PHARMACOLOGIE CLINIQUE
PS-001Adverse drug reactions reported with BCR/ABL1 tyrosine kinase inhibitors
G Tournairea, F Despasb, V Rousseaua, JL Montastruca, E Bondon-Guittona aService de Pharmacologie Medicale et Clinique, Centre Midi-Pyrenees de
Pharmacovigilance, Pharmacoepidemiologie et Informations sur le Medicament, Pharmacop^ole Midi-Pyrenees, Faculte de Medecine de l’Universite de Toulouse, Centre Hospitalier Universitaire– Toulouse (France);bService de Pharmacologie Medicale et
Clinique, Faculte de Medecine de l’Universite de Toulouse, Centre Hospitalier Universitaire– Toulouse (France)
Introduction: Imatinib (Glivecâ), dasatinib (Sprycelâ) and nilotinib (Tasignaâ) are three BCR/ABL1 tyrosine kinase inhibitors (TKI) used in chronic myeloid leukemia (CML). They also inhibit many other receptors: c-kit, DDR1, DDR2, PDGF. Since receptor affinity varies according to the BCR/ABL1 TKI, their adverse drug reactions (ADRs) should also be different. Retrospective studies suggest that the frequency of vascular adverse events in patients receiving imatinib is significantly lower than that observed with nilotinib. We performed an observational study to describe ADRs reported in France with imatinib, dasatinib and nilotinib. We also investigated the association between exposure to these TKIs and the occurrence of specific ADRs. Material and methods: We used the French PharmacoVigilance Database to select ADRs reported with imatinib, dasatinib and nilotinib from their marketing (23 July 2001, 1 October 2006 and 1 January 2007 respectively) until 31 Octo-ber 2014. A descriptive analysis was performed to identify the most frequently reported ADRs and then, a case/non-case study to measure the association between the TKIs and their most frequently reported ADRs. Reporting odds ratios (ROR) with the relevant 95% confidence intervals were calculated.
Results: We found 899 cases of ADR with imatinib, 221 with dasatinib and 131 with nilotinib. Among all ADRs, the most frequently reported were peripheral edema and pruritus with imatinib (4.3% and 4% respectively), pleural effusion and pul-monary arterial hypertension with dasatinib (29.4% and 15.8% respectively), and peripheral arterial occlusive disease and myocardial infarction with nilotinib (11.1% and 5.8% respectively). Among “serious” ADRs, the most frequent were the same than previously cited for dasatinib and nilotinib, and for imatinib, they were hepatitis and pleural effusion. All these ADRs, except pruritus, were significantly more often reported with the TKI than with all other drugs registered in the French Phar-macoVigilance Database. ROR were between 2.8 [1.9–4.0] for hepatitis with imatinib and 1570.0 [808.2–3049.8] for peripheral arterial occlusive disease with nilotinib. Discussion/Conclusion: Imatinib, dasatinib and nilotinib are three BCR/ABL1 TKI with a different spectrum of ADRs. Physicians have to be aware about the risk of fluid retention and hepatic disorders with imatinib, respiratory disorders with dasatinib and cardiovascular disorders with nilotinib.
PS-002
Asthmatic patients in pharmacies: asthma control and treatment adherence. The SPOC study
A Zukowskia, M Molimardb, J Bezinb aUniversite de Bordeaux – Bordeaux (France); bUniversite de Bordeaux, CHU de Bordeaux, Service de Pharmacologie Medicale,
INSERM U657, Bordeaux PharmacoEpi, INSERM CIC1401– Bordeaux (France) Introduction: Asthma is a fluctuating disease influenced by many etiological or seasonality factors, difficult to correct, but also others such as medication and its adherence. The objective of this study was to evaluate the asthma control and treatment adherence of asthmatic patients treated with background treatment. Material and methods: This transversal descriptive study was performed by ques-tioning asthmatics patients in five Gironde’s pharmacies during the period from 1 January 2015 to 6 December 2015. Inclusion criteria were i) age of 18 years old and over, ii) asthma for more than 3 months, and iii) treated with background asthma treatment. The study questionnaire was composed of 3 parts: demographic charac-teristics, asthma control (Asthma Control Test, ACTTM
) and treatment adherence (Patient Medication Adherence Questionnaire over the last 3 days and the preceding Weekend, PMAQ-3W). Associated factors to asthma control and treatment adher-ence were evaluated using multivariate stepwise logistic regression.
Results: One hundred eleven patients were included in the study. Median age was 40 years (interquartile range: 28–55) and 52.3% of patients were men. A majority of patients were treated with corticosteroids and long-acting beta-agonists in fixed-combination (73.9%). Questionnaire showed that 36.9% of patients had controlled asthma and 41.4% of patients were completely adherent to background asthma treatment. Multivariate analysis showed that workers compared to retired or unem-ployed (Odds Ratio (OR): 3.48, 95% confidence interval (CI): 1.30; 9.30) and smokers compared to non-smokers or past-smokers (OR: 2.98, 95% CI: 1.22; 7.27) were more at risk of having an uncontrolled asthma. Similarly, it showed that patients without comorbidities compared to those with (OR: 3.59, 95% CI: 1.22; 10.56) and smokers compared to non-smokers or past-smokers (OR: 2.43, 95% CI: 1.05; 5.60) were more at risk to be non-adherent to background asthma treatment.
Discussion/Conclusion: This study showed that uncontrolled asthma and non-adherence to asthmatic treatment were frequent among asthmatic patients. This study allowed to identify a high-risk patient profile, and validates the use of the questionnaire for the pharmacy’s practice.
PS-003
Validation of an automated whole blood extraction coupled with liquid chromatography/tandem mass spectrometry assay applied to high throughput routine therapeutic drug monitoring of cyclosporine A, tacrolimus, everolimus and sirolimus
G Deslandes, M Gregoire, C Renaud, C Monteil-Ganiere, C Azoulay, A Pineau, P Jolliet Evin, E Dailly University Hospital of Nantes– Nantes (France)
Introduction: The whole blood extraction for liquid chromatography/tandem mass spectrometry (LC-MS/MS) simultaneous quantification of cyclosporine A
(Cys A), tacrolimus (Tacrs), sirolimus (Siros) and everolimus (Evers) is usually a manual work. A fully automated method was developed and validated to reduce the manual work using a liquid handler.
Material and methods: The identification of samples by barcode reading for producing of a sample list which is transfered to LC-MS/MS system, homogeniza-tion of whole blood, sampling of whole blood by primary tube cap-piercing, whole blood mixing after adding ZnSO4/methanol containing deuterated internal standards, centrifugation and recovering of deproteinised supernatants were auto-mated. The 96-well V-bottom micro-plate prepared by the robotic system is ana-lyzed by the LC-MSMS system with online solid phase extraction followed by separation on a phenyl hexyl analytical column.
Results: The inter- and intra-day imprecision and inaccucary were lower than 15% for all the drugs. No cross–contamination was observed. The comparison between manual and automated extraction investigated by linear regression showed a high correlation between results [(Tacrs “automated”) = 1.0927 x (Tacrs “manual”)0.36; (Cys A “automated”) = 1.0367 x (Cys A “man-ual”)+4.7133; (Siros “automated”) = 0.9775 x (Siros “manual”)+0.7157; (Evers “automated”)= 1.0186 x (Evers “manual”)+0.0112].
Discussion/Conclusion: This automated method is accurate, sensitive and pre-cise and is applied for high throughput (over 100 samples daily) therapeutic drug monitoring of immunosuppressive drugs in routine practice leading to an increase in quality.
PS-004
Current state of specific pediatric reports: misuse, abuse, overdose and medication error
J Mahe, G Veyrac, P Jolliet Department of Clinical Pharmacology, Institute of Biology, University Hospital– Nantes (France)
Introduction: The early detection of adverse drug reactions (ADRs) is an essen-tial part of Pharmacovigilance (PV), especially in pediatric population for which data from clinical trials are limited. European directive include in the ADR defini-tion overdose, misuse, abuse and medicadefini-tion error (ME) nodefini-tion. The aim of this study is to assess the ADRs reports associated with overdose, misuse, abuse and ME in pediatric population and to estimate the trend since the implementation of new directive in November 2012.
Material and methods: A retrospective study was conducted between January 1995 and November 2015. Data were extracted from the French PV database according to: source (Nantes), date, origin (ambulatory care or hospital), case type (overdose, abuse, ME), drug’s data (misuse) and age-groups: newborns (0– 27 days), infants (28 days–23 months), children (2–11 years) and teenagers (12–17 years). Each effect was classified according to the severity and System Organ Classification (SOC). Each drug was classified using Anatomical Therapeu-tic and Chemical system.
Results: During this period, 95 reports met the criteria and are serious for 72%. For newborns were found 3 ME; for infants 12 ME, 2 misuses and 3 overdoses; for children 1 abuse, 15 ME, 5 misuses and 17 overdoses; for teenagers 3 ME, 6 misuses and 28 overdoses. Reports are more common under the “nervous sys-tem” and “psychiatric” SOCs. The most represented drugs are psycholeptics and analgesics. Only 10 reports (misuse and ME) come from ambulatory care with miscellaneous drugs. Since November 2012, we observed an increase of 150% in these types of cases.
Discussion/Conclusion: This study conducted with stratification by age groups allows us to define different profiles. ME occurs more frequently in population aged 0–12 years with important seriousness under 2-year-old (vulnerable group, not suitable formulations, complex dose calculation). Misuse concerns all age-groups and all drugs, and is usually associated with non-serious neuropsychiatric effects. For overdoses must be distinguished: i) accidental overdoses, observed in children with psychotropic drugs prescribed for their parents ii) voluntary over-doses, observed in teenagers and predominantly involves acetaminophen. Despite the underreporting, our collaborations with pediatric, toxicology and risk man-agement departments have enabled us to improve the number of reports. The implementation of corrective and preventive actions needs to promote and improve the quality of pediatric ADRs, especially in ambulatory care.
PS-005
Effect of weight-loss induced by bariatric surgery on morphine glucuronidation
C Lloret-Linaresa, H Luob, A Rouquettec, C Poitoud, J Tordjmand, L Labatb, JF Bergmanne, X Declevesb aDepartement de medecine interne, H^opital Lariboisiere –
Paris (France);bD
epartement de pharmacologie et toxicologie, H^opital Cochin – Paris (France);cUnite INSERM U1178, UniversitesParis Sud et Paris Descartes – Paris
(France);dService de Nutrition, Groupe Hospitalier Piti
e-Salp^etriere – Paris (France);
eDepartement de medecine interne, H^opital Lariboisiere, Toxicologie, H^opital Cochin –
Paris (France)
Introduction: We previously demonstrated that Roux-en-Y gastric Bypass (RYGB) and its associated weight loss increased the rate at which oral morphine is absorbed, the morphine Cmax and AUC0-inf in comparison with their preoper-ative level [1].
The main purpose of the present study was to study the morphine glucuronida-tion, catalyzed by the UDP-glucuronosyltransferase (UGT) UGT2B7, assessed by the metabolic ratios AUC0-inf (M3G+M6G)/morphine, before and after RYGB and its associated weight loss. The secondary objective was to identify the clinical or biological factors involved in the variation of glucuronidation.
Material and methods: The obese subjects were given a single oral dose of 30 mg of morphine sulphate oral solution before (n= 25; BMI=43.2 kg/m2 (35.4–61.9)) and six months after RYGB (n = 19; BMI=32.3 kg/m2 (25.4–46.0)) in obese volunteers. Preoperative, peroperative and postoperative clinical and bio-logical data were collected including body composition assessment, data on hep-atic steatosis and fibrosis, the adipocyte volume. Morphine and its major metabolites (M3G and M6G) were analyzed in plasma by a validated method using liquid chromatography mass spectrometry in tandem (LC-MS/MS). The
plasma morphine, M3G and M6G concentrations vs. time data obtained from each individual subject were submitted to a non-compartmental pharmacokinetic analysis using WinNonlinâ.
Results: The metabolic ratio AUC0-inf M3G+M6G/Morphine decreased between the preoperative and 6 months postoperative periods (48.8 (23.8–124.5) to 31.0 (14.5–69.6)).
The change in glucuronidation was associated with the change in several clinical and biological data: change BMI (rho=0.5, P = 0.02), fat mass in Kg (rho=0.5, P= 0.04), and triglycerides (rho=0.5, P = 0.04). The change in glucuronidation was not associated with the amount of steatosis, fibrosis or NASH of the liver. Discussion/Conclusion: In this prospective study, the glucuronidation capacity of morphine is decreased after surgery induced weight loss. This change is associ-ated with the reduction of several markers of adiposity and of triglyceride levels that may be independently involved in morphine glucuronidation capacity. Reference:
[1] Lloret-Linares C et al. Clin pharmacokinet (2014) 53 919–930.
PS-006
Initial dose optimization of busulfan in pediatric onco-hematology: a new method increasing the achievement of the therapeutic target
M Philippea, N Bleyzaca, Y Bertranda, M Neelyb, S Goutellec aInstitut d’Hematologie
et d’Oncologie Pediatrique – Lyon (France);bLaboratory of Applied Pharmacokinetics,
Children Hospital of Los Angeles, University of Southern California– Los Angeles (USA);
cService Pharmacie, H^opital Pierre Garraud, Hospices Civils de Lyon – Lyon (France)
Introduction: Busulfan is used as myeloablative agent for hematopoietic stem cell transplant conditioning (16 doses over 4 days). It has a narrow therapeutic index, with an exposure (AUC) target range of 900 to 1500lM min/dose. Many studies have proposed dose regimens based on population PK models [1–3], but none of them was specifically built to optimize the achievement of the AUC target range. The objective of this work was to develop a new PK method for busulfan initial dose deter-mination in pediatrics for maximizing the probability of target attainment (PTA). Material and methods: This method was based on a nonparametric population PK model of busulfan [4]. This model has been used to estimate the individual PK parameters and concentrations from 163 children treated by intravenous busulfan between 2006 and 2015. For each patient and any given dose, the model was used to calculate 29 possible AUC values and to calculate the prior probability that the AUC is within the target range. The individual optimal dose (OPT dose) has been determined as the dose associated to the highest PTA. Then, OPT doses have been simulated in each patient using their individual PK parame-ters. Simulated AUC after one (AUC1) and 16 doses (AUC16) have been calcu-lated and compared to the recommended target range. Finally, we compared our method with three other model-based PK methods for initial dosing: Nguyen [1], Paci [2] and McCune [3]. The main endpoint of this study was the PTA after the 1st dose (AUC1) and the 16th dose (AUC16).
Results: Mean OPT dose was 1.49 mg/kg (min – max: 1.22–1.92) for AUC1 and 1.16 mg/kg (0.84–1.73) for AUC16. On average, OPT dose was higher than the other methods. After the 1st dose, the PTA for AUC1 was 76.1% with OPT dose, compared to 41.7% with the Nguyen dose, 36.2% with the Paci dose and 46.6% with the McCune dose (P< 0.001). After 16 doses, the PTA for AUC16 was 74.9%, compared to 64.4% with the Nguyen dose, 58.9% with the Paci dose and 68.7% with the McCune dose (P< 0.001).
Discussion/Conclusion: This original method for initial dose calculation is asso-ciated with a faster and greater target attainment than currently used methods for busulfan dosing. This work being mainly based on simulations, it must be prospectively confirmed by a clinical study.
References:
[1] Nguyen et al. Bone Marrow Transplantation (2004) 33, 979–987. [2] Paci et al. Ther Drug Monit 2012) 34, 198–208.
[3] Mc Cune et al. Clin Cancer Res (2014) 20(3), 754–63. [4] Neely et al. submitted to Therapeutic drug monitoring.
PS-007
Misuse of benzodiazepines in the French population: a cohort study in the Echantillon Generaliste de Beneficiaires between 2007 and 2012 A Panes, R Lassalle, MA Bernard, C Dureau-Pournin, A Pariente,
A Fourrier-Reglat Universite de Bordeaux – Bordeaux (France)
Introduction: Benzodiazepines are commonly used in France. A recent study per-formed by the health authorities has reported that 17% of the French population had a benzodiazepine dispensation at least once in 2012. Numerous studies have shown that benzodiazepine use and especially their misuse is associated with risks such as falls, bone fractures, dementia, road traffic accidents and work injuries. In the context of the DRUGS-2M program, the study objective was to estimate the frequency of ben-zodiazepine misuse in France between 2007 and 2012 using a French insurance claims database (EGB, Echantillon Generaliste de Beneficiaires).
Material and methods: Between 2007 and 2012, every subject contributing to the EGB with a first benzodiazepine dispensation (hypnotics including derivatives, i.e. zopiclone, zolpidem, and anxiolytics), and with at least one-year history and follow-up in the database was included in the study. The date of first dispensation was the index date. Three misuse criteria were defined: i) frequency of concomi-tant dispensations of two benzodiazepines of the same type within 30 days fol-lowing the index dispensation; ii) frequency of index dispensations covering more than 4 weeks of treatment for hypnotics and more than 12 weeks for anxiolytics; iii) frequency of at least one new dispensation of a hypnotic or anxiolytic over the 2 months following the end of the treatment coverage period.
Results: About 28 000 subjects were identified each year between 2007 and 2012 as new users of benzodiazepines (about 10 000 hypnotics and 18 000 anxiolytics each year). According to the year of benzodiazepine initiation, 27% to 30% of hypnotic users and 17% to 20% of anxiolytic users had at least one mis-use criterion. The most frequent mismis-use criterion was renewal of the first dispen-sation over the 2 months following the end of the treatment coverage period, which varied between 2007 and 2012 from 19 to 22% for hypnotics and from 10 to 12% for anxiolytics. Misuse by a treatment covering more than 4 weeks
for hypnotics varied from 14 to 16%, and covering more than 12 weeks for anxi-olytics varied from 11 and 19%. Misuse by concomitance varied from 4 to 6% for both hypnotics and anxiolytics.
Discussion/Conclusion: According to the considered criteria, one-third of hyp-notic users and one-fifth of anxiolytic users in France presented with misuse of benzodiazepines. These results confirm that actions to improve good prescription and use of benzodiazepines are still needed in France.
PS-008
Association of the OPRM1 and COMT genes’ polymorphisms with the efficacy of morphine in Tunisian cancer patients: impact of the high genetic heterogeneity in Tunisia?
I Chattia, I Creveauxb, JB Woillardc, S Langlaisb, A Amaraa, L Ben Fatmad,
A Saada, M Gribaaa, F Liberte aCHU Farhat Hached, Laboratoire de Cytogenetique, de
Genetique Moleculaire et de Biologie de la Reproduction Humaine – Sousse (Tunisia);
bFaculte de Medecine, Laboratoire de Biochimie medicale – Clermont-Ferrand (France); cUniversite Limoges, CHU Limoges, INSERM UMR 850 – Limoges (France);dCHU
Farhat Hached, Service de carcinologie– Sousse (Tunisia);eService de Pharmacologie,
H^opital Gabriel Montpied, CHU de Clermont-Ferrand, Clermont Universite, INSERM, U1107 NEURO-DOL– Clermont-Ferrand (France)
Introduction: Opioid therapy is a mainstay in acute and chronic pain manage-ment especially for cancer related pain. Today, more evidence suggests that genetic variability plays an important role in the opioids’ clinical efficacy. The doses of morphine needed for pain relief vary highly between individuals and this variation is only partly explained by morphinic bioavailability and by differences in the intensity of pain stimuli. The goal of this study was to investigate the asso-ciation between 3 singles nucleotid polymorphisms (SNPs) in the Mu opioid receptor gene (MOR1; rs17174629, rs1799972 and rs1799971) and 1 in the COMT gene (rs4680) on the morphine doses needed to decrease the pain inten-sity in Tunisian cancer patients.
Material and methods: One hundred twenty-nine cancer patients treated with different doses of morphine were included in this study. Associations between dose (continuous), dose escalation (yes/no) and SNP or haplotypes were investi-gated using linear multiple regressions and logistic regressions respectively adjusted on metastases and pain covariates in the R software.
Results: Unlike other studies on Caucasian and Chinese populations [1–3], no significant association was found in the present study between 3 SNPs in OPRM1 and 1 SNP in COMT and dose escalation or dose requirement.
Discussion/Conclusion: No association has been detected in our population group, unlike other studies for other populations. This result can be explained by the strong genetic heterogeneity of our population, which has already been described. Indeed, Fadhlaoui-Zid et al. have demonstrated the extreme genetic heterogeneity in some countries of North Africa, taking the example of Sousse, where we recruited most of our patients [4]. This fact will have to be taken into account for further studies.
References:
[1] Rakvag T.T. et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain (2005) 116(1–2) 73–8.
[2] Chou W.Y. et al. Association of l-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol. Scand. (2006) 50(7) 787–92. [3] Reyes-Gibby C.C. et al. Exploring joint effects of genes and the clinical efficacy
of morphine for cancer pain: OPRM1 and COMT gene. Pain (2007) 130(1–2) 25–30.
[4] Fadhlaoui-Zid K. et al. Sousse: extreme genetic heterogeneity in North Africa. J Hum Genet (2015) 60(1) 41–9.
PS-009
Good use and knowledge of paracetamol among self-medicated patients: prospectivs study in community pharmacies
N Petitpaina, AE Severina, J Scala-Bertolab, C Latarchec, M Yelehe-Okoumaa,
P Di Patriziod, P Gilleta aCentre R
egional de Pharmacovigilance de Lorraine, CHRU de Nancy– Nancy (France);bLaboratoire de Pharmacologie clinique, Toxicologie, CHRU
de Nancy– Nancy (France);cDirection de la Qualit
e, CHRU de Nancy – Nancy (France);
dDepartement de Medecine Generale, Universite de Lorraine – Nancy (France)
Introduction: Paracetamol, the highest over-the-counter selling drug in France [1], is also the first cause of acute hepatic failure [2]. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. Material and methods: We conducted a prospective observational study in ran-domly selected community pharmacies of Metz-agglomeration (230 000 inhabitants, France). Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous auto-questionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Results: 24 community pharmacies participated and 302 questionnaires were collected. Patients were mainly females (63.0%) and belonged to the 35–55 years old range (41.4%). Most of patients (84.4%) could be considered as « good users» and independent factors of good use were (i) a good knowledge of aceta-minophen (OR=5.3; P < 0.0001) and more surprisingly, (ii) the fact of having no children (parentality: OR= 0.1; P = 0.006). Responses corresponding to involun-tary overdosage were mostly due to a too short interval between drug intakes (3 h). Only 30.8% of patients were aware of liver toxicity of acetaminophen and only 40.7% knew the risk of the association with alcohol. Both good use and knowledge were significantly higher in patients looking for information from their pharmacist, physician and package leaflet.
Discussion/Conclusion: Patients should definitely be better informed about acetaminophen to warrant a better safety of its consumption. Pharmacists and physicians have to remind patients the risk factors of intentional overdose and liver toxicity. Package leaflets have also to be more informative.
References:
[1] ANSM. Analyse des ventes de medicaments en France en 2013 [Internet]. [cited 2015 Mar 9];Available from: http://ansm.sante.fr/var/ansm_site/stor-age/original/application/3df7b99f8f4c9ee634a6a9b094624341.pdf.
[2] Gulmez S et al. Liver transplant associated with paracetamol overdose: results from the seven-country SALT study. Br J Clin Pharmacol (2015) 80, 599–606.
PS-010
Hydroxychloroquine induce hearing loss: first case of positive rechallenge and review of the French pharmacovigilance databasis JN Chateleta, M Auffreta, J Benea, L Gaboriaua, M Lambertb, S Gautiera aCRPV de
Lille– Lille (France);bService de medecine interne CHRU de Lille – Lille (France) Introduction: Hydroxychloroquine (HCQ) is a 4-aminoquinoline derivate approved in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis. Hearing loss is described with HCQ and other drugs with similar structures: quinine and chloroquine but is still under debate about the drug responsibility.
Material and methods: We report a case of hearing loss induced by HCQ with a positive rechallenge 16 years later and review cases reported to the French pharmacovigilance database (FPVD).
Results: A woman, with systemic lupus diagnosed 20 years earlier, was initially treated with HCQ 400 mg/d and corticosteroids. In December 1997, aged 33, after several years of treatment, she presented bilateral hearing loss associated with vestibular syndrom. HCQ was stopped and methylprednisolone bolus were initiated leading to an improvement. Two etiologies were evocated: HCQ role or lupus flare. Between 1998 and 2013, she was treated with methotrexate and coticosteroids. In July 2013, due to a lasting joint pain, HCQ was started again (400 mg/d 5d/7). Three months later, in October 2013, she presented with a vestibular syndrom. A neuritis was diagnosed. An RMI was performed and found no anomalies. HCQ was stopped. In March 2014, a bilateral sensorineural hear-ing loss persisted. Corticosteroids bolus were introduced in April 2014. In September 2014, there was no improvement of hearing loss but no worsening. A hearing aid was then proposed to the patient. The role of the disease could not be totally excluded in the onset of hearing loss, but the role of HCQ was discussed again. In the FPVD, 22 cases of hearing loss induced by HCQ were found. Bilat-eral and unilatBilat-eral damages were described. Time of onset varied from sevBilat-eral days to several years after HCQ initiation. In most of the cases (12/22), the trou-ble was irreversitrou-ble, in 7 cases, a partial or total amelioration was observed. Discussion/Conclusion: Ototoxicity of HCQ is described but there has never been a positive rechallenge reported. The mechanism involved is not known and several explanations have been proposed to explain chloroquine ototoxicity: accu-mulation of chloroquine in melanocytes that could interfere with melanine metabo-lism, injuries to the cochlear sensory hair, decrease in neuronal population, loss of supporting hair cells and atrophy of stria vascularis. Physicians should be aware of this side effect of HCQ that can lead sometimes to irreversible hearing loss.
PS-011
Detection of drug-induced hydro-electrolytic adverse reactions by retrospective analysis of renal and metabolic physiological investigations data
H Bagheri, LA Dinh, N Mongkhonmath, M Vallet, I Tack, JL Montastruc Pharmacologie– Toulouse (France)
Introduction: Several drugs can induce hydro-electrolytic Adverse Drug Reac-tions (ADRs). Despite their seriousness, these ADRs remain often under-reported. Our previous research showed interest of laboratory data to improve the collec-tion of ADRs [1].
Material and methods: The aim of our study was to identify cases of drug-induced hydro-electrolytic disorders from analysis of renal and metabolic physio-logical investigations.
Results: A total of 2147 patients (855 in 2012, 837 in 2013 and 455 in the first semester of 2014) were investigated. In 19 cases [0.9%, 7 in 2012 (0.8%), 6 in 2013 (0.8%) and 6 in the first semester of 2014 (1.5%)], a drug was sus-pected. Mean age of patients was 60.0 29.0 (63% males). Previous medical history was: arterial hypertension (n= 8), diabetes (n = 4). The table summarizes the cases and the drugs involved. Outcome was favorable: 12 cases after with-drawal of suspected drug, 1 case spontaneously resolved. Outcome was unknown in 5 another cases. In 2 cases, ADRs persisted due to the continuation of the sus-pected drugs. Only, 1 case of ADRs was spontaneously reported to the Center of Pharmacovigilance (under-reporting rate=95%).
Adverse drug reactions Drugs n
Hypomagnesemia Esomeprazole 4
Pantoprazole
Metabolic acidosis Zonisamide 2
Topiramate
Hyponatremia Oxacarbazepine 2
Eslicarbazepine
Hyperkaliemia Irbesartan 1
Urinary lithiasis Atazanavir 4
Topiramate Tubulopathy Indinavir 8 Ifosfamide Tenofovir Cisplatine/ Carboplatine
Discussion/Conclusion: Our results suggest that hydro-electrolytic disorders requiring physiological investigations are explained by drugs in 1 out of 100 patients. The rate of under-reporting is high. According to our previous studies, these data confirm that laboratory data analysis could be an interesting tool to detect some serious ADRs.
Reference:
[1] Noize et al. Life threatening drug-associated hyperkaliemia: a retrospective study from laboratory signals. Pharmacoepidemiol Drug safe, 2011, 20:747– 53.
PS-012
Hypoglycemic coma with fatal outcome in a patient treated with cotrimoxazole and sulphonylurea
C Joyaua, G Veyraca, L Nicoletb, P Jollieta aPharmacology Department, Biology
Institute, University Hospital– Nantes (France);bIntensive care unit, University
Hospital– Nantes (France)
Introduction: Hypoglycemia can lead to severe neurological complications such as coma. Some drugs can cause this disorder, such as sulfonylureas. Hypo-glycemia is also a known side effect of cotrimoxazole. We report a fatal case of hypoglycemic coma in a patient treated with glimepiride and cotrimoxazole. Material and methods: This case concerns a 62-year-old male patient, with a medical history of high blood pressure, dyslipidemia and type 2 diabetes treated with glimepiride. In August, 2015 a treatment with cotrimoxazole was started in a context of a Staphylococcus aureus infection after right hemicolectomy for polyp. After surgery, a kidney failure was found to 157lmol/L. A few days later, the patient develops a malaise, unsteady gait and then is found in a coma. The Glasgow score was 3 and the capillary blood sugar level was 0,13 g/L. Despite the correction of hypoglycemia, the patient presents no alarm sign, a kidney fail-ure at 186lmol/L was reported. The diagnosis of hypoglycemic coma is retained. The outcome is unfavourable marked by the absence of awakening and the patient died 7 days after the beginning of the first symptoms.
Discussion/Conclusion: Glimepiride is a sulphonylurea. Fixation on potassium channel ATP-sensitive in the beta cells of the islets of Langerhans causes inhibi-tion of the potassium efflux, resulting in a cellular cell depolarizainhibi-tion causing insulin release. Sulfamethoxazole is a sulfonamide chemically similar to sulpho-nylureas. In addition, glimepiride is metabolized by cytochrome 2C9 and sul-famethoxazole is a potent inhibitor of this cytochrome. These data suggest a pharmacodynamic and pharmacokinetic interaction. The kidney failure has also played a role in allowing the accumulation of drugs. In the summary of products characteristics (SPC) of glimepiride, potentiation of the hypoglycemic effect is mentioned with certain drugs including long acting sulfonamides. A change in metabolism when used in combination with inhibitors of cytochrome 2C9 is also reported. In cotrimoxazole SPC, a safety precaution is noted with chlorpropamide, tolbutamide (two sulfonylureas). In the literature, several publications suggest an increased risk of hypoglycemia when cotrimoxazole is associated with glyburide or glipizide. But we did not find any publication mentioning an interaction between cotrimoxazole and glimepiride. Diabetic patients being more susceptible to infection, health professionals should remain vigilant for hypoglycemia in patients receiving associations of these drugs.
PS-013
Linezolid induced tongue discoloration: a rare adverse effect to know G Veyraca, J Mahea, E Bordb, V Davidc, P Jollieta aDepartment of Clinical
Pharmacology, Institute of Biology, University Hospital– Nantes (France);
bDepartment of Neurotraumatology, University Hospital– Nantes (France); cDepartment of Pediatric, University Hospital
– Nantes (France)
Introduction: Linezolid is an oxazolidinone antimicrobial drug. The most com-mon side effects are nausea, vomiting, diarrhea and headache. Bone marrow sup-pression and neuropathies may occur in patients taking for more than two weeks. We report 2 cases where significant association of linezolide intake with black tongue was found.
Material and methods: Cases of tongue discoloration, with or without hairy, associated with linezolid were searched in the French pharmacovigilance data-base (FPD), in Vigilyze (OMS datadata-base) and in the literature.
Results: Only two cases are notified and only to the regional pharmacovigilance center of Nantes in the FPD. The black discoloration of the tongue was appeared after being prescribed linezolid for pulmonary staphylococcus in a child suffering from cystic fibrosis. The child was treated with tablet linezolid 600 mg twice daily for two weeks. The blackish pigmentation was reported on the fourteenth day, the discoloration of tongue totally disappeared after 7 days after the stop of linezolid. In the second case, linezolid has been started on 600 mg every 12 h during 3 weeks for meningitis after a spinal meningioma surgery in a woman adult. Black tong associated with dysgeusia were reported 29 days after the beginning of treatment. Tongue discoloration returned gradually to normal after 6 weeks after discontinuation of linezolid. In the literature, we have found 9 recent case reports with linezolid induced black tongue, in 5 children and 4 adults, sometimes associated with black hairy tongue or brown tooth discol-oration. In Vigilyze, 69 cases of discoloration tongue among 7 tooth discoloration and 7 dysgeusia were reported in the world.
Discussion/Conclusion: This effect is uncommon, benign and reversible in some weeks after the stop of the drug but this effect is not well known. This rare effect is reported in 1.1% of 548 patients in comparator-controlled trials. Abnormal coloration of the tongue and discoloration of tooth are reported in the summary of characteristics of the product but not dysgeusia. The exact mechanism of drug induced black tongue is unknown but concomitant risk fac-tors like smoking, use of medications causing dry mouth, poor oral hygiene should be avoided. The addition of an often advocated for black tongue antifun-gal treatment unnecessarily burdens the treatment of patients with severe dis-eases and should be avoided for interaction risk. The prospective counseling of patients on the importance of good oral hygiene when taking linezolid may be warranted.
PS-014
Monitoring of inosine 50-monophosphate dehydrogenase activity in red blood celles using HPLC
A Citterio-Quentina, A Beringerb, R Obenza-Oterob, C Gustinb, R Clarkec,
A El Mahmoudib, JP Salvib, R Boulieud aCHU de Lyon– Lyon (France);bUniversite
Lyon1– Lyon (France);cTrinity College
– Dublin (Ireland);dUniversite Lyon1 et CHU
de Lyon– Lyon (France)
Introduction: The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine (6-MP), are commonly used to treat autoimmune diseases or to prevent trans-plant rejection. Adverse drug events were observed in 10 to 30% of patients and lead to thiopurine discontinuation. Many studies reported that intolerance to therapy is mediated in part by genetic polymorphisms in thiopurine S-methyl-transferase (TPMT), an enzyme involves in the metabolism of thiopurines. How-ever, TPMT polymorphism explains only 30–60% of cases with thiopurine intolerance. Among various possible candidate enzymes involves in the metabo-lism of thiopurines, inosine 50-monophosphate dehydrogenase (IMPDH) deficiency could be associated with adverse events during azathioprine therapy. Few data are available on the IMPDH activity in red blood cells (RBCs) in patients treated with thiopurines. Therefore, considering that thiopurine metabolites (6-TGN and 6-MeMPN) and other enzymes involved in thiopurine metabolism, TPMT and ITPA are currently determined in RBCs, we propose a HPLC method to determine IMPDH activity in RBCs to investigate the relationship with the occurrence of adverse events during azathioprine therapy.
Material and methods: IMPDH activity was assessed by the enzymatic conver-sion of inosine 50-monophosphate (IMP) to xanthosine 50-monophosphate (XMP). The XMP formed was analysed by HPLC using a LunaâNH2 column, a weak anion exchange phase that exhibits both ionic and hydrophobic properties. IMPDH activity was measured in red blood cells from 30 healthy volunteers, 50 adult and 62 pediatric patients treated with thiopurines.
Results: XMP was eluted below 10 min. Intra-assay and inter-assay precisions were below 9% for RBCs supplemented with 2, 40 and 80 mmol/L of XMP. The method was linear in the range 1–250 lmole/L with a coefficient correlation of 0.999. The quantification limit was 1lmole/L with an intra-assay and inter-assay CV below 10%. A wide interindividual variability in IMPDH activity in RBCs was observed in healthy volunteers and patients. No difference in IMPDH activity was found between healthy volunteers, adult and pediatric patients on thiopurine therapy (mean value 11.8, 7.9 and 7.8 nmol/XMPgHb/h respec-tively).
Discussion/Conclusion: The method described is useful to determine IMPDH activity in RBCs, concomitantly with TPMT and IPTA activity as we previ-ously reported, to investigate the potential role of IMPDH in thiopurine metabo-lism in patients treated with thiopurine drugs.
PS-015
Are cancer patients overexposed to psychotropic drugs during the early phase of their treatment? Comparison of incident use in cancer patients and in the general population
C Contea, M Ruetera, R Bourrelb, F Despasc, M Lapeyre-Mestrec aUMR1027
Inserm-Universite Paul Sabatier/Service de Pharmacologie Clinique, Centre Hospitalier Universitaire de Toulouse– Toulouse (France);bCaisse Nationale d’Assurance Maladie
Midi-Pyrenees – Toulouse (France);cUMR1027 Inserm-Universit
e Paul Sabatier/ Service de Pharmacologie Clinique, Centre Hospitalier Universitaire de Toulouse/ Laboratoire de Pharmacologie Medicale et Clinique, Faculte de Medecine, Universite Paul Sabatier– Toulouse (France)
Introduction: Psychological disorders are frequent in oncology [1–2]. Several studies are suggesting an overconsumption of psychotropic drugs by cancer patients [3–4]. The aim of this study was to compare the incident use of psy-chotropic drugs in patients newly diagnosed with Non-Hodgkin’s lymphoma (NHL) and Colorectal cancer (CC), to that observed in the general population and in patients with a non-cancer disorder.
Material and methods: We conducted a pharmacoepidemiological cohort study with data extracted from Midi-Pyrenees SNIIRAM database and from the EGB (representative sample of beneficiaries) in 2012. Subjects were defined as incident users if they were not exposed to any psychotropic drug during 2011. Incidence of psychotropic drug use was compared in patients with a first occurrence of NHL and CC diagnosis, to patients with a first diagnosis of myocardial infarction or knee replacement surgery in 2012.
Results: Incidence of psychotropic drug use in NHL patients was 32.2% (n= 301; 95% CI: [26.8–37.5]) compared to 7.6% (n = 2 299 022; [7.56– 7.63]) in the general population in Midi-Pyrenees. In the EGB, incidence of psy-chotropic drug use in CC patients was 33.5% (n= 188; [26.6–40.4]), com-pared to 23.2% (n= 572; [19.7–26.8]) in patients with myocardial infarction, and 22.4% (n= 281; [17.4–27.4]) in patients with a first knee-replacement surgery.
Discussion/Conclusion: These results suggest that new use of psychotropic drugs is three times higher in cancer patients than in the general population. Moreover, this incidence remains higher when compared to patients hospital-ized for myocardial infarction or for knee surgery. It should be relevant to explore factors associated with overconsumption of psychotropic drugs by can-cer patients.
References:
[1] Singer S et al. Prevalence of mental health conditions in cancer patients in acute care–a meta-analysis. Ann Oncol (2010) 21,925–930.
[2] Mitchell AJ et al. Prevalence of depression, anxiety and adjustment dis-order in oncological, haematological and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol (2011) 12,160– 174.
[3] Desplenter F et al. Incidence and drug treatment of emotional distress after cancer diagnosis: a matched primary care case-control study. Br. J. Cancer (2012) 107,1644–1651.
[4] Ng CG at al. Prescription patterns for psychotropic drugs in cancer patients; a large population study in the Netherlands. Psychooncology (2013) 22,762–767.
PS-016
Etonogestrel and efavirenz drug interaction: risk of contraception inefficacy
AL Ruellana, G Veyraca, C Brunet-Cartierb, L Jarnetc, P Jollieta aDepartment of
Clinical Pharmacology, Institute of Biology, University Hospital– Nantes (France);
bDepartment of Tropical and Infectious Diseases, University Hospital
– Nantes (France);cDepartment of Planning Family, University Hospital– Nantes (France) Introduction: Contraceptive failure has been observed during concomitant use with some antiretroviral therapy regimens and hormonal contraceptive, particularly in the case of combined oral contraceptive, due to pharmacokinetic interaction which reduce bioavailability. There is a lack of data on the interaction between the etono-gestrel (ENG) and antiretroviral therapy. In this context, we report two cases of efa-virenz (EFV) and ENG interaction leading to unwanted pregnancy.
Material and methods: The first case concerns a 32-year-old woman patient treated with EFV, emtricitabine and tenofovir association since September 2009 and with ENG implant since July 2010. The second case concerns a 28-year-old woman, who was treated with the same antiretroviral regimen since October 2011 and an ENG implant since June 2012. She was not taking other medica-tions associated with potential interacmedica-tions or herbal remedies. An unplanned pregnancy was confirmed for these women, and then an abortion was decided. Discussion/Conclusion: It is known that any drug that induces microsomal enzymes can increase the clearance of sex hormones, thus reducing their contra-ceptive efficacy. EFV is a CYP450 inducer particularly of CYP3A4 and could modify the expression of p-glycoproteins resulting in decreased levels of drugs metabolized by the CYP450 system. ENG is a CYP3A4 isoenzyme substrat and EFV, as a potent inducer of this isoenzyme activity, can increase the ENG metabolism. A pharmacokinetic interaction can explain the inefficacy of the contraception in these cases. To support this hypothesis, some authors have shown that EFV decreased the bioavailability of the ENG released from the implant and increased luteal activity, which could impair the efficacy of this contraceptive [1]. Landolt et al. have shown possible signs of ovulation based on single endogenous progesterone measurement in subjects treated concomitantly with EFV and ENG [2].
These observations suggest that the concomitant use of EFV based therapy and ENG implants require caution, since the World Health Organization recommends “no restrictions on the use of any hormonal contraceptive method for women liv-ing with HIV or at high risk of HIV”. Despite a potential interindividual variabil-ity in the bioavailabilvariabil-ity of sex steroid hormones, an alternative mode of contraception should be recommended in this context.
References:
[1] Vieira CS et al. J Acquir Immune Defic Syndr. (2014); 66: 378- 385. [2] Landolt NK et al. J Acquir Immune Syndr. (2014); 66: e50-e51.
PS-017
A survey on drug safety for physician resident
M Abou Taam, C Ga, T Trenque Centre Regional de Pharmacovigilance et de Pharmacoepidemiologie – Reims (France)
Introduction: The lack of adequate knowledge poses a barrier in the provision of pharmacovigilance reporting within the health care professional community. The purpose of this study was to determine the knowledge and attitude towards pharmacovigilance by community physician resident.
Material and methods: A survey was conducted in an area of 1.3 M inhabi-tants. Physician residents were interviewed about selected aspects of pharma-covigilance knowledge, attitudes, and perception using a pretested structured questionnaire. The survey was sent to members of the Regional Association of physician residents regarding their practice patterns and opinions on the phar-macovigilance. Determinants included demographic characteristics, pharmacovig-ilance university education, medical speciality, years in practice, knowledge on pharmacovigilance, reporting pratices and ideas on how to improve pharma-covigilance reporting. The percentage response was collected for each item. A software (LimeSurvey*) was used to prepare, send and analyze the survey. Results: Ten percent of the physician residents have participated.
60% of the study respondents had heard or read about pharmacovigilance on university. 50 had also inquired by their own means. 70 percent of the respon-dents knew the serious adverse drug reaction definition, while 80% did not know their regulatory obligation. 50 percent of the subjects believed that medical device concerned pharmacovigilance. Only 20% had reported adverse reaction at least once, especially serious or unexpected with relationship confirmed. 53% ignored the notifi-cation procedure when 36% did not diagnose adverse reactions. For 60%, stimula-tion by pharmacovigilance team is a good way to improve reporting.
Discussion/Conclusion: Residents are very acquainted with pharmacovigilance but have many erroneous beliefs about it. That explains underreporting. There is a need of enhancement of health political communication. University education should be also supported. Stimulated notification is also a way to improve physi-cian knowledge about drug safety and their ethical and regulatory obligations.
PS-018
Psychotropic drug initiation in patients having a CML diagnosed: a population-based study
M Gauthier, S De Barros, A Palmaro, M Lapeyre-Mestre, F Despas Faculte de Medecine, Service de Pharmacologie Medicale et Clinique, CAPTOR WP3 ANR-11-PHUC-0001, CHU de Toulouse, INSERM U1027– Toulouse (France)
Introduction: Psychotropic drugs (PD) are often used close to a cancer diagnosis and can precede it. We aimed to determine the incidence of anxiolytics, hyp-notics, antidepressants and antipsychotics initiation around a diagnosis of chronic myelogenous leukemia (CML).
Material and methods: Retrospective cohort. Data for Midi-Pyrenees were extracted from SNIIRAM, a near-whole-population French insurance database. Patients with incident refund for a CML tyrosine-kinase inhibitor (TKI) from Jan-uary 10th, 2011 to JanJan-uary 4th, 2014 without evidence of an alternative diag-nosis consistent with a CML TKI indication were included. Pre-cancer (9 months before to 3 months before diagnosis) and cancer (3 months before to 9 months after diagnosis) phases were defined. Our main evaluation criterion was the
initi-ation of PD between pre-cancer and cancer phase. We described incident PD use and studied its determinants using a logistic regression model. We compared pre-cancer and pre-cancer health care consumption.
Results: The cohort was constituted of 103 patients [mean age 60.8 (years), sex-ratio 1.15]. 35.9% of patients initiated at least one PD, anxiolytics being the most initiated PD (59.5%). Age was associated with PD initiation in univariate and multivariate analysis (OR=1.003, 95%CI=1.000–1.006 and OR=1.029, 95% CI=1.001–1.056). The number of consultations during the pre-cancer phase and female gender tended to be associated with increased risk of PD initiation in uni-variate analysis. For PD initiators, health care consumption was greater in can-cer but not in pre-cancan-cer phase.
Discussion/Conclusion: PD initiation is a frequent finding around a CML diag-nosis. Its risk increases with age. It could be a way to identify a subgroup with higher health care consumption.
PS-019
Are our local recommendations for tacrolimus dose adjustment in kidney transplant patients based on CYP3A5 genotype adequate? Y Noblea, M Buchlera, A Bouvarelb, H Longueta, JM Halimia, P Gataulta, C Barin-Le Guellecb aTransplantation renale, CHU de Tours – Tours (France); b
Laboratoire de biochimie et biologie moleculaire, CHU de Tours – Tours (France) Introduction: Adaptation of the initial tacrolimus dose to the CYP3A5 genotype of the recipient after kidney transplantation is necessary to avoid acute toxicity and reduce the period of low immunosuppression. Recommendations about the initial dose based on genotype are not univocal. In our institution, the following doses are recommended: 0.075 mg/kg/12 h for wild-type homozygous patients (CYP3A5*3/*3) and 0.10 mg/kg/12 h for carriers of at least one functional allele (CYP3A5*1/*3 or CYP3A5*1/*1).
Material and methods: We retrospectively assessed a cohort of kidney trans-plant patients in whom initial tacrolimus prescription was done according to our guideline, with a target trough tacrolimus concentration of 8 to 12 ng/mL. We retrieved from the patient’s chart all tacrolimus concentrations measured between Day 0 (D0, date of treatment initiation) and Day 10. A concentration≥12 ng/mL was considered as an overexposure. Results were analyzed according to recipient’s CYP3A5 genotypes, categorized as slow, intermediate and extensive metabolizers (3/ *3, *3/*1, *1/*1, respectively). All patients received mycophenolate mofetil and ster-oids. Induction treatment was either basiliximab or thymoglobulin.
Results: One hundred patients, selected between August 2013 and June 2015, were assessed (77 CYP3A5*3/*3, 20 CYP3A5*3/*3 and 3 CYP3A5*1/*1). The median initial dose of tacrolimus was 0.07 mg/kg/12 h, 0.06 mg/kg/12 h and 0.1 mg/kg/12 h for*3/*3, *3/*1 and *1/*1 respectively. Overexposure in the first 10 days occurred more frequently in*3/*3 than in *3/*1 patients (85 vs. 45%, P= 0.0003). Overexposure also occurred earlier in the *3/*3 group (3 2.1 days) as compared to the*3/*1 group (5.2 3.3 days). None of the *1/*1 patients had tacrolimus overexposure. There was no significant difference in the rate of delayed graft function between the*3/*3 and the *3/*1 groups (22 vs. 15%, P = 0.75). The dose of tacrolimus given after 10 days of treatment was lower than the initial dose for the *3/*3 group (0.06 mg/kg/12 h) whereas it was higher in the *3/*1 (0.08 mg/kg/12 h) and in the*1/*1 (0.15 mg/kg/12 h) groups.
Discussion/Conclusion: These results encourage us to modify the initial dose of tacrolimus of kidney transplant recipients: *3/*3: 0.05 mg/kg/12 h, *3/*1: 0.1 mg/kg/12 h and*1/*1: 0.15 mg/kg/12 h. Prospective evaluation of these new guidelines will be performed after 12 month. The additional value of CYP3A4*22 genotyping will also be assessed.
PS-020
Stability of a pholcodine 1 mg/mL aqueous solution for allergy skin tests N Petitpaina, J Scala-Bertolab, S Henn-Menetrec, A Rivierd, MC Escanyeb,
N Gambierb, P Gilletb aCentre Regional de Pharmacovigilance de Lorraine, CHRU de Nancy– Nancy (France);bLaboratoire de Pharmacologie Clinique, Toxicologie CHRU
de Nancy– Nancy (France);cPharmacie CHRU de Nancy
– Nancy (France);
dLaboratoire d’Hygiene environnementale CHRU de Nancy – Nancy (France)
Introduction: Anaphylaxis to neuromuscular blocking agents is a major con-cern for anesthesiologists. Pholcodine has been proposed by Scandinavian teams to be a cross sensitizing agent [1–2]. Therefore pholcodine begins to be included in skin tests performed by several allergologists, sometimes with dilutions of a marketed pholcodine containing syrup whereas a pholcodine solution would be preferable. We formalized a protocole of pholcodine in saline solution [3]. Knowing that that one of the impurities of pholcodine is codeine and that codeine may induce false positive cutaneous tests, we wanted to test the sta-bility of our 12-month stored pholcodine 1 mg/mL aqueous solution and particu-larly to follow the amounts of codeine during storage.
Material and methods: A solution of pholcodine monohydrate 1 mg/mL in NaCl 0,9% was prepared by the hospital pharmacy and 0.2lm filtrated into 5 mL glass sterile vials [3]. Vials were stored in the dark at 4°C and room temperature. During 1 year, stability was monthly checked by liquid chromatography according to the European Pharmacopeia (EP) with Elite LaChromâchromatographic system, diode array detector and injector coupled to EZChrom EliteTMSoftware Chromatography Data System. Microbiological sterility was controlled according to the EP technique. Results: During the 12-month period, the measured amount of pholcodine did not vary significantly, ranging between 95 and 105% of the theoretical value of 1 mg/mL regardless of the storage temperature. The chromatogram analysis showed that impurities, including codeine, stayed within the authorized limit of 0.2%. No new impurity was detected with a threshold of 0.1%. The total amount of impurities remained under the highest specification (0.7%). Microbiological sterility tests remained negative over the whole period.
Discussion/Conclusion: Our pholcodine 1 mg/mL aqueous solution remained stable and sterile during a 12 months period, with particularly no increased amount of codeine. This result is essential for its routine use (after dilution) in skin allergy tests such as prick-tests and intradermal reaction.
References:
[1] Florvaag E, Johansson SGO. Pholcodine in cough medicines and IgE-sensitiza-tion in the EU: an urgent task. Allergy (2012) 67, 581–582.
[2] Florvaag E et al. IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market. Allergy (2011) 66, 955–960.
[3] Barbier P et al. Stability of a 1.0 mg/mL aqueous pholcodine solution for allergy skin testing. Br J Clin Pharmacol (2014) 78, 1172–1174.
PS-021
Risk of hospital admission for liver injury in users of NSAIDs and non-overdose paracetamol (EPIHAM)
E Gulmez, R Lassalle, A Chartier, A Grolleau, N Moore Universite de Bordeaux, Bordeaux Pharmacoepi, INSERM CIC1401– Bordeaux (France)
Introduction: Hepatotoxicity is a cause of drug withdrawal or discontinuation of drug development. In SALT-I study, similar per-user risk of acute liver failure leading to liver transplantation (ALFT) between NSAIDs, and a 3-fold higher rate of ALFT in non-overdose paracetamol (NOP) users were found.
The objective of EPIHAM study is to identify risks of hospital admission for acute liver injury (ALI) associated with NSAIDs and NOP.
Material and methods: Case-population study in French population healthcare database (EGB). ALI was identified in hospital discharge summaries ICD-10 codes K71.1, 71.2, 71.6, 71.9, 72.0 from 01/01/2009–31/12/2013. Exposure for cases was dispensation of NSAID or NOP resulting in exposure within 30 days before admission. Population exposure was number of patients using the drugs and total number of DDD dispensed.
Results: Of 63 cases of ALI, 13 were exposed to NSAIDs, 24 to paracetamol. Event rates per million DDD [95%CI] ranged from 0.46 [0.09–1.34] for ketoprofen to 1.43 [0.04–7.97] for diclofenac combinations, from 0.43 [0.23–0.73] for all NSAIDs com-bined to 0.62 [0.40–0.94] for NOP. Per-user risk ranged from 19.49 [5.31–49.90] for ibuprofen to 37.19 [19.79–63.59] for all NSAIDs combined, and 56.93 [36.09– 85.42] for NOP. There was a linear relationship between increasing average treat-ment duration and increasing per-user risk (r2= 0.60, P < 0.05 for NSAIDs, r2= 0.99, P < 0.01 for paracetamol. No association was found between ALI inci-dence per million DDD and average treatment duration.
Discussion/Conclusion: The risk profiles of NSAIDs and NOP for ALI were simi-lar and indicative of a type A effect. ALFT had a pattern suggestive of type B reactions. Event rates for ALI were not predictive of risk of ALFT. ALI and ALFT probably have different mechanisms, even if one may be the prelude to the other.
PS-022
Intravenous iron extravasation and dyschromia: analysis from the French pharmacovigilance database
A Hermittea, N Petitpainb, D Swiegotb, S Babaic, C Lebellerd, A Defaulte,
P Gilletb aPharmacie CHR Metz-Mercy– Metz (France);bCentre Regional de
Pharmacovigilance de Lorraine CHRU de Nancy– Nancy (France);cCentre Regional de
Pharmacovigilance de Creteil, CHU Henri Mondor – Creteil (France);dCentre Regional de Pharmacovigilance H^opital Europeen G. Pompidou – Paris (France);eCentre
Regional de Pharmacovigilance de Marseille – Marseille (France)
Introduction: Intravenous iron infusion is required when iron deficiency cannot be corrected by oral iron administration. Intravenous iron extravasation is an expected adverse event for which recommendations have been made and recalled. Unlike antineoplastic drugs extravasation, iron does not lead to skin necrosis. However it causes dyschromia which may last several months and per-haps much more. We aimed to describe spontaneously reported dyschromias induced by intravenous iron in terms of size, colour and duration.
Material and methods: The French pharmacovigilance database was querried for a 15-year period (Jan-2000 to Dec-2014) with the MedDRA preferred terms “skin dyschromia” and “extravasation”, for the intravenous iron products marketed in France i.e. FERINJECT, VENOFER, FER MYLAN, FER SANDOZ, FER ACTAVIS, FER PANPHARMA. All cases without dyschromia were excluded from the study. Results: We identified 37 patients with skin dyschromia after iron extravasation (32 females and 5 males). The median age of this group was 36.5 years [min: 2; max: 91]. Three patients had had subcutaneus injection instead of an intra-venous one. The colour of dyschromia was brown in most of cases. A persisting dyschromia was clearly described in 26 cases (70.3%) with a median follow-up duration of 23 days. Of them, 5 persisting dyschromias had a follow-up longer than 6 months (max: 13 months). The coloured area, defined in 16 cases, ranged from 3 cm around the injection point to the whole arm. Management had been handled with alcohol dressings in half of cases.
Discussion/Conclusion: We confirm that long lasting dyschromia can occur after iron extravasation, causing an aesthetic prejudice especially for young peo-ple. Our follow-up period is limited by the difficulties to get back to the notifying person but it may be speculated that dyschromia may be permanent in some patients. Risk minimization measures e.g. cautious intravenous injection and a close survey during infusion, are essential since usual management of iron extravasation with alcohol dressings remains uneffective on dyschromia. Other measures for the management of dyschromia, such as the recently proposed in-frared laser technique [1], are awaited.
Reference:
[1] Hammami Ghorbel H et al. Successful treatment with 532-nm Q-switched Nd:YAG laser of cutaneous siderosis following intravenous iron extravasa-tion. J Eur Acad Dermatol Venereol (2015) 29,818–819.
PS-023
Development of a UPLC/MS/MS method for the quantitative analysis of squalamine analogues
A Sakr, N Doudka, J Dupouey, R Guilhaumou, O Blin Service de Pharmacologie Clinique et Pharmacovigilance, AP-HM, Pharmacologie integree et interface clinique et industriel, Institut des Neurosciences Timone– AMU-CNRS 7289, Aix Marseille Universite, F-13385 – Marseille (France)
Introduction: Twelve new squalamine analogues have been synthesized and are currently under development for various clinical indications including
antimicro-bial agents. Here we describe the development of an ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS) method for the quan-tification of these molecules.
Material and methods: Analytes separation was performed using the Acquity UPLC H-Class system (Waters Corporation, Milford, USA). Different gradients and columns were tested to optimize separation and peak shapes. MS/MS detection was achieved using Triple Quadrupole Mass Spectrometer (Quattro Premier TM XE; Waters Corporation, Milford, USA) equipped with an electrospray ionization source operating in multi-reaction monitoring (MRM) in positive ion mode. Acquisition settings were set as follow: source temperature 120°C; desolvation temperature 350 °C; desolvation gas flow 900L/h; cone gas flow 25L/h and collision gas pressure (argon) 3.39 103mbar.
Results: Prednisolonoe-d6 was used as internal standard. Spiked samples in normal saline solution were vortex-mixed with 3.5% NaOH. Solid phase extraction was used for sample clean-up and analyte concentration. Phenom-enex Kinetex F5 column 50mmx2.1 mm 1.7lm at 40 °C was used. 12 com-pounds were detected and quantified over a total run time of 5 min. Gradient conditions (% 0.1% formic acid/% acetonitrile) were as follow: initial condi-tions 30/70 at 0 min, 80/20 at 2.7 min and return to initial condicondi-tions 30/ 70 at 2.8 to 5 min. Auto sampler was maintained at 10°C. Optimized MRM transitions, cone voltages, and collision energies were selected on the maxi-mum response of the product ion (Table below). Validation procedure results will be presented. Analyte MRM transitions (m/z) Collision energy (eV) Cone voltage (V) Retention time (min) 1 321.2->300.1 14 30 0.78 321.2->283 14 2 345.1->314.1 14 30 0.87 345.1->135.6 30 3 403.2->343. 14 34 1.7 403.2->86.6 28 4 215.8->178.6 10 22 1.75 215.8->80.6 20 5 229.9->71.5 20 25 1.79 229.9->80.6 20 6 244->85.6 16 25 1.83 244->192.9 22 7 258.1->71.6 20 20 1.89 258.1->116.7 14 8 272.2->130.7 14 20 1.99 272.2->78.8 14 9 286.2->144.9 14 20 2.09 286.2->85.7 20 10 300.3->158.7 14 20 2.14 300.3->92.6 20 11 314.4->172.8 14 22 2.25 314.4->99.7 24 12 628.6->483.3 26 20 2.55 628.6->200.9 30 prednisolone d-6 367.2->149.9 26 24 0.4 367.2->175.9 24
Discussion/Conclusion: >In conclusion, a sensitive, accurate and precise UPLC/MS/MS method for quantification of squalamine analogues was developed and is now available for in vitro trials and will be adapted for future animal/ human.
PS-024
Incident use of benzodiazepines in France from 2006 to 2012: a population-based study
A Benard-Laribierea, P Noizeb, E Pambruna, F Bazina, H Verdouxc, M Tournier, B Begaudd, A Parienteb aINSERM, U657, Universite de Bordeaux – Bordeaux
(France);bINSERM, U657, Universite de Bordeaux, CHU Bordeaux, Service de pharmacologie medicale, CIC Bordeaux CIC1401 – Bordeaux (France);cINSERM,
U657, Universite de Bordeaux, Centre Hospitalier Charles Perrens – Bordeaux (France);dINSERM, U657, Universite de Bordeaux, CHU Bordeaux, Service de
pharmacologie medicale – Bordeaux (France)
Introduction: To estimate and describe the incident use of benzodiazepines (BZD) in France. This study was part of the DRUGS-SAFE program funded by the French Medicine Agency (Agence Nationale de Securite du Medicament et des Pro-duits de Sante, ANSM).
Material and methods: A yearly repeated cross-sectional study was conducted from 2006 to 2012 within the Echantillon Generaliste de Beneficiaires, a 1/97th
sample of the French national healthcare insurance system beneficiaries. BZD new users were defined as users with no BZD reimbursement in the year prior to the date of first dispensing of BZD over each year.
Results: Over the study period, the incident use of BZD use steadily decreased (4.8% in 2012, relative to the estimated incidence in 2006). This decrease concerned hypnotic BZD and was more pronounced in patients aged 18– 64 years than in those aged 65 years and older. Regarding anxiolytics, the incidence of use remained stable for the class; however, it decreased for long half-life BZD (bromazepam, prazepam), this being counterbalanced by an increase for short half-life BZD (alprazolam, oxazepam). Finally in 2012, the overall incidence of use was 5.9% (95%CI: 5.8–6.0). This incidence was 0.5% (0.5–0.6) in patients under 18 years; 7.2% (7.2–7.3) in those aged 18–64 years; 7.7% (7.5–7.9) in those aged 65 years and older. The highest incidence of use was observed among women aged 18–64 years (8.8%; 8.7– 8.9). The incidence of use was 4.0% (3.9–4.1) for anxiolytic BZD and 1.6% (1.6–1.6) for hypnotic BZD; both were higher among women. Relative to the number of prevalent users of BZD estimated in 2012 by the ANSM, new users would represent around one-third of BZD users, and one-quarter of hypnotic BZD users. Alprazolam was the most prescribed BZD at treatment start in 2012 (3.8%; 3.7–3.8) despite bromazepam remained the most inci-dent BZD (1.5%; 1.4–1.6) in patients aged 65 years and older. BZD new users under 18 years almost only used diazepam (0.13%) and alprazolam (0.13%).
Discussion/Conclusion: Although the prevalence of BZD use remained stable over the study period according to recent reports, the incidence of BZD use slightly decreased in France. Taken together, these results could indicate that treatment duration did not decrease over the period. Even if the incidence of long half-life BZD decreased to the benefit of short half-life BZD, as guidelines recommend, the most incident BZD in the elders in 2012 was a long half-life BZD.
PS-025
Use of benzodiazepines in the French population: overall prevalence and use in circumstances at increased risk of adverse effects
A Benard-Laribierea, P Noizeb, E Pambruna, F Bazina, H Verdouxc, M Tournierc,
B Begaudd, A Parienteb aINSERM, U657, Universit
e de Bordeaux – Bordeaux (France);bINSERM, U657, Universite de Bordeaux, CHU Bordeaux, Service de
pharmacologie medicale, CIC Bordeaux CIC1401 – Bordeaux (France);cINSERM,
U657, Universite de Bordeaux, Centre Hospitalier Charles Perrens – Bordeaux (France);dINSERM, U657, Universit
e de Bordeaux, CHU Bordeaux, Service de pharmacologie medicale – Bordeaux (France)
Introduction: To estimate the overall prevalent use of benzodiazepines (BZD) and the specific prevalent use in circumstances at increased risk for BZD adverse effects in the French community-dwelling population. This study was part of the DRUGS-SAFE program, funded by the French Medicine Agency (Agence Nationale de Securite du Medicament et des Produits de Sante, ANSM).
Material and methods: A cross-sectional study was performed using data from the Echantillon Generaliste de Beneficiaires, a 1/97th sample of the national healthcare insurance system beneficiaries. Prevalence of use was estimated by considering as users individuals who had at least one BZD reimbursement dur-ing the year 2013 (first BZD reimbursement identified in 2013 defined as index date). The following at-risk circumstances for BZD use were explored: i) drug-drug interactions (DDIs) at risk for sedation and respiratory depression; ii) comorbidities at risk for potential adverse respiratory effects or at risk for falls or fracture. DDIs were assessed considering a 30-day period prior and after index date, and comorbidities considering a 90-day period prior index date.
Results: Overall, the prevalence of BZD use in France in 2013 was estimated at 13.8% (95%CI: 13.7–13.8); it was higher among women and increased with age. This prevalence of use was 10.6% (10.5–10.7) for anxiolytic BZD, and 6.1% (6.0–6.1) for hypnotic BZD. Roughly half of BZD users (48.1%; 47.8–48.5) were in at least one circumstance at increased risk for BZD adverse effects at index date; this proportion increased with age. DDIs represented the most prevalent at-risk circumstance; it concerned 39.3% (38.9–39.6) of BZD users. The drugs most frequently involved were opioids: analgesics (15.9%; 15.6–16.2) and antitussives (6.8%; 6.6–6.9). Comorbidities at increased risk for adverse respiratory effects were found in 11.3% (11.1–11.6) of BZD users (13.9% in those aged 65–69; 13.4–14.5) and comorbidities at increased risk for falls or fracture in 7.0% (6.8–7.2) of BZD users (13.4% in those aged ≥80; 12.7– 14.0).
Discussion/Conclusion: This study identified a high prevalence of at-risk cir-cumstances in BZD users, most commonly related to drug-drug interactions. These findings are concerning, given that benzodiazepines are frequently used especially among the elders.
PS-026
Acute pancreatitis and phosphodiesterase 5 inhibitors: a first case report A Gaiffea, J Caissuttib, MB Valnet-Rabiera, S Davania aCentre Regional de
pharmacovigilance de Franche-comte – Besancon (France);bCentre Hospitalier Louis
Pasteur– Dole (France)
Introduction: The two well-known risk factors of acute pancreatitis are biliary lithiasis and alcohol abuse. Drug-induced pancreatitis is relatively rare but the diagnosis is difficult because there are no clinical, radiologic or biologic character-istics, to distinguish drugs from other causes of pancreatitis. We report a first case of a patient who presented two pancreatitis episodes where each event was immediately preceded by the use of oral phosphodiesterase 5 (PDE-5) inhibitors: CIALISâ(tadalafil).
Results: A 47-year-old man, without medical or surgical history was hospitalized in June 2015 for acute pancreatitis. The outcome was rapidly favorable. The patient did not present risk factor for acute pancreatitis (no alcohol consumption,
