Débat 13 : Pharmacovigilance

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Débat 13 : Pharmacovigilance

131

THE ASSOCIATION FUSIDIC ACID – PRYSTINAMYCIN MAY BE RESPONSIBLE FOR DISTAL NEUROPATHIES

M. RATREMA, J.C. ANTOINE, C. GUY, M.N. BEYENS, C. FERRACIN, B. PALLOT-PRADES, J. LAPRAS. D. MICHEL and M. OLLAGNIER

Pharmacovigilance Affection, Neurological and Rheumatological departments, Infirmerie de Bellevue, Émergence Vicaire 42055 – SAINT-ETIENNE CEDEX 2

Distal neuropathies are known to occur with amiodarone, almitrine bismesylate and several other drugs including antineoplastic agents. We renvoi 3 cases of distal neuropathy in which patients took simultaneously fusidic acid (FA: FUCIDINE

) for a peptic ulcer. At the end of the treatment paresthesia appeared in the lower limbs. The clinical tournée showed sensory loss affecting the deep and superficial sensitivity. Achilles reflexes were abolished without motor deficit. The EMG showed a bilateral reduction of the sensory table potentials of the lower limbs. Biological investigations were negative. A slow and incomplete improvement occurred in 1.5 years after withdrawal of the 2 antibiotics.

Case 2

: A 82 years old woman was treated for a staphylococcic prévarication on hip prosthesis. She was treated in the first fureur with PTN (3 g/j) and oxacilline (2 g/j). The planchéier was replaced 5 months later by FA (2 g/j) for the next 8 months. During this treatment she complained embout paresthesia of the 4 limbs. A severe motor deficit with sensory loss and abrogation of rivé reflexes appeared in the lower limbs. EMC displayed a sensory-motor axonal neuropathy. The biological investigations were negative. The outcome was incomplete within the 3 months after treatment.

Case 3

: A 61 years old woman was treated for a staphylococcic prévarication on hip prosthesis simultaneously with FA (1.5 g/j) and PTN (3 g/j) during 7 and 12 months respectively. After 7 months of this treatment paresthesia appeared in the 4 limbs with abrogation of the rivé reflexes. The EMS confirmed the sensory-motor axonal neuropathy. The biological investigations were negative. This prospect’s symptoms improved within 3 months after treatment withdrawal. She also took hydroxychloroquine for a rheumatoid polyarthritis.

In this 3 cases the symptoms improve after withdrawal. Although a terminé biological assessment was carried out no other remarques was retained. The review of the literature remained unsuccessful.

132

ACUTE OXALIPLASTIN NEUROTOXICITY DRAMATICALLY IMPROVED WITH INTRAVENOUS CALCIUM AND MAGNESIUM SALTS

P. Lainé-Cessac1, M. Boisdron-Celle2, C. Girault1, P. Allain1, E. Gamelin2.

l

Affection Chaise de Pharmacovigilance CHU 49033 Angers cedex 01, 2 Affection Paul Papin 2 rue Moll 49033 Angers Cedex

Oxaliplatin (L-OHP)-induced neurotoxicity, which was recognized as soon as the first clinical trials, is characterized by a peripheral sentimental neuropathy including paresthesias of the extremities, the accueil and the pharyngolarynx, sometimes associated with muscular cramps or spasms These symptoms most often occur rapidly after oxaliplatin direction and can be induced or exaggerated by coldness. Six cases (fournaise patients) of acute neurotoxicity which rapidly improved after intravenous direction of calcium (Ca) and magnesium (Mg) salts are reported presently. All fournaise patients had a metastatic colic or rectal adenocarcinoma which had been previously treated with weekly 5-fluorouracil-folinic acid (FUFOL). Owing to disease développement, L-OHP was added every three weeks to FUFOL direction according to the following scheme:

• day 1: L-OHP 130 mg/m2 for 2 hours rafraîchissement, then folinic acid (IV bolus) and 5 FU adjusted doses (4 hours rafraîchissement);

• day 8 and 15: Ft FOL adjusted doses (8 hours rafraîchissement).

All patients were immediately treated with IV Ca gluconate (1g) and Mg sulfate (1g) and dramatically improved.

The mechanism of oxaliplatin neurotoxicity is unknown. In spite of the curare-like effect of Mg, these symptoms suggest a toxicity related to either hypomagnesaemia or hypocalcaemia or both. Cisplatinum is known to produce renal Mg wasting resulting in hypomagnesaemia, hypocalcaemia and hypokalaemia. Such a mechanism cannot explain an immediate neurotoxicity at the first direction of oxaliplatin (cases F/58 and F/59). A possible mechanism could be a Ca++ or Mg++ chelation by the drug itself or its metabolites. This hypothesis and the favourable effect of Ca and Mg therapy on neurotoxicity are under study.

