Thrombocytopenic purpura after measles, mumps and rubella vaccination: a retrospective survey by the French regional pharmacovigilance centres and pasteur-mérieux sérums et vaccins.

BACKGROUND: Thrombocytopenic purpura (TP) after vaccination with measles, mumps and rubella has occasionally been reported. OBJECTIVES: To evaluate the incidence and characteristics of thrombocytopenic purpura reported in France after measles, mumps or rubella vaccination with monovalent or multivalent vaccines. METHODS: A retrospective epidemiologic survey was conducted. All confirmed cases of TP reported spontaneously either to the French Regional Pharmacovigilance Centres or to the manufacturer (Pasteur-Mérieux Sérums et Vaccins) between 1984 and June 30, 1992, were reviewed. RESULTS: Sixty cases of TP in children between 1 and 11 years of age occurred 2 to 45 days after administration of 1 of 7 vaccines. The reported incidence of TP varied from 0.17 and 0.23/100,000 doses of measles or rubella vaccines, respectively, given alone to 0.87/100,000 doses of combined measles-rubella vaccines and 0.95/100,000 doses of the measles-mumps-rubella vaccine. The mean platelet count was 8000 +/- 6000/mm3 and was lower than 10,000/mm3 in 58% of cases. The immediate outcome was favorable in 89.5% of cases. CONCLUSIONS: According to the clinical course and biologic findings, vaccine-associated TP appears to be similar to that occurring after natural measles or rubella infections and is not distinguishable from acute childhood idiopathic thrombocytopenic purpura not associated with vaccination. Such observations, combined with a clear temporal relationship between measles-mumps-rubella vaccination and the occurrence of TP, make a causal relationship highly plausible. Nevertheless the incidence of these events remains relatively low with a favorable immediate outcome.

Five vs. ten days of antibiotic therapy for acute otitis media in young children.

BACKGROUND: Many publications in recent years have argued in favor of shortened therapy for acute otitis media. However, doubt persists regarding children younger than 2 years, and some authors therefore restrict short course therapy to children older than 2 years. METHODS: In a prospective, comparative, double blind, randomized, multicenter trial we compared cefpodoxime-proxetil, 8 mg/kg/day in two divided doses for 10 days, with an identical 5-day regimen followed by a 5-day placebo period. RESULTS: Between October, 1996, and April, 1997, 450 children (mean age, 14.3 months) were enrolled, 227 in the 5-day group and 223 in the 10-day group. In the per protocol analysis clinical success was obtained on Days 12 to 14 after the beginning of treatment (main analysis) in 175 (84.1%) of the 208 children receiving the 5-day regimen and 194 (92.4%) of the 210 children receiving the 10-day regimen (P = 0.009). The superiority of the standard regimen was more marked among children cared for outside their homes (92.5% vs. 81.5%). Clinical success persisted on Days 28 to 42 among 134 (85.4%) of the 157 assessable patients in the 5-day group and 144 (83.7%) of the 172 assessable patients in the 10-day group (P = 0.68). CONCLUSIONS: The 10-day regimen resulted in a higher success rate at the conclusion of therapy, but there were no differences between the two study groups 4 to 6 weeks after enrollment in the study protocol.

Fetal risks with dextrans during delivery.

Epidural analgesia for caesarean section is increasingly used and is gradually replacing general anaesthesia. Hypotension is one of the main risks: preloading of the maternal circulation is used to prevent maternal hypotension and its consequences. For this, various colloid and crystalloid solutions are used. We report a case of maternal anaphylactoid reaction with apparent death in a neonate after dextran administration to the mother. After 100ml of a dextran 40 solution administered intravenously, immediately before an epidural blockade, the mother fainted and developed urticaria and mild respiratory disturbances, without hypotension. At that point dextran infusion was stopped. An apparently dead neonate was rapidly delivered. Immediate and vigorous cardiopulmonary resuscitation was successful. Clonismus appeared 12h later, followed by 3 general epileptic fits treated by phenytoin infusion and subsequently oral phenobarbital. No aetiology was found. After 2 months of treatment, barbiturates were stopped following clinical and electroencephalogram (EEG) improvement. Several similar cases of neonatal disorders resulting from preventive dextran administration during delivery were studied in a national pharmacovigilance survey in France. There were 32 cases reported with moderate maternal anaphylactoid reaction associated with severe acute fetal distress; it is probably advisable to take a cautious approach and avoid preventive fluid preload by dextran administration. Gelatins or crystalloid solutions should be preferred, with intravenous vasopressive amine administered promptly and repeated if necessary should significant maternal hypotension occur during epidural anaesthesia.

Possible interaction between phenobarbital, carbamazepine and itraconazole.

We report a case of a possible interaction between itraconazole, phenobarbital and carbamazepine. The first plasma itraconazole concentration, measured when the patient had been taking phenobarbital for 2 months, was very low. The second measurement, 2 months after withdrawing phenobarbital, was higher but below the therapeutic range. However, carbamazepine, a well known enzyme inducer, had been initiated 15 days before. 20 days after carbamazepine was withdrawn, the itraconazole concentration 4 hours after administration was near the lower end of the therapeutic range. The mechanism of this possible interaction is probably the same for phenobarbital and carbamazepine, involving hepatic microsomal enzyme system induction.

Sudden infant death syndrome and diphtheria-tetanus-pertussis-poliomyelitis vaccination status.

Because diphtheria, tetanus, pertussis and poliomyelitis vaccine is routinely given during the period of highest incidence of sudden infant death syndrome (SIDS), we carried out a retrospective case-control study to assess whether such vaccination increased the risk of SIDS. The vaccination status of 118 SIDS and 332 control children, matched for sex, date of birth and age of the victims at death, was compared: the victims of SIDS were not significantly more often vaccinated than control children, the odds ratio was estimated at 1.9 with a 95% confidence interval from 0.9 to 3.9. There was a statistical difference between vaccination status of SIDS cases and controls aged less than three months. Nine percent of SIDS cases under 3 months had been vaccinated whereas the matched controls had not. In our study DTCP vaccination was not a risk factor for SIDS; although more of the SIDS infants less than 3 months of age had been vaccinated. This result however, concerns only one subgroup of the population studied and needs to be confirmed with another study of only SIDS infants less than 3 months of age, because DTCP vaccination was not a risk factor for SIDS when considering the total sample of the study.

Is monitoring plasma levels of netilmicin necessary in neonates?

Thirty-two neonates were treated with netilmicin 3 mg/kg every 12 h by IV infusion for 30 min for suspected infections, colonization, or proven infections. Pharmacokinetic studies were performed in order to define the situations in which monitoring of plasma levels would be appropriate. Mean plasma levels were within the therapeutic range and did not differ in fullterms and preterms. In the 4 children who had 2 successive pharmacokinetic studies, plasma levels were increased between H1 and H5 at the second evaluation due to netilmicin accumulation. Plasma half-life was longer in proven infections and seemed to decrease in preterms with increased gestational age. These results suggest that the dosage schedule should be left inchanged, but that administration time should be reduced from 30 to 20 min and that peak and trough plasma levels should be measured only in proven infections, in very premature babies (gestational age less than 33 wk), and during netilmicin treatment longer than 5 d.

[Determination of drug posology in pediatrics]. / Détermination de la posologie des médicaments en pédiatrie.

The dosage of drugs which might be used in children must be determined to avoid empirical use, even when no application has been submitted for a paediatric licence. Toxicological evaluation and assessment of the effects on growth, an adapted pharmaceutical form and paediatric pharmacokinetic and adult clinical data are essential before conducting trials designed to determine the paediatric dosage. The dose used during preliminary studies is extrapolated from the adult dose expressed in relation to weight, tested in a dose-effect study, and then more accurately defined on the basis of pharmacokinetic data in different age groups. Obtaining consent from both parents for studies whose direct benefit is not always obvious, as well as the global cost of these studies, constitute drawbacks to paediatric drug development. Incentives to determine a paediatric dosage could consist of public participation in funding, prolongation of the patent, and granting an advantageous price for a specifically paediatric pharmaceutical form or indication.

[Can the sub-notification of drug adverse effects by capture/recapture method be evaluated?]. / Est-il possible d'évaluer la sous-notification des effets indésirables médicamenteux par la méthode capture/recapture?

The incidence of adverse effects of a drug can be evaluated from the relationship between adverse effects reported to the drug company and to French drug surveillance centres and the number of patients exposed to the drug. Many adverse effects are never reported and this under-reporting is variable. The capture/recapture method can be used in drug surveillance to evaluate the importance of under-reporting for an adverse effect of a drug. This method, based upon the intersection of two different data sources with the aim of identifying the number of common cases, can estimate the number of unreported cases if at least two independent data sources are available. Scrupulous identification of each case and of common cases and study of the independence of the two systems are essential for this method. The application of the capture/recapture method to spontaneous reporting permits the estimation of the total number of cases and the completeness of registration of the two data sources (the drug company and the French drug surveillance centres). This application of the capture/recapture method needs to be validated by comparing the results to the results of prospective studies whenever possible.

[Adverse effects of oxybutynin chloride (Ditropan). Evaluation of the official survey of Regional Pharmacovigilance Centers]. / Effets indésirables du chlorure d'oxybutynine (Ditropan). Bilan de l'enquête officielle des Centres Régionaux de Pharmacovigilance.

We analyzed the 200 reported cases of adverse reactions to Ditropan (209 side-effects) collated by the Centres Régionaux de Pharmacovigilance and Laboratoire Debat since the drug was first marketed. The frequency of such side-effects was of the order of 1 per 20,917 treatment months. Children were affected four times more frequently than adults. The manifestations resembled atropine overdose in 103 cases (52 children, 51 adults), and were mainly neurological (59%) and ocular (22%). Two cases of erythema multiform and 33 of miscellaneous allergic skin reactions occurred. The fact that atropine overdose was more frequent in children can be explained by the proportionately higher dosage. Dose adjustment based on pediatric pharmacokinetic studies appears to be essential. In children, the drug is prescribed most frequently (56%) for conditions outside the licensed indications, particularly nocturnal enuresis, a condition for which the efficacy of Ditropan has not been established. We consider that this calls for a specific contraindication in isolated nocturnal enuresis and in children aged less than five years.

[Pulmonary toxicity of nilutamide (Anandron). Cooperative evaluation of French Regional Pharmacovigilance Centers]. / Toxicité pulmonaire du nilutamide (Anandron). Bilan coopératif des centres français de pharmacovigilance.

We have studied 12 reports of pneumonitis associated with nilutamide (Anandron) and notified to the French regional ADR monitoring centers between November 1987 and June 1990. The mean age of the patients was 71.5 +/- 9.5 years, and 35% (5/12) had a history of lung disease. All 12 patients developed dyspnea, cough and fever, 4.7 +/- 6 months after starting nilutamide. Ten patients (83%) required admission to hospital. The symptoms revolved in 11 cases when the drug was withdrawn. In the other case, they disappeared when another drug was stopped and the dose of nilutamide was reduced. Six patients were treated with glucocorticoids. The severity of nilutamide-associated pneumonitis appears to be related to the time between the onset of dyspnea and consultation.

[Esophageal involvement after tetracycline ingestion]. / Atteines oesophagiennes secondaires à l'ingestion de tétracyclines.

Between 1985 and 1992, 81 spontaneous oesophageal injuries associated with tetracycline were notified to the French Regional Pharmacovigilance Centres. The side effects were oesophageal ulcers (79 per cent), esophagitis (11 per cent) and dysphagia (10 per cent). Esophagitis and dysphagia appeared sooner (4 days) than the ulcers (15 days). The mean age of the patients was 29 +/ 13 years and 73 per cent were women. In 92 per cent of cases, the recommendations for administration were not observed (medication taken at bedtime with not enough or without water). With 96 per cent of patients, doxycycline was the tetracycline in question; this prevalence could be explained by its irritant and cytotoxic properties. The oesophageal injuries were 22 times more frequent with capsules than with tablets, because of their easier adhesion to the oesophageal surface. Oesophageal injuries are potentially serious and must be avoided by clear information to patients and prescribers on tetracycline administration; consumption in the middle of a meal with an adequate quantity of water and never less than one hour before bedtime.

[Aseptic meningitis after mumps vaccination]. / Méningites aseptiques après vaccination anti-ourlienne.

The aim of this retrospective study was to evaluate the incidence and the characteristics of spontaneously reported aseptic meningitis (AM) in France following mumps vaccination with monovalent or multivalent vaccines containing the Urabe strain. Fifty-four cases of AM were reported to the regional drug surveillance centres or to the manufacturer from the time each vaccine was launched up until June 1992. Twenty cases were associated with the time off administration of a monovalent mumps vaccine and 34 with a trivalent measles, mumps and rubella vaccine (MMR). A mumps virus was isolated in four cases in the cerebrospinal fluid and an Urabe-like strain was characterised twice by polymerase chain reaction (PCR). A probable mumps origin was assumed in 17 other cases where the patients presented with other clinical or biological signs of mumps infection. The clinical outcome of AM was always favourable. The global incidence of mumps vaccine-associated AM was 0.82/100,000 doses, which is significantly lower than the incidence in the unvaccinated population. Even considering that the actual incidence of AM is much higher when assessed by active surveillance studies, the risk/benefit ratio of mumps vaccine remains in favour of vaccination. The incidence of mumps vaccines containing Jeryl Lynn (ROR Vax et Imu ORR) associated with AM needs to be evaluated.

[Thrombocytopenic purpura after isolated or combined vaccination against measles, mumps and rubella]. / Purpura thrombopénique après vaccination isolée ou associée contre la rougeole, la rubéole et les oreillons.

A retrospective epidemiological survey was conducted to evaluate the incidence and characteristics of thrombocytopenic purpura (TP) reported in France following measles, mumps or rubella vaccination with monovalent or multivalent vaccines. Sixty cases of TP were reported i.e an incidence/100,000 doses of 0.23 and 0.17 for measles or rubella vaccines respectively given alone, to 0.87 for combined measles-rubella vaccine and 0.95 for MMR vaccine. The mean age was 21 +/- 12 months and the delay of diagnosis was 16 +/- 6 days after vaccination. Thrombopenia was severe (mean platelet count: 8000 +/- 6000/mm3) and always associated with purpura. The immediate outcome was favourable in 89.5 per cent of cases. Vaccine-associated TP appears to be similar to acute childhood idiopathic thrombocytopenic purpura but the clear temporal relationship between MMR vaccination and the occurrence of TP make a causal relationship highly plausible. Acute TP seems a rare complication of measles-rubella and MMR vaccination but clinicians had to be informed of the possibility of their occurrence. Acute TP following vaccination should be reported by physicians to their Regional Drug Surveillance Centre.

[Pentasa (mesalazine) and pregnancy]. / Pentasa (mésalazine) et grossesse.

We analysed the outcome of 11 pregnancies in women treated for inflammatory bowel disease with mesalazine (Pentasa) during part of or throughout pregnancy. There were 9 healthy babies, one spontaneous abortion (the woman had an uterine malformation) and one infant with multiple malformations (but the mother was not treated with mesalazine during organogenesis). Because of the relatively small number of pregnancies exposed to mesalazine (Pentasa) in this study, these data need to be confirmed by other studies.

[Comparison of plasma concentration and tolerance of a single dose of human calcitonin by intradermal and subcutaneous administration]. / Comparaison des concentrations plasmatiques et de la tolérance d'une dose unique de calcitonine humaine administrée par voie intradermique et sous-cutanée.

UNLABELLED: The aim of the study was to compare plasmatic levels of calcitonin obtained after intradermic (ID) and usual subcutaneous (SC) route of administration. METHOD: 6 volunteers between 18 and 40 years old received calcitonin 0.5 mg (Cibacalcin, Ciba-Geigy Laboratory) by ID and SC routes in a random order but at the same site of injection. Each administration was spaced by 8 days. Plasmatic levels were measured by R.I.A. before administration then 2 (M2), 7 (M7), 15 (M15), 30 (M30) minutes and 1 (H1), 2 (H2), 4 (H4), 8 (H8), 12 (H12) hours after each administration. RESULTS: Tmax were at 23.6 +/- 10 min and 16.2 +/- 7.5 min for SC and ID routes respectively. With ID route, Tmax was reached simultaneously or earlier (3 times). Cmax is significantly higher with ID route. Neither mean plasmatic levels at each plasmatic dosage nor mean areas under the curve between 0 to 1,440 min or between 0 to 480 min (this latest AUC calculate to minimize the importance of calcitonin basal level) were significantly different with ID and SC routes. 16 mild side effects (8 with each administration) were observed in 4 subjects. They appeared before 5 min. and were transient (1 hour) for cutaneous manifestations, and later between hours 3 and 7 for nausea and vomiting or asthenia. The mean lowering of calcemia was 0.29 +/- 0.21 and 0.18 +/- 0.11 mmol/l respectively for SC and ID route. In this study ID and SC routes for calcitonin administration are not different with regard to plasma levels and side effects.

[Does the placebo effect exist in newborn infants?]. / L'effet placebo existe-t-il chez le nouveau-né?

