Kamel Masmoudi

Extrapyramidal adverse drug reactions associated with trimetazidine: a series of 21 cases.

Over the last few years, a number of cases of extrapyramidal disorders associated with trimetazidine (TMZ) use has been reported. Here, we report on a series of 21 cases. All but one of the patients (mean age 74) had been taking TMZ for several years. The indication for prescription of TMZ could not be identified in seven cases. The TMZ‐associated adverse drug reactions were typical parkinsonism (akinesia and/or rigidity and/or rest tremor) in 17 cases, gait disorders in three cases (one with orthostatic tremor), and restless leg syndrome in one case. Discontinuation of TMZ led to complete disappearance of the symptoms in 16 cases and a significant reduction in the five other patients. TMZ has the same piperazine core as the dopamine antagonists flunarizine and cinnarizine (both of which have been reported to induce extrapyramidal symptoms). Hence, striatal D2 receptor blockade could result in the onset or the worsening of extrapyramidal disorders. Even though this adverse drug reaction is now listed in TMZ’s Summary of Product Characteristics (because of the initial reports), the risk remains poorly known by clinicians. There is a need to raise awareness of this phenomenon and to reassess TMZ ‘s risk‐benefit ration, especially in the elderly.

Effets indésirables « graves » du tramadol : bilan 2010-2011 de pharmacovigilance en France

OBJECTIVE Tramadol is a weak opioid used as a step 2 analgesic, approved in France for moderate to severe pain. After dextropropoxyphene withdrawal, a national pharmacovigilance follow-up of tramadol was decided by the French Drug Agency. METHODS All Serious Adverse Drug Reactions (SADR) notified with tramadol to the French PharmacoVigilance Centres (CRPV) and pharmaceutical companies between August 1(st), 2010 and July 31(th), 2011 were analyzed. RESULTS During the study period, 296 cases of SADR were notified to CRPV and 59 to pharmaceutical companies. Apart from opiate-related SADR, tramadol induced serotoninergic SADR, including seizures or serotoninergic syndromes. Several « unlabelled » SADR were also identified: some of them, like hyponatremia or hypoglycemia, are poorly known by health professionals. Other were never published: peripheral edema or pancreatitis. CONCLUSION This study shows that besides well-known opioid or serotoninergic ADR, tramadol can also induce 2 other relatively unknown ADR: hypoglycemia and hyponatremia.

Risk Factors for Bleeding in Hospitalized at Risk Patients With an INR of 5 or More Treated With Vitamin K Antagonists.

AbstractVarious predictive scores for vitamin K antagonist (VKA)-related bleeding have been developed and validated in outpatients and in patients treated for specific indications (when VKAs are used under optimal therapeutic conditions). However, there are few published data on the evaluation of bleeding risk factors in hospitalized, at-risk patients (with a high international normalized ratio [INR]) treated with VKAs. The objective of the present study was to identify the most relevant bleeding risk factors in 906 VKA-treated patients with an INR of 5 or more hospitalized in a French university medical center.Over a 2-year period, we screened all consecutive VKA-treated adults with a risk of major bleeding (defined as an INR ≥ 5 on admission). Demographic and clinical characteristics, medications, and bleeding characteristics were recorded prospectively.The overall incidence of bleeding was 26.6% (serious bleeding: 21.4%; fatal bleeding: 5.4%). An INR ≥ 8.5, a history of recent digestive tract lesions, trauma in the preceding 2 weeks, and known noncompliance were independent risk factors for bleeding and serious bleeding.Our present findings emphasize that VKAs should not be prescribed to patients with a high risk of bleeding (noncompliant patients and those with recent trauma or recent gastrointestinal lesions). It is essential to monitor the INR on a frequent basis and adjust oral anticoagulant treatment appropriately.

