Aurore Gouraud

Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs

AIMS The risk of hypoglycaemia with tramadol (TRM) is not well described. Our aim was to analyze spontaneous reports of hypoglycaemia registered in the French Pharmacovigilance database and to compare these data with two other step-2 analgesic drugs. METHODS Cases of hypoglycaemia associated with TRM, dextropropoxyphene (DXP) and codeine (COD) recorded between 1997 and November 2010 in the French pharmacovigilance database were compared. RESULTS Seventy-two cases of hypoglycaemia associated with DXP and 43 with TRM were retained for evaluation (the single case reported with COD was not further considered). Most patients were elderly people with no significant difference in age between DXP- and TRM-treated patients (71.2 ± 21 vs. 69.4 ± 22.5 years). Hypoglycaemia occurred after a median of 4 and 5 days with DXP and TRM treatment, respectively. The mean lowest serum glucose concentration was 2.1 ± 0.9 mmol l(-1) in the DXP group compared with 2.5 ± 1 mmol l(-1) in the TRM group (P = 0.072). At least, one risk factor of hypoglycaemia was found in most patients, with no significant difference between groups (58.3% in the DXP group and 58.1% in the TRM group). In particular, 31.9% patients from the DXP group had diabetes compared with 41.8 % from the TRM group (P = 0.28) and 18% of DXP patients had renal insufficiency compared with 16.3% of TRM patients (P = 0.8). CONCLUSIONS Our study confirms that TRM is associated with the occurrence of hypoglycaemia in elderly or predisposed patients, with characteristics similar to those previously reported with DXP.

Terappel : description et exemple(s) d’exploitation

Risk assessment and recommendations regarding the use of medicines during pregnancy or in women of childbearing age is an important task of pharmacovigilance. As a drug information resource, the network of French regional pharmacovigilance centres is involved in providing a personalized risk assessment and individualized counselling during pregnancy. It must also ensure systematic follow-up of exposed pregnancies for which it has been contacted. To ensure harmonized data collection and follow-up, a dedicated database was set-up in 1984 by the Lyon pharmacovigilance centre, which was later made available to 18 other centres. Prospective data from this database is regularly used by the network for descriptive or comparative collaborative studies at the national level or by participating to studies initiated by the European Network of Teratology Information Services in order to provide information on the safety profile of drug exposure in pregnant women. The characteristics of this database and examples of utilization are described in this article.

Drugs and Sleep Apneas? A review of the French Pharmacovigilance database

The present work reviews the case reports of drug-induced sleep apnea recorded in the French pharmacovigilance database. Notifications are very rare (around 1/100 000 notifications). This paper shows that sleep apnea can be aggravated or revealed by some drugs. Main drugs involved were psychotropics (benzodiazepines, neuroleptics) and opioids.

Delayed methotrexate elimination: Incidence, interaction with antacid drugs, and clinical consequences?

The aim of this retrospective cohort study was to investigate the incidence of delayed methotrexate elimination in patients treated with high‐dose methotrexate (≥1 g/m2) for haematological malignancy and to identify the impact of interacting drugs, especially proton‐pump inhibitors (PPIs) and ranitidine. All patients treated with high‐dose methotrexate over a 6 year period in the haematology department of the Lyon Sud University Hospital (Hospices Civils de Lyon, France) were included. Potential risk factors for delayed methotrexate elimination were tested in a generalized linear model by univariate analysis: patient age, gender, methotrexate dose, administration of PPI or ranitidine, and concomitant nephrotoxic drugs. A total of 412 cycles of methotrexate were administered to 179 patients. Proton‐pump inhibitors were co‐administered with methotrexate in 127 cycles and ranitidine in 192 cycles. Ninety‐three cycles included no antacid drugs. A total of 918 plasma methotrexate assays were performed. Methotrexate concentrations were checked at 24 hours in 92% of cycles. Delayed methotrexate elimination was observed in 20.9% of cycles. A total of 63 cycles with delayed methotrexate elimination were only identified on plasma methotrexate measures at 72 hours: ie, plasma methotrexate was in the normal range at 24 and 48 hour post injection. Use of PPI/ranitidine or no antacid drugs did not increase risk of delayed elimination, with respectively delayed methotrexate elimination in 20.5%, 21.9%, and 19.4% of cycles (P = .89). Impaired baseline creatinine clearance showed significant association in univariate analysis. Fifteen patients showed grade 1 acute kidney injury, 1 grade 2, 2 grade 3, and none grade 4. For half of these cases, delayed methotrexate elimination was observed and the 2 grade 3 events appeared in patients treated with PPIs. This retrospective study suggests that there is no association between concomitant use of proton‐pump inhibitors (pantoprazole and esomeprazole) or ranitidine and delayed methotrexate elimination.

Duloxetine and gingival bleeding: a case-report and reviews of the French and World PharmacoVigilance Databases and literature

Duloxetine is a serotonin-noradrenaline reuptake inhibitor (SNRI) used for major depression, anxiety disorder, diabetic pain, and fibromyalgia [1]. Common adverse drug reactions (ADRs) are nausea, headache, dry mouth, somnolence, and dizziness [2]. Association between bleeding and antidepressants is discussed. Serotonin reuptake inhibitors (SRIs) or SNRIs can inhibit serotonin-induced platelet aggregation amplification, decreasing platelet aggregability and prolonging bleeding time [3–5]. We describe a report of gingival bleeding (GB) and reviewed other reports in PharmacoVigilance databases and in literature. A 35-year-old woman was treated for Bfibromyalgia^ by duloxetine 60 mg/day. Two months later, she suffered from spontaneous GB, associated with dry mouth, observed throughout the whole day and during 2 months until withdrawal. GB disappeared after discontinuing duloxetine. There was no previous medical history. The patient also received omeprazole (20 mg/day), paracetamol (2 g/day), and codeine (120 mg/day). Biological tests were normal. Medical examination failed to find any buccal lesion. Causality assessment was Blikely^ according to the French method [6]. In the French PharmacoVigilance database, we found three other reports with duloxetine Bsuspected.^ The first was a 36-year-old woman without previous medical history, suffering from GB 3 weeks after duloxetine introduction for chronic pain. Duloxetine (dose unknown) was the sole drug received and was withdrawn. Evolution was unknown and causality Bpossible.^ The second involved a 39-year-old woman without medical history with GB 6 days after duloxetine introduction (60 mg/day ) fo r dep re s s ion . Du loxe t ine was discontinued and GB resolved within a few days. No other drug was associated (causality: Bplausible^). The third report involved a 70-year-old psychotic woman treated by duloxetine (60 mg/day) for many years with risperidone (2 mg/day), alprazolam (0.75 mg/day), and zolpidem (10 mg/day). GB occurred after dental extraction and was observed during at least 1 month. Evolution remained unknown: duloxetine was not stopped (causality Bpossible^). Among the 14,873,497 ICSRs in VigiBase®, the WHO Global Individual Case Safety Report (ICSR) database [7], 23 were GB with duloxetine Bsuspected.^ They occurred mainly in women (78%) and between 18 and 44 years (26.0%). Other reports involved 5 patients between 45 and 64 years, 4 between 65 and 74 years, 3 in patients ≥75 years (5 with age unknown). BCo* Jean-Louis Montastruc jean-louis.montastruc@univ-tlse3.fr

Decrease in factor V activity in patients treated with azathioprine or 6-mercaptopurine.

BACKGROUND AND OBJECTIVE A decrease in factor V activity has been reported in some patients treated with azathioprine or 6-mercaptopurine. This may lead to unnecessary treatment discontinuation in otherwise asymptomatic patients. Our aim was to review spontaneously reported cases of decreased factor V activity associated with both drugs and to identify the possible impact on patient care. METHODS Cases of decrease in prothrombin (PT) or factor V activity involving purine analogs were extracted from the French pharmacovigilance database. Reports with evidence of disseminated intravascular coagulation, signs of acute hepatocellular failure, liver cirrhosis or concomitant vitamin K antagonist treatment were excluded. RESULTS Twenty-four cases (azathioprine: 13 and 6-mercaptopurine: 11) were retained. Therapeutic indications were inflammatory bowel diseases in 11 patients, acute leukemia in eight, and other autoimmune diseases in five. PT activity before treatment was normal in all nine tested patients. The decrease in PT or factor V activity occurs after a median of 10 weeks of treatment and all patients were asymptomatic. The median PT and factor V activities values were 51.5% and 36.4%, respectively. Other coagulation factors were inconsistently decreased. Full recovery was observed within 3-60 days following purine analogs discontinuation. In four patients, drug rechallenge was associated with recurrence of the coagulation disorders. CONCLUSIONS Although the mechanism remains unknown, this series that includes cases with positive drug reintroduction strongly suggests the causative role of these drugs. As all patients remained asymptomatic, treatment discontinuation should be carefully considered in patients who clearly benefits from this treatment.