Session 13 : Pharmacovigilance

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Session 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 Centre, Neurological and Rheumatological departments, Hôpital de Bellevue, Boulevard Pasteur 42055 – SAINT-ETIENNE CEDEX 2

Distal neuropathies are known to occur with amiodarone, almitrine bismesylate and several other drugs including antineoplastic agents. We report 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 investigation 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 action 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 infection on hip prosthesis. She was treated in the first place with PTN (3 g/j) and oxacilline (2 g/j). The latter was replaced 5 months later by FA (2 g/j) for the next 8 months. During this treatment she complained about paresthesia of the 4 limbs. A severe motor deficit with sensory loss and abolition of tendon 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 infection 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 abolition of the tendon reflexes. The EMS confirmed the sensory-motor axonal neuropathy. The biological investigations were negative. This patient’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 complet biological assessment was carried out no other cause 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

Centre Régional de Pharmacovigilance CHU 49033 Angers cedex 01, 2 Centre 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 sensitive neuropathy including paresthesias of the extremities, the face and the pharyngolarynx, sometimes associated with muscular cramps or spasms These symptoms most often occur rapidly after oxaliplatin administration and can be induced or exaggerated by coldness. Six cases (four patients) of acute neurotoxicity which rapidly improved after intravenous administration of calcium (Ca) and magnesium (Mg) salts are reported presently. All four patients had a metastatic colic or rectal adenocarcinoma which had been previously treated with weekly 5-fluorouracil-folinic acid (FUFOL). Owing to disease progression, L-OHP was added every three weeks to FUFOL administration according to the following scheme:

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

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

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 administration 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. Parquet**

Centre Régional de Pharmacovigilance, Lille; * Service de Psychiatrie, CH d’Arras; ** Clinique Michel Fontan, CHetU de Lille

Adverse drug reactions (ADRs) represent an important part of adverse drug events in hospitalized patients, and are responsible for an increase of hospitalization cost because they require additional treatments and investigations and prolong the length of stay. We have investigated ADRs occurring in hospitalized patients with psychiatric disorders, to analyse 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 rate 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 prolongation of length of stay (+ 430 days) and the increase cost was evaluated to 1.2 millions FF, e.g. 3% of total hospitalization cost. Nevertheless, among the 72 ADRs, 27 only induced a prolongation 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 conclusion 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

Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Information sur le Médicament, Faculté de Médecine, Hôpitaux de Toulouse; 2 Service de Pharmacologie Clinique, Centre Régional de Pharmacovigilance, CHU de Brest; 3 Centre Cochrane Français, Lyon ; 4 Département d’Oncologie Médicale, Institut Claudius Regaud, Toulouse; 5 Service de Pharmacologie Clinique, CHU de Bordeaux, France

The aim of this study was to assess the incidence of cardiac adverse 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, radiation therapy) versus other treatments except those containing 5FU, were sought by electronic and handsearching of the medical literature and databases from 1983 to 1996. Trials where adverse 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), digestive tract, (13), stomach (9). There was no increase in the risk of cardiac events related to 5FU versus comparative treatments with an overall Mantel-Haenzel’s odds ratio of 1.07 (95% Cl [0.76-1.52]). The incidence 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 ratio 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, exclusion of patients with cardiovascular diseases were not found to be related to a modification of risk.

These results suggest that cardiac events related to 5FU use are frequent but unfortunately is a so called type B (” unexpected “) reactions. In conclusion, 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. Jean-Pastor, M.E. Larida, F. Rodor, C.Locatelli, D. Gambini, N. Nguyen, E. Obedia, J. Jouglard.

Centre Régional de Pharmacovigilance, Hôpital Salvador, 249, bd. De Ste Marguerite, 13009 Marseille, France.

Fin décembre 1996, une lettre d’information sur le bon usage et les effets indésirables du PRIMPERANC

(métoclopramide) a été envoyée par le Laboratoire fabricant aux professionnels de Santé.

L’objectif de ce travail était d’évaluer l’impact de cette lettre d’information, un an après, selon trois axes:

– Analyse des notifications de troubles extrapyramidaux au métoclopramide recueillies au Centre de Pharmacovigilance en 1997: 33 signalements (en augmentation par rapport aux années précédentes) avec 24 fois un non respect de la posologie ou du rythme des prises (8 automédications) et 18 hospitalisations (plus 7 consultations en service d’accueil des urgences hospitalières); un seul EEG abusif.

– Sondage par fax auprès de Pharmaciens Sentinelles pour la Santé Publique: pas de souvenir de la lettre d’information, 20 fois (sur 44 réponses), méconnaissance des conseils de bon usage pouvant accompagner la délivrance de métoclopramide, 24 fois.

– Sondage téléphonique auprès des seuls médecins généralistes (42) ayant appelé le Centre de Pharmacovigilance pendant deux mois et auprès de témoins tirés au sort (41). La possibilité d’un syndrome extrapyramidal au métoclopramide est connue de beaucoup de médecins (35/42, 24/41). Mais les règles de prescription (posologie, rythme des prises) et les modalités thérapeutiques sont encore mal connues par 60 % d’entre eux.

Cette évaluation confirme la nécessité d’une réflexion sur la communication sur le risque: cibles, modalités, périodicité…

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*

*Service de Dermatologie, Hôpital Fournier, 36 quai de la Bataille 54035 Nancy, France; °CRPV Hôpital Central 54035 Nancy, France; **Laboratoire d’Immunologie, Faculté de Médecine, 9 avenue de la Forêt de Haye 54500 Vandoeuvre les Nancy, France.

Les tests cutanés, avec le médicament suspecté, sont supposés être utiles pour confirmer la cause d’une toxidermie, mais l’intérêt et la spécificité de ces tests restent à définir. Dans une étude prospective sur 4 ans, 72 patients ayant développé une toxidermie pour laquelle un médicament était fortement 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. Dans cette série, 37 médicaments différents étaient impliqués. Six à 10 semaines après leur toxidermie, les 72 patients ont tous bénéficié de tests épicutanés, de prick-tests dans 42 cas et de tests intradermiques (IDR) dans 30 cas (réalisés alors avec surveillance hospitalière, en utilisant des dilutions séquentielles de solutions préparées stérilement) avec lectures immédiates et retardées de ces tests médicamenteux. Parmi ces patients, 52 (72 %) avaient un test cutané positif, respectivement pour 43 %, 24 % et 67 % des patch, prick-tests et IDR réalisés. Les résultats des tests cutanés variaient selon la molécule testée et le type clinique de la toxidermie, puisqu’un nombre plus élevé de patch-tests positifs était observé dans les EMP comparés aux urticaires (p = 0,001). Dans les 72 cas, aucune sensibilisation aux excipients testés n’a été observée. Cette étude souligne l’intérêt de la pratique des tests cutanés séquentiels, suivant des règles rigoureuses pour rechercher la cause d’une toxidermie. Cette étude confirme aussi la nécessité de comparer les résultats de tout test cutané médicamenteux avec des contrôles négatifs appropriés, pour éviter la déclaration de tests faussement positifs.