Medication errors with tramadol drops in children

Tramadol is a Mu receptor agonist and a serotonin and noradrenaline reuptake inhibitor. It is used as analgesic in order to manage moderate to severe pain. This drug is metabolized by CYP2D6 in O-desmethyltramadol (an active metabolite), leading to a higher risk of adverse drug reactions in ultrarapid metabolizers [1] and to a risk of lower effectiveness in poor metabolizers. In June 2013, the Pharmacovigilance Risk Assessment Committee of the European Medicine Agency contraindicated codeine to children aged below 12 years [2]. Consequently, tramadol became the only oral step 2 analgesic in children aged less than 12 years old in France. The pediatric form of tramadol (oral solution) is licensed in France for children from 3 years old. Flasks contain 10 ml (1000 mg) of tramadol, with a dropper. The common dose is 1–2mg/kg per intake and each drop contains 2.5 mg tramadol. Following a report of medication error with a fatal issue to the French Pharmacovigilance System, we assessed adverse drug reactions (ADRs) due to medication errors with this pediatric tramadol oral solution in France. We analyzed all Bserious^ reports of ADRs registered in the French Pharmacovigilance Database [3] from August 1, 2011 to December 31, 2015 in children (aged <18 years) where exposure to tramadol was recorded. Seventy-four reports of Bserious^ ADRs due to tramadol were identified. Among these, 13 (18%)were medication errors, including 8with the oral solution form. In 5 cases, the prescribed dose per intake (in mg or in number of drops) was multiplicated by the child weight leading to tramadol overdose. Among them, 2 prescriptions were confusing, the dosage being written in mg per intake or in mg per day. Consequently, a calculation by the pharmacist or the patient was needed to convert dose in number of drops. Among these 5 cases, children were aged from 3 to 8 years old, and 4 were boys. In 4 cases, ADRs were life threatening, due to one or several ADRs: respiratory depression (n = 3), disturbances in consciousness (n = 3) or seizures (n = 1). In one case, ADRwas vertigo leading to hospitalization. In each case, patients fully recovered. In the 3 other cases, medication errors were: 1/ confusion about tramadol dosage with betamethasone dosage (150 drops) co-prescribed after a tonsillectomy, leading to euphoria; 2/ off-label prescription of tramadol to a 2-year-old boy (aged < 3 years), leading to agitation and abnormal crying; and 3/ tramadol overdose occurring in a 3year-old boy leading to respiratory depression, coma, cardiorespiratory arrest, and death. An error in the number of drops administered was suspected although no evidence for ultrarapid metabolizer CYP2D6 polymorphism was found. The present study is the first to demonstrate that medication errors with tramadol oral solution in children can lead to BThe French Drug agency (ANSM) allowed us to use the French PharmacoVigilance database. Authors of this article are solely responsible for its content and conclusions. The content of this article only involved its authors and is not validated by the ANSM.^

Cefixime-induced Oromandibular Dystonia in an Adult: A Case Report

INTRODUCTION Cefixime, a third-generation cephalosporin, is commonly used in different infections. Tolerance is pretty good even if some side effects can be frequent like digestive disorders. Other effects, not mentioned in the Summary of Product Characteristics, can occur. METHODS We report a case of recurrent, acute oromandibular dystonia in a cefixime-treated adult. CASE-REPORT After the third dose of cefixime, prescribed for a bronchial infection, a patient experienced a first episode of oromandibular dystonia. Then, after each ingestion, the same effects appeared. After the discontinuation of cefixime, there was no recurrence. The diagnosis of acute oromandibular dystonia has been confirmed by a neurologist. DISCUSSION Some cases of dystonia have been published with other β-lactams antibiotics and with cefixime but they concerned children. Different mechanisms are proposed to explain the occurrence of dystonia during a treatment with cefixime. They involved certain neurotransmitters like dopamine, acetylcholine or GABA. CONCLUSION Even if dystonia is not a side effect mentioned in the SPC, the drugs potential causal role must always be considered in case of involuntary contraction of muscles in a patient treated with cefixime or any other β-lactam antibiotics.

Adaptation and validation of an adverse drug reaction preventability score for bleeding due to vitamin K antagonists.

AbstractAlthough drug therapy is inherently associated with the risk of adverse drug reactions (ADRs), some of these events are preventable. The estimated proportion of preventable ADRs varies from one study or clinical context to another. Bleeding caused by antithrombotic agents (and particularly vitamin K antagonists, VKAs) constitutes one of the most frequent causes of ADR-related hospitalization.Hence, the objective of the present study was to adapt and validate an ADR preventability score for bleeding due to VKAs and evaluate the preventability of bleeding in 906 consecutive hospitalized, VKA-treated adult patients with a risk of major bleeding (defined as an international normalized ratio ≥5) over a 2-year period. A specific preventability scale for VKA-associated bleeding was developed by adapting a published tool.Overall, 241 of the 906 patients in the study experienced at least 1 VKA-associated bleeding event. The scales reliability was tested by 2 different evaluators. The inter-rater reliability (evaluated by calculation of Cohens kappa) ranged from “good” to “excellent.” Lastly, the validated scale was used to assess the preventability of the VKA-associated bleeding. We estimated that bleeding was preventable or potentially preventable in 109 of the 241 affected patients (45.2%).We have developed a useful, reliable tool for evaluating the preventability of VKA-associated bleeding. Application of the scale in a prospective study revealed that a high proportion of VKA-associated bleeding events in hospitalized, at-risk adult patients were preventable or potentially preventable.