Although comparison with a placebo is necessary to demonstrate the "true" effect of a drug, neonatologists are usually reluctant to use a placebo. The reason given is the lack of placebo effect in neonates. We studied heart and respiration rates and behaviour in normal neonates during heelstick for diagnosis of phenylketonuria. In this open randomized study we compared no treatment with an "analgesic" treatment consisting of water and sucrose. There was no difference in heart and respiration rates and behaviour between the two groups. These results do not demonstrate a "suggested" placebo effect and can in part be explained by the model and tools used to measure pain. The results do not support the non-use of placebo in drug evaluation trials in children.

[Drug utilization at the end of pregnancy]. / Consommation médicamenteuse en fin de grossesse.

To evaluate drug utilization during the last 15 days of pregnancy, one hundred six women were interviewed post-delivery in the CHU Bretonneau in Tours. Eighty-three percent received at least one drug during the 15 days preceding delivery and 27% more than 3 different drugs. Treatments for venous disorders (31% of patients), iron (31%), analgesics (25%), antacids (11%), magnesium (11%) and laxatives (11%) were most frequently used. In 92% of cases the drug was prescribed. Five women received a drug with potential risk for the neonate. However only one infant developed and adverse effect, possibly due to benzodiazepine (hypotonia).

[Are theophylline determinations useful to the clinician during treatment with a sustained-release form of theophylline?]. / Les dosages de théophylline sont-ils utiles au clinicien au cours des traitements par théophylline à libération continue?

The aims of the study were the correlation between dosage and plasmatic levels of slow release theophylline and the reason for dosage adjustment. 64 pharmacokinetic studies were performed in 58 asthmatic children between 17 months and 16 years. Plasmatic levels of theophylline were performed by fluoroimmunology technique at H0 (before the dose) 2 (H2), 4 (H4), 6 (H6) and 8 (H8) hours after the dose of slow release theophylline. The best correlation between dose and plasmatic levels were observed at H4 and H6 for Armophylline and Euphylline respectively. Dosage adjustment were based both upon clinical state and plasmatic levels in 55 cases. In 9 cases the modification of dose were decided only because of plasmatic levels out the therapeutic range. The authors proposed a schema of dosage modifications based upon clinical state; plasmatic levels must be used as a guide for dose adjustment in patients clinically uncontrolled.

[Methodology of preparing a list of educational objectives: example of application to pharmacology. Groupe Objectifs Pédagogiques de L'Association des Enseignants de Pharmacologie]. / Méthodologie d'élaboration d'une liste d'objectifs éducationnels: exemple d'application à la pharmacologie. Groupe Objectifs Pédagogiques de l'Association des Enseignants de Pharmacologie.

Using a structured approach to categorize pharmacological knowledge and a systemic analysis of prescribing practice, we identified the knowledge needed to optimally prescribe and manage treatments with drugs. The approach consisted in finding the branched chains of knowledge beginning with each operation required to solve each problem which arises in prescribing and managing drugs at the most elementary level. This elementary knowledge is then transformed into educational objectives. The next step is to share the educational objectives between basic medical training, continuing medical education and acquisition of therapeutic knowledge. The method could be applied in other medical teaching domains.

[Toxicology of reproduction: predictive value of experimental models. Round Table No 1 at Giens XIII]. / Toxicologie de la reproduction: valeurs prédictives des modèles expérimentaux. Table Ronde No 1 de Giens XIII.

The carrying out of clinical trials with a view to the marketing of drugs for human use is directly related to results of some animal studies. This workshop was devoted to evaluation of the quality and interest of these experimental models in reproductive toxicology. The predictive ability of preclinical trials to make extrapolations from animals to man decreases from foetotoxic to tetratogenic risks respectively and from the effects on fertility in both sexes to postnatal risks. As a result of this workshop, we propose the following improvements: (1) standardization and generalization of fertility test evaluations, especially the spermogram, in order to improve animal and human correlations; (2) development of knowledge and standardization of the follow up of the oestral cycle; (3) improvement of standardization, harmonization and diffusion of postnatal tests that prove relevant in animals; (4) increase in initiatives aimed at better mutual understanding of all drug partners; (5) creation of registers for new drugs, as soon as possible during clinical trials, to study their effects on the whole reproductive process; (6) recommendations for the creation of guidelines for International Conference on Harmonisation (ICH) to enable classification of observed effects in experimental models. This could lead to specific (potentially for each phase of the reproductive cycle) guidelines, precautions for use and/or contraindications which are listed in the summary of product characteristics.