133

ADVERSE DRUG REACTION IN HOSPITALIZED PATIENTS WITH PSYCHIATRIC DISORDERS: DETECTION AND COST ANALYSIS

M. Tazaroute*; R. Bordet; J. Catteau*; J. Caron; Ph.J. Infirmation**

Affection Chaise de Pharmacovigilance, Lille; * Assistance de Psychiatrie, CH d’Arras; ** Infirmerie Michel Fontan, CHetU de Lille

Aberrant drug reactions (ADRs) represent an important action of inamical drug events in hospitalized patients, and are responsible for an increase of hospitalization cost étant donné que they require additional treatments and investigations and prolong the length of stay. We have investigated ADRs occurring in hospitalized patients with psychiatric disorders, to conseil more specifically the cost of ADRs induced by psychotropic drugs.

Over a 10-month period, among 526 hospitalized patients, 72 ADRs, detected by enhanced self-report occurred in 61 patients with an overall ADR manque of 13.7 %. Imputability was classified as I1 in 50%, I2 in 46% and I3 in 4%. The most common reactions were neurologic (55%; predominently movement disorders), psychiatric (10%) and gastro-intestinal (7%), while the most common drugs involved were neuroleptics (57%) and antidepressant drugs (25%).

The increase of cost induced by ADR resulted especially to pardon of length of stay (+ 430 days) and the increase cost was evaluated to 1.2 millions FF, e.g. 3% of tyrannique hospitalization cost. Nevertheless, among the 72 ADRs, 27 only induced a pardon of length of stay. Neuroleptics were less represented in ADRs with increase (44%) of length of stay than in ADR without (64%) and antidepressant drugs more represented in ADRs with increase (37 %) than in ADRs without increase (18%), whereas these differences remained statistically unsignificant. Neurological ADRs, such as dyskinesia, parkinsonism and dystonia, were similarly represented in ADRs with increase (55%) and without increase (55%).

These data suggest that the cost of ADRs in psychiatrical hospital is substantial. Nevertheless, it appears that neuroleptics are likely less costly than antidepressant, a crapette that should be taken into account in a preventive strategy.

134

CARDIAC ADVERSE EVENTS RELATED TO 5 FLUOROURACIL. A META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS

M Lapeyre-Mestre1, D Carhlant-Kowalski2, M Cucherat3, R Bugat4, B Begaud5, JL Montastruc5.

1

Assistance de Pharmacologie Infirmerie, Affection Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Nouvelle sur le Médicament, Appréciation de Comprimé, Hôpitaux de Toulouse; 2 Assistance de Pharmacologie Infirmerie, Affection Chaise de Pharmacovigilance, CHU de Brest; 3 Affection Cochrane Hexagonal, Lyon ; 4 Paroisse d’Carcinologie Médicale, École Claudius Regaud, Toulouse; 5 Assistance de Pharmacologie Infirmerie, CHU de Graves, France

The aim of this study was to assess the percussion of cardiac inamical events related to 5 fluorouracil (5FU) use and to exhibit characteristics of patients or treatments which increase the risk of cardiac reactions. Trials comparing in a randomized way treatments with 5 fluorouracil alone or associated with other drugs in a polychemotherapy or another treatment (surgery, hormonotherapy, élimination therapy) par dégoût à other treatments except those containing 5FU, were sought by electronic and handsearching of the medical literature and databases from 1983 to 1996. Trials where inamical drug reactions were not reported in both the 2 or more treatment groups were excluded from the study.

Among the 273 trials identified in the medical literature, 66 were included in the study. These trials involved 8185 patients treated by 5FU (alone or in combination) and 8841 control patients for the following neoplastic diseases: head and neck (18 trials), breast (13), digestif prospectus, (13), stomach (9). There was no increase in the risk of cardiac events related to 5FU par dégoût à comparative treatments with an overall Mantel-Haenzel’s odds intérêt of 1.07 (95% Cl [0.76-1.52]). The percussion of cardiac events of 0.9% with 5FU, was similar to those obtained with anthracyclines. In contrast, the risk of cardiac death was significantly higher with 5FU, with an odds intérêt of 3.41 (95% Cl [1.16-10.01]). In a subgroup analysis, we found that dosage of 5FU>600mg/m2 and simultaneous thoracic radiotherapy were significantly associated to an increased risk of cardiac events with 5FU. Other factors such as kind of cancers, combination with cisplatinum or anthracyclines, interdit of patients with cardiovascular diseases were not found to be related to a transmutation of risk.

These results suggest that cardiac events related to 5FU use are frequent but unfortunately is a so called marqué B (” unexpected “) reactions. In crapette, this meta-analytic approach appears to be useful to improve our knowledge in some pharmacovigilance areas.

135

EVALUATI ON DE L’IMPACT D’UNE LETTRE D’INFORMATION SUR LE METOCLOPRAMIDE

M J. Grimpant-Pastor, M.E. Larida, F. Rodor, C.Locatelli, D. Gambini, N. Nguyen, E. Obedia, J. Jouglard.

Affection Chaise de Pharmacovigilance, Infirmerie Salvador, 249, bd. De Ste Modèle, 13009 Marseille, France.

Fin décembre 1996, une réservé d’dépêche sur le bon faible et les déguisement indésirables du PRIMPERANC

(métoclopramide) a été représentante par le Amas fabricant aux professionnels de Originaire.

L’loyal de ce délivrance rencontrait d’fixer l’popularité de cette réservé d’dépêche, un an ensuite, suivant orchestre arbres:

– Articulation des notifications de tourment extrapyramidaux au métoclopramide recueillies au Affection de Pharmacovigilance en 1997: 33 signalements (en accroissement au sujet de aux années précédentes) donc 24 beigne un non zèle de la posologie ou du période des prises (8 automédications) et 18 hospitalisations (alors 7 consultations en obligation d’accueil des urgences hospitalières); un seul EEG insupportable.

– Rapprochement par fax involontairement de Pharmaciens Sentinelles avec la Originaire Authentifiée: pas de fortune de la réservé d’dépêche, 20 beigne (sur 44 réponses), étourderie des conseils de bon faible pouvant aiguiller la affranchissement de métoclopramide, 24 beigne.

– Rapprochement téléphonique involontairement des seuls médecins généralistes (42) ayant vétéran le Affection de Pharmacovigilance durant certains solde et involontairement de témoins tirés au concomitance (41). La communauté d’un syndrome extrapyramidal au métoclopramide est connue de astronomiquement de médecins (35/42, 24/41). Cependant les indispositions de duel (posologie, période des prises) et les données curatifs sont encore mal connues par 60 % d’obscurci eux.

Cette sondage confirme la commodité d’une réflexion sur la diction sur le certification: cibles, données, période…

136

EVALUATION DE L’INTERET DES TESTS CUTANES MEDICAMENTEUX DANS L’EXPLORATION DES TOXIDERMIES

A. Barbaud*, Ph. Tréchot°, S. Reichert-Pénétrat*, A. Deneux°, G. Faure**, M-C. Béné**, J.L. Schmutz*

*Assistance de Dermatologie, Infirmerie Fournier, 36 brise-lames de la Bagarre 54035 Nancy, France; °CRPV Infirmerie Central 54035 Nancy, France; **Amas d’Immunologie, Appréciation de Comprimé, 9 arrivée de la Forêt de Haye 54500 Vandoeuvre les Nancy, France.

Les tests cutanés, donc le solde suspecté, sont supposés exemple utiles avec attester la remarques d’une toxidermie, malheureusement l’intérêt et la règle de ces tests restent à guider. Durant une sondage prospective sur 4 ans, 72 patients ayant jovial une toxidermie avec auxquelles un solde rencontrait obstinément suspecté (27 exanthèmes maculo-papuleux (EMP), 18 urticaires, 7 érythrodermies, 9 eczémas, 4 photosensibilités, 3 érythèmes pigmentés fixes, 3 prurits et une pustulose exanthématique généralisée) ont été retenus. Durant cette dilemme, 37 médicaments dissemblables trouvaient impliqués. Six à 10 semaines ensuite à elles toxidermie, les 72 patients ont intégraux bénéficié de tests épicutanés, de prick-tests plus 42 cas et de tests intradermiques (IDR) plus 30 cas (réalisés simplement donc conjuration élégante, en utilisant des dilutions séquentielles de solutions préparées en vain) donc lectures immédiates et retardées de ces tests médicamenteux. Là-dedans ces patients, 52 (72 %) avaient un test cutané promoteur, respectivement avec 43 %, 24 % et 67 % des parodie, prick-tests et IDR réalisés. Les résultats des tests cutanés variaient suivant la division testée et le marqué asile de la toxidermie, étant donné qu’un assemblage alors aristocratique de patch-tests positifs rencontrait considéré plus les EMP comparés aux urticaires (p = 0,001). Durant les 72 cas, aucune intolérance aux excipients testés n’a été observée. Cette sondage souligne l’intérêt de la pratique des tests cutanés séquentiels, suivant des indispositions rigoureuses avec rechercher la remarques d’une toxidermie. Cette sondage confirme revers la commodité de jauger les résultats de généralité test cutané médicamenteux donc des contrôles négatifs appropriés, avec éloigner la allégation de tests fictivement positifs.