Can tramadol really induce hyponatraemia? A pharmacovigilance study.

Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992-2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed: (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39-1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs.

Parkinsonism associated with gabapentinoid drugs: A pharmacoepidemiologic study.

BACKGROUND: Use of gabapentinoids is increasing. Following recent case reports, we investigated a putative risk of parkinsonism with pregabalin or gabapentin. METHODS: A disproportionality analysis of 5,653,547 individual case safety reports in the World Health Organization individual case safety report database, VigiBase, compared all patients with parkinsonism who were receiving gabapentinoids with other patients. Results are shown as reporting odds ratios and the information component, an indicator of disproportionate Bayesian reporting. Sensitivity analyses included comparisons with drugs used for similar indications (amitriptyline, duloxetine) and exclusion of drugs that induce parkinsonism. RESULTS: Among 5,653,547 reports, 4925 parkinsonism reports were found with pregabalin and 4881 with gabapentin. Gabapentin and pregabalin were associated with increased reporting odds ratio (2.16 [2.10-2.23], 2.43 [2.36-2.50]). Similar trends were found using information components after excluding drugs that induce parkinsonism and for pregabalin compared with amitriptyline or duloxetine. CONCLUSIONS: This study found that gabapentinoids (particularly pregabalin) can be associated with parkinsonism. © 2019 International Parkinson and Movement Disorder Society.

Adverse drug reactions in infants, children and adolescents exposed to antidepressants: a French pharmacovigilance study.

PURPOSE: Despite their frequent use in children and adolescents, the evidence for efficacy and safety of antidepressants (ATDs) in this population is scarce and off-label prescribing common. The aim of this study was to describe reported adverse drug reactions (ADRs) associated to ATDs over a 30-year period using the French Pharmacovigilance Database (FPVD). METHODS: We performed an analysis of ADRs registered in the FPVD from 1985 to 2016, occurred in children and adolescents receiving an ATD. Descriptive statistics were used to obtain an overview of ADRs types and characteristics, and data were stratified by age. RESULTS: Among the 45,070 pediatric cases reports registered into the FPVD, we identified 1366 reports (3.0%) in which ATDs were "suspected" as the cause of 2922 ADRs. ADRs were more frequently reported in female (n = 743; 55.5%) and adolescents (n = 627; 49.3%). Neuropsychiatric ADRs were the most reported, mainly sleepiness, agitation, and suicidal thinking and behavior, followed by gastrointestinal and hepatobiliary disorders, mainly vomiting, abdominal pain, hepatitis, nausea, and three unexpected ADRs of pancreatitis. There was an increase of annual reporting between 1986 and 2003, followed by a plateau state then a decrease from 2003 to 2012, and a rapid escalation until 2016, while an increase in the number of reporting of suicidal thinking and behavior was observed after 2003, highlighting a possible impact of black box warnings on reporting practices and ATD use. CONCLUSION: This pediatric pharmacovigilance study underscored the high prevalence of neuropsychiatric and gastrointestinal ADRs, including three unexpected cases of pancreatitis.

Drug-induced tics: An observational postmarketing study.

OBJECTIVES: While drug-induced tics have been described, in particular with neuroleptics, psychostimulants, or anti-epileptics, the strength and the direction of these associations are still debated. The aim of this study was to investigate the association between tics and drug exposure through a two-step analysis in two pharmacovigilance databases. METHODS: We first performed a descriptive clinical analysis of cases registered in the French pharmacovigilance database (FPVD) from January 1985 to December 2018. We then performed a disproportionality analysis in VigiBase®, the WHO pharmacovigilance database, from January 1967 to June 2019, through the calculation of reporting odds ratio (ROR). RESULTS: The drugs most frequently associated with tics in the FPVD were methylphenidate, lamotrigine, montelukast, tramadol, mirtazapine, venlafaxine, aripiprazole, and risperidone. In VigiBase®, we found a significant ROR with methylphenidate (ROR 37.54, 95% confidence interval [CI] 34.81-40.48), montelukast (ROR 12.18, 95% CI 10.29-14.41), aripiprazole (ROR 7.40, 95% CI 6.35-8.62), risperidone (ROR 4.40, 95% CI 3.72-5.21), and venlafaxine (ROR 1.52, 95% CI 1.14-2.03). CONCLUSION: This postmarketing study confirmed a potential harmful association with methylphenidate (the highest association, as expected), aripiprazole, risperidone, lamotrigine, and venlafaxine and, interestingly, found a strong signal with montelukast, which, to our knowledge, had never been published before.

Breast cancer and spironolactone: an observational postmarketing study.

INTRODUCTION: Recent studies have discussed the risk of breast cancer with antihypertensive drugs. For spironolactone, data are conflicting. The present paper investigates this potential signal in VigiBase®, the World Health Organization Global Individual Case Safety Report (ICSR) database. METHODS: In VigiBase®, we performed a case/non-case study using data registered from 1981 (spironolactone's marketing authorization) to December 31, 2017. Among women ≥ 50 years, we measured the risk of reporting "Breast malignant tumors" compared with all other adverse drug reactions (as a crude and adjusted (a) reporting odds ratio (ROR 95% CI)) for spironolactone compared with first, all other drugs and second, pseudo aldosterone antagonists (amiloride, triamterene). ROR were adjusted for age, year of report, continent of report, number of drug prescribed, and completeness score. Sensitivity analyses were performed after exclusion of drug competitors (i.e., drugs like estroprogestative therapy and progestogens that could mask a putative signal) and reports from health professionals. RESULTS: During the study period, 125 ICSRs reported spironolactone exposure and breast malignant cancer in women ≥ 50 years. We failed to find a positive association between spironolactone exposure and breast cancer in comparison with exposure to other drugs (aROR = 0.63 95% CI [0.52-0.75]) or pseudo aldosterone antagonists (amiloride, triamterene) (0.56 [0.44-0.72]). Similar trends were found after exclusion of drug competitors and/or reports from health professionals. CONCLUSION: This study did not find evidence for breast cancer associated with spironolactone.

Drug-induced osteoporosis/osteomalacia: analysis in the French and Spanish pharmacovigilance databases.

INTRODUCTION: Osteomalacia and osteoporosis are two metabolic bone disorders that increase the risk of fracture due to several causes. In terms of drugs, apart from corticosteroids, which are known to induce bone disorders, several other drugs used in chronic disease management have also been linked with an increased risk of osteoporosis and osteomalacia. PURPOSE: The aim of this study was to describe spontaneous reports of drug-induced osteoporosis and osteomalacia in the French (FPVDB) and Spanish (SPVDB) pharmacovigilance databases. METHODS: Data were provided by the FPVDB and SPVDB. All reports of osteoporosis and osteomalacia recorded from 1985 up to 31 December 2015 inclusive were selected. Taking the time to onset of bone loss into account, all cases occurring in less than 1 month were excluded. RESULTS: A total of 369 reports (44 cases of osteomalacia, 325 cases of osteoporosis) were registered in the FPVDB and 64 (22 cases of osteomalacia, 42 cases of osteoporosis) in the SPVDB. In France, the top 5 drugs involved in the onset of osteoporosis were corticosteroids accounting for approximately half of the reports (n = 170) followed by systemic antiviral (n = 87), antacid (n = 29), antiepileptic (n = 27) and antithrombotic (n = 24) drugs. The 2 main classes of drugs implicated in osteomalacia were systemic antiretroviral drugs for half of the reports (n = 21) and antiepileptic drugs (n = 15). In Spain, corticosteroids were involved in 35.7% of reported cases of osteoporosis (n = 15) followed by systemic antiviral drugs (n = 12). There was no spontaneous report for antacid drugs. For osteomalacia, the 2 main drug classes were systemic antiretroviral drugs (n = 18, 81.8%) followed by antiepileptics (n = 2, 9.0%). In both countries, concomitant administration of systemic corticosteroids with other suspected drugs did not significantly modify the time to onset of drug-induced osteoporosis. CONCLUSION: Despite some differences between the French and Spanish PVDBs, our data consistently show that bone loss is not only restricted to glucocorticoids but also involves antivirals, antiepileptic drugs, antacid drugs or antidepressants. Further analysis might prove useful in exploring the characteristics of drug-induced bone loss on a larger scale.

Ergot and non-ergot dopamine agonists and heart failure in patients with Parkinson's disease.

PURPOSE: Some studies have suggested a potential risk of heart failure in patients with Parkinson's disease receiving dopamine (DA) agonists. However, the results are conflicting. We used VigiBase®, the World Health Organization (WHO) Global Individual Case Safety Reports (ICSRs) database, to investigate a potential signal strengthening of heart failure with DA agonists in Parkinsonian patients older than 45 years. METHODS: A case/non-case (disproportionality) analysis was performed in Vigibase® using ICSRs registered between 1978 and May 2016. The signal of disproportionality was calculated using reporting odds ratios (ROR). In our study, 154 ICSRs of heart failure occurring in 154 Parkinsonian patients (mean age 69.6 years, 51 % women) treated with DA agonists were included. RESULTS AND CONCLUSION: There was a significant signal between occurrence of heart failure and exposure to pergolide or cabergoline in particular and ergot derivatives in general. In contrast, none signal was found for rotigotine, pramipexole, apomorphine, or ropinirole in particular and non-ergot derivatives in general. The present study underlines the importance to prescribe as DA agonists in Parkinsonian patients only non-ergot derivatives, excluding ergot drugs.

Atropinic (Anticholinergic) Burden in Parkinson's Disease.

Use of atropinic drugs remains controversial in Parkinson's disease (PD) because there is insufficient evidence about their efficacy and they can induce serious adverse drug reactions. Atropinic risk scales were developed to help to identify atropinic drugs in prescription forms and to evaluate their burden in clinical practice. In the present review, we discuss the few studies investigating atropinic burden in PD and present the results of our study indicating that atropinic drugs are still widely prescribed in PD (almost 3 of 5 prescriptions) with a clinically significant atropinic burden in around 1 of 6 PD patients. Drugs mainly responsible for high values of atropinic burden were those used for nonmotor symptoms. Clinically significant atropinic burdens were mainly induced by associations of several "low-risk" drugs. Physicians must be aware that in addition to classical atropinic antiparkinsonian drugs, many others (psychotropics) can contribute to increased atropinic burden in PD patients. © 2016 International Parkinson and Movement Disorder Society.

[Bariatric surgery and drugs: Review of the literature and Adverse Drug Reactions analysis in French National Pharmacovigilance Database]. / Chirurgie bariatrique et médicaments : revue de la littérature et analyse des effets indésirables dans la banque nationale de pharmacovigilance.

INTRODUCTION: Bariatric surgery is the only treatment for severe obesity (BMI>35kg/m2) currently recognized as effective both in achieving tangible and lasting weight loss, and in improving obesity-related comorbidities such as type 2 diabetes, hypertension, and cardiovascular complications. Bariatric surgery, like any other surgery of the digestive tract, can have an impact on nutrient absorption, as well as on drug absorption. The literature on drug management in bariatric surgery patients concerned mainly of case reports and retrospective studies involving a small number of patients. No official guidelines are available. METHODS: We conducted a literature search on the consequences of bariatric surgery in terms of drug bioavailability and/or effect. The Medline® (PubMed) database was searched using the following keywords: "bariatric surgery", "bioavailability", "gastric bypass", and "obesity". We completed this review with an analysis of reports of adverse drug reactions (ADRs) in post-bariatric surgery patients for obesity registered in the National pharmacovigilance database (PVDB). We selected all cases with the mention of "bariatric surgery and/or gastrectomy" as "medical history". After reading the cases, we excluded those in which the patient had undergone surgery for an indication other than obesity, where the route of administration was other than oral, and cases in which ADRs resulted from voluntary overdose, attempted suicide, allergy, switch to Levothyrox® new formulation, meningioma under progestative drugs, inefficacy related to generic substitution and medication error. RESULTS: The literature search identified mainly "case report" about the impact of bariatric surgery on so-called "narrow therapeutic window" drugs. We identified 66 informative cases out of a total of 565 cases selected (11%) in the PVDB. Nevertheless, the information does not allow a clear relationship between the occurrence of the ADR and the influence of bariatric surgery. CONCLUSION: There is a lack of official information and/or recommendations on medication use in subjects who have undergone bariatric surgery. Apart from under-reporting, ADRs reports remain largely uninformative. Health professional and patients would be awareness for improving, quantitatively and qualitatively the reporting of ADRs in this population.

Renal Complications Related to Checkpoint Inhibitors: Diagnostic and Therapeutic Strategies.

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have unprecedentedly improved global prognosis in several types of cancers. However, they are associated with the occurrence of immune-related adverse events. Despite their low incidence, renal complications can interfere with the oncologic strategy. The breaking of peripheral tolerance and the emergence of auto- or drug-reactive T-cells are the main pathophysiological hypotheses to explain renal complications after ICI exposure. ICIs can induce a large spectrum of renal symptoms with variable severity (from isolated electrolyte disorders to dialysis-dependent acute kidney injury (AKI)) and presentation (acute tubule-interstitial nephritis in >90% of cases and a minority of glomerular diseases). In this review, the current trends in diagnosis and treatment strategies are summarized. The diagnosis of ICI-related renal complications requires special steps to avoid confounding factors, identify known risk factors (lower baseline estimated glomerular filtration rate, proton pump inhibitor use, and combination ICI therapy), and prove ICI causality, even after long-term exposure (weeks to months). A kidney biopsy should be performed as soon as possible. The treatment strategies rely on ICI discontinuation as well as co-medications, corticosteroids for 2 months, and tailored immunosuppressive drugs when renal response is not achieved.

Drug-Induced Hearing Loss in Children: An Analysis of Spontaneous Reports in the French PharmacoVigilance Database.

INTRODUCTION: Hearing loss can have a negative impact on communication, with significant vocational, educational, and social consequences. Drugs are one of the causes of hearing loss in children. OBJECTIVES: The objective of our study was to describe drug-induced hearing loss in the pediatric population. METHODS: Reports of hearing loss from 1985 to December 2019 in the pediatric population (< 18 years) were extracted from the French PharmacoVigilance Database (FPVD). We performed a retrospective and descriptive analysis of adverse drug reaction (ADR) reports. RESULTS: A total of 70 ADR reports were identified among the 51,216 reports registered in the FPVD, 37 involving adolescents (12-17 years, 52.9%), 28 children (2-11 years, 40.0%), and 5 infants (28 days-23 months, 7.1%). Overall, 40 reports (57.1%) involved girls. A total of 56 reports (80.0%) were "serious." The most frequent hearing disorders were deafness (n = 31, 44.3%) and hypoacusis (n = 22, 31.4%). Suspected drugs (ATC 5th level) were amikacin (n = 11, 15.7%), cisplatin (n = 11, 15.7%), doxorubicin (n = 4, 5.7%), vincristine (n = 4, 5.7%), clarithromycin (n = 4, 5.7%), ceftriaxone (n = 3, 4.3%), isotretinoin (n = 3, 4.3%), and vancomycin (n = 3, 4.3%). CONCLUSIONS: This study shows that about three out of four cases of drug-induced hearing loss in the pediatric population were "serious". It also underlines the under-reporting of these ADRs and the importance of strengthening hearing monitoring in children during and long after drug exposure.

[Not Available]. / Hyperglycémies d'origine médicamenteuse : étude dans la Base Nationale Française de PharmacoVigilance (BNPV).

OBJECTIVE: To analyse drugs inducing hyperglycemia by using data reported to the French spontaneous reporting system and recorded in the French PharmacoVigilance Database (FPVD). METHODS: All cases with a report of hyperglycemia and/or diabetes in the French database between 1985 and 2008 were included in the study. We estimated the risk of hyperglycemia linked to drugs by the case/non-case method. Cases were reports including hyperglycemia and non cases all other reports. This risk was estimated through calculation of reporting odds ratios (ROR). RESULTS: During this period, 1219 reports including the words "hyperglycemia and/or diabetes" were registered (0.34% of the database). This adverse drug reaction occurred 1 fold over 4 in diabetics or as a part of HIV infection. Effect was "serious" in approximatively 50% of cases.We found an increase of risk during exposition with methylprednisolone [ROR=43.5; 95% CI (37.3-50.8)], tacrolimus [ROR=25; 95% CI (17.9-34.8)], olanzapine [ROR=19.9; 95% CI (14.9-26.5)], prednisone [ROR=18.9; 95% CI (15.7-22.8)] or pentamidine [ROR=15.4; 95% CI (8.2-28.3)]. CONCLUSION: Drug classes most frequently found in FPVD linked to hyperglycemia are antiretroviral, steroidal anti-inflammatory, second generation neuroleptic, immunosuppressive and diuretic drugs.

[Drug-induced hyperglycemia: a study in the French pharmacovigilance database]. / Hyperglycémies d'origine médicamenteuse : étude dans la Base Nationale Française de PharmacoVigilance (BNPV).

OBJECTIVE: To analyse drugs inducing hyperglycemia by using data reported to the French spontaneous reporting system and recorded in the French PharmacoVigilance Database (FPVD). METHODS: All cases with a report of hyperglycemia and/or diabetes in the French database between 1985 and 2008 were included in the study. We estimated the risk of hyperglycemia linked to drugs by the case/non-case method. Cases were reports including hyperglycemia and non cases all other reports. This risk was estimated through calculation of reporting odds ratios (ROR). RESULTS: During this period, 1219 reports including the words "hyperglycemia and/or diabetes" were registered (0.34% of the database). This adverse drug reaction occurred 1 fold over 4 in diabetics or as a part of HIV infection. Effect was "serious" in approximatively 50% of cases. We found an increase of risk during exposition with methylprednisolone [ROR=43.5; 95% CI (37.3-50.8)], tacrolimus [ROR=25; 95% CI (17.9-34.8)], olanzapine [ROR=19.9; 95% CI (14.9-26.5)], prednisone [ROR=18.9; 95% CI (15.7-22.8)] or pentamidine [ROR=15.4; 95% CI (8.2-28.3)]. CONCLUSION: Drug classes most frequently found in FPVD linked to hyperglycemia are antiretroviral, steroidal anti-inflammatory, second generation neuroleptic, immunosuppressive and diuretic drugs.

Fluoroquinolone-Induced Photosensitivity: A Chemical Fragment-Based Approach by a Case/Non-case Study in VigiBase®.

INTRODUCTION: Fluoroquinolones are widely used to treat bacterial infections. Many in vitro and in vivo studies have established a chemical relationship between fluoroquinolones' particular chemical structure and photosensitivity. The aim of this study was to establish a relationship between the chemical structure of fluoroquinolones and the risk of photosensitivity adverse effects from real-world data. METHODS: All the Individual Case Safety Reports (ICSRs) related to fluoroquinolones and registered in the World Health Organization global database (VigiBase®) up to December 31, 2017 were collected. A disproportionality analysis was performed in order to quantify the photosensitivity risk for each fluoroquinolone by calculating their reporting odds ratio (ROR). RESULTS: Up to December 31, 2017, 282,805 ICSRs related to fluoroquinolones were selected, of which 1647 were photosensitivity adverse event cases. Sparfloxacin had the highest adjusted ROR of 161.10 (95% confidence interval [CI] 133.66-194.02) followed by grepafloxacin (40.30 [26.30-59.60]) closely followed by lomefloxacin (32.61 [28.61-37.07]), then enoxacin (11.04 [8.33-14.32]) and fleroxacin (8.22 [5.06-12.56]). CONCLUSION: This study confirms the high reporting rate of photosensitivity adverse effects for sparfloxacin from real-world data. Moreover, our data suggest more photosensitivity adverse effects reporting for fluoroquinolones with a halogen at their 8th position.

Frequency and Nature of Adverse Drug Reactions Due to Non-Prescription Drugs in Children: A Retrospective Analysis from the French Pharmacovigilance Database.

INTRODUCTION: Studies that evaluate the safety of non-prescription drugs in children remain scarce. OBJECTIVES: The aim of the present study was to compare adverse drug reactions (ADRs) due to prescription versus non-prescription drugs in children. METHODS: We conducted a retrospective analysis of ADR notifications for a pediatric population (aged <18 years) registered in the French PharmacoVigilance Database (FPVD) between January 1985 and December 2016 by the Midi-Pyrénées PharmacoVigilance Center (in the south of France). We compared ADR profiles according to drug prescription status using a Chi-squared test. RESULTS: We included 2218 notifications concerning 3687 ADRs in the study. Non-prescription drugs were involved in 506 notifications (22.8%). Patients were younger in the non-prescription drug group (6.7 ± 5.3 vs. 8.4 ± 5.7 years in the prescription drug group). No difference by sex was found. Neurological ADRs were more frequent with prescription drugs (21.0%) than with non-prescription drugs (14.2%, p = 0.0008), whereas dermatological disorders (37.2 vs. 29.1%, respectively) and general ADRs (30.8 vs. 20.1%, respectively) were more frequent with non-prescription than with prescription drugs (p = 0.0006 and p < 0.0001, respectively). The frequency of "serious" ADRs was higher with prescription drugs than with non-prescription drugs (40.9 vs. 34.2%, p = 0.007). The non-prescription drugs most frequently implicated with serious ADRs were ibuprofen (n = 37; 4.2%), tuberculosis vaccine (n = 23; 2.6%), aspirin (n = 20, 2.3%), and paracetamol (n = 17; 1.9%). ADRs from prescription drugs involved asparaginase (n = 27; 3.1%), immunoglobulins (n = 25; 2.9%), and amoxicillin (n = 23; 2.4%). CONCLUSIONS: Non-prescription drugs, usually considered safe, were frequently responsible for ADR notifications. The non-prescription medication most frequently involved in serious ADRs was ibuprofen.