledge, self-harm ideation without any history of psychiatric disorders has ever been described and this case raises the issue of compulsive self-mutilation behavior during the titration period of perampanel. It also reflects the predictive value of behavioral studies in animals receiving perampanel as self-mutilation was observed during preclinical studies [3]. A pharmacodynamic effect involving a dosagerelated effect seems to explain this ADR. The time of onset of self-harm ideation suggests a favorable chronological relationship to perampanel as the effect occurred less than 1 week after dosage increase. The disappearance of the effect is also chronologically compatible with a shortened half-life of elimination of perampanel due to a drug-drug interaction with oxcarbazepine that increases the total clearance of perampanel by twofold through induction of its metabolism [4]. To date, self-mutilation ideation especially those not related to suicidal purpose and the risk of psychiatric ADR during dosage increase remain not clearly identified in the SCP of Fycompa®. Only ADRs such as aggressive behavior, suicidal ideation, or attempt are mentioned. Self-harm ideation is stated only in the patient package leaflet which is not often read by patients. Moreover, it * Joëlle Micallef joelle.micallef@ap-hm.fr

Urinary retention associated with aripiprazole: Report of a new case and review of the Literature

Therapie - In Press.Proof corrected by the author Available online since mercredi 22 novembre 2017

Estimated glomerular filtration rate but not solute carrier polymorphisms influences anemia in HIV-hepatitis C virus coinfected patients treated with boceprevir or telaprevir-based therapy.

Objectives:Ribavirin (RBV) induced anemia may be influenced by host genetic factors affecting RBV transport solute carrier (SLC) or metabolism inosine triphosphatase (ITPA), as already reported. We investigated the influence of single nucleotide polymorphisms (SNPs) on SLC genes on anemia, RBV trough concentration (Ctrough) and response in HIV–hepatitis C virus coinfected patients receiving triple therapy with boceprevir or telaprevir. Methods:Patients from the ANRS HC26/HC27 studies were genotyped for SLC28A3 SNPs (rs10868138 and rs56350726) and SL29A1 SNPs (rs760370). Hemoglobin (Hb) decline was collected at baseline day 0 (D0), week 4 (W4) and week 8 (W8), and RBV Ctrough was measured at W4 and W8 by HPLC. A multivariate analysis including SLC SNPs, estimated glomerular filtration rate (eGFR), ITPA deficiency and RBV Ctrough was performed to determine predictive factors of anemia and response. Results:SLC genotyping was performed in 130 patients. Neither SLC28A3 nor SLC29A1 SNPs were associated with Hb decline both at W4 and W8. No association was found between SLC polymorphisms and RBV Ctrough. Independent predictive factors of Hb decline at W4 were D0 Hb, ITPA deficiency and W4 RBV Ctrough in the multivariate analysis (P < 0.05). Only D0 Hb, W4 RBV Ctrough and eGFRD0–W8 were predictive of anemia at W8 (P < 0.05). Response was not influenced by SLC SNPs. Conclusion:eGFR, but not SLC polymorphisms, influences anemia in HIV–hepatitis C virus coinfected patients receiving boceprevir-based or telaprevir-based therapy. RBV is still a cornerstone of hepatitis C treatment, thus renal function and RBV Ctrough should be monitored in patients receiving RBV regimen combined with first-generation direct-acting antiviral agent.