Confusion, a Rather Serious Adverse Drug Reaction with Valproic Acid: A Review of the French Pharmacovigilance Database

Valproic acid-induced hyperammonemic encephalopathy is a rare yet serious adverse drug reaction. Medication interactions such a valproic acid and topiramate can precipitate an event. We present the case of a 52-year-old female that presented with acute mental status change and hypersomnolence due to hyperammonemia caused by a valproic acid derivative. The patient improved after withdrawal of the offending medications and treatment with lactulose. Clinicians should remain hypervigilant in monitoring for valproic acid-induced hyperammonemic encephalopathy and risk factors such as polypharmacy.

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Adverse Drug Reaction Reports Containing AMR-Relevant MedDRA Terms in the Dutch Pharmacovigilance Database

10.20944/preprints202108.0031.v1 ◽

2021 ◽

Author(s):

Jean Marie Vianney Habarugira ◽

Linda Harmark ◽

Albert Figueras

Keyword(s):

Adverse Drug Reaction ◽

Drug Resistance ◽

Drug Reaction ◽

Descriptive Analysis ◽

Pathogen Resistance ◽

Pharmacovigilance Centre ◽

Off Label Use ◽

Off Label ◽

Pv Systems ◽

Pharmacovigilance Database

(1) Background: Antimicrobial resistance (AMR) requires urgent multidisciplinary solutions, and Pharmacovigilance (PV) has the potential to strengthen current antimicrobial stewardship (AMS) strategies. This study aimed to characterise AMR-relevant adverse drug reaction (ADR) reports submitted to The Netherlands Pharmacovigilance Centre (Lareb); (2) Methods: We carried out a descriptive analysis of ADR reports submitted to Lareb, coded with AMR-relevant MedDRA Preferred Terms (PTs).; (3) Results: Between 1998 and Jan 2019, 252 AMR-relevant ADR reports were submitted to Lareb. The most frequent antibiotics were tobramycin (n=89; 35%), colistin (n=30; 11,9%), ciprofloxacin (n=16; 6,35%), doxycycline (n=14; 5,5%) and aztreonam (n=12; 4,76%). The most frequently used PTs were drug ineffective (n=71; 28%), pathogen resistance (n=14; 5%) and drug resistance (n=13; 13%). A total of 119 reports (74%) suggested use-related issues. Watch antibiotics were in 54% of the reports and Reserve antibiotics were in 19%. In the Watch group, “Off label use” and “Product use in unapproved indication” were the most frequent PTs and majority of reports on Reserve antibiotics were coded as “Off label”. (4) Conclusions: Addressing AMR using the PV methods will provide an opportunity for PV expansion and could encourage further investment in both in AMS programs and PV systems.

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Tramadol-induced hiccups: a case–noncase study in the European pharmacovigilance database

Therapeutic Advances in Drug Safety ◽

10.1177/20420986211021230 ◽

2021 ◽

Vol 12 ◽

pp. 204209862110212

Author(s):

Montserrat García ◽

Unax Lertxundi ◽

Carmelo Aguirre

Keyword(s):

Adverse Drug Reaction ◽

Drug Reaction ◽

World Health Organization ◽

Case Reports ◽

Opioid Analgesic ◽

World Health ◽

Plain Language ◽

The World ◽

Pharmacovigilance Database ◽

Health Organization

Background: Hiccups are usually benign and self-limiting, but can sometimes be persistent. If left untreated, they can provoke severe discomfort, and even death. Hiccups can be idiopathic, organic, psychogenic, and caused by drugs. Although some case reports have suggested a possible association between tramadol and hiccups, to our knowledge, no study has analyzed this possible relationship. The aim of this study was to analyze whether a disproportionate number of cases of hiccups are reported for tramadol in the EudraVigilance database. Methods: A case–noncase study was conducted to assess the association between hiccups and tramadol, calculating reporting odds ratios (RORs) from 1 January 1995 to 11 September 2020. Cases were selected using the preferred term ‘Hiccups’. The noncases used as controls were all other adverse drug reaction reports recorded in EudraVigilance during the same period. Exposure was defined as exposure to tramadol among cases and noncases. To reduce the risk of confounding by indication, the RORs for tramadol compared with other opioids were obtained. Additionally, we performed a confirmatory analysis in the World Health Organization pharmacovigilance database, VigiBase®. Results: There were 3089 cases of hiccups in the 7,213,623 reports. Tramadol was involved in 50 cases. The ROR for tramadol exposure was 3.35 [95% confidence interval (CI) 2.53–4.43]. This association persisted when comparing tramadol with other opioids; ROR: 2.13 (95% CI 1.52–2.99). Disproportionality was also observed in VigiBase®: ROR 1.69 (95% CI 1.47–1.93). Conclusion: Our study confirms, for the first time, a possible signal for a tramadol–hiccups association. Nevertheless, observational analytical studies are needed to confirm these results Plain Language Summary Evaluation of the relationship between the tramadol and the risk of hiccups Introduction: Hiccups are sudden involuntary contractions of the diaphragm. This involuntary contraction causes the vocal cords to close very briefly, which produces the characteristic sound of a hiccup. Hiccups are usually benign and self-limiting, but can sometimes be persistent. If left untreated, they can provoke severe discomfort, depression, disability, and in the most extreme cases, even death. Drugs are a rare cause of hiccups. Methods: This study investigated the possible association between tramadol and hiccups (an unmentioned adverse drug reaction in the Summary of Product Characteristics) in the European pharmacovigilance database (EudraVigilance) and a confirming analysis in the World Health Organization pharmacovigilance database (VigiBase). Results: Our analysis shows that hiccups is relatively more frequently reported in association with tramadol than with other medicinal products, with EudraVigilance and VigiBase confirming this association. Conclusion: Tramadol is an opioid analgesic indicated, alone or in combination with dexketoprofen or paracetamol for pain with various causes, so healthcare professionals and patients should be aware of this possible association.

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Valproic acid-induced hyperammonemic encephalopathy – a potentially fatal adverse drug reaction

SpringerPlus ◽

10.1186/2193-1801-2-13 ◽

2013 ◽

Vol 2 (1) ◽

Cited By ~ 9

Author(s):

Carla Sousa

Keyword(s):

Adverse Drug Reaction ◽

Valproic Acid ◽

Drug Reaction ◽

Hyperammonemic Encephalopathy

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Signal for a Different Risk of Thrombosis Between Eltrombopag and Romiplostim

Blood ◽

10.1182/blood.v124.21.2170.2170 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2170-2170

Author(s):

Thi Thanh Loan N'Guyen ◽

Maryse Lapeyre-Mestre ◽

François Montastruc ◽

Jean-Louis Montastruc ◽

Guillaume Moulis

Keyword(s):

Adverse Drug Reaction ◽

Drug Reaction ◽

Risk Factor ◽

Oral Contraceptive ◽

Venous Thrombosis ◽

Cerebrovascular Accident ◽

Arterial Thrombosis ◽

Increased Risk ◽

Pharmacovigilance Database ◽

Venous Thromboses

Abstract Introduction:Eltrombopag and romiplostim are two thrombopoietin receptor agonists (TPO-RAs) marketed for the treatment of immune thrombocytopenia (ITP). Thrombotic events have been reported with both drugs. Whether there exists a differential risk of thrombosis between the two TPO-RAs is unknown. Indeed, there exist pharmacological arguments to sustain a differential risk: i) the two drugs have different structures and different sites of action: romiplostim is an Fc-peptide fusion protein binding to the extracellular TPO receptor domain, while eltrombopag is a small non-peptide molecule that binds to a transmembrane site of the TPO receptor; ii) consequently the intracellular signaling pathways activated by TPO-RAs are not strictly identical in vitro; iii) in clinical practice, a patient who stops a given TPO-RA due to inefficacy, adverse drug reaction (ADR) or important platelet fluctuations can be efficiently rechallenged with the other TPO-RA; and iv) a disproportionality study carried out in the French PharmacoVigilance Database suggested a signal for a different pattern of ADRs between the two drugs. The aim of this study was to assess whether there exists a signal for a different risk of thrombosis, arterial thrombosis, venous thrombosis, ischemic stroke (IS) and myocardial infarction (MI) between romiplostim and eltrombopag. Methods:We carried out a disproportionality analysis (case/non-case method) in the World Health Organization PharmacoVigilance Database (VigiBase®). We selected all the adverse drug reaction (ADR) reports with exposure to eltrombopag or romiplostim between 01 January 2011 and 31 December 2013. Cases were all reports of thrombosis, identified thanks to validated standardized queries and checked by two independent investigators. Non-cases were all other reports. We searched an exposure to eltrombopag (versus romiplostim) in cases and in non-cases, allowing the calculation of Reporting Odds Ratios (RORs). All analyses were adjusted on thrombotic risk factors recorded in the database: age, gender, indication, exposure to oral contraceptive, danazol, polyvalent immunoglobulins, and other pro-thrombotic drugs. We conducted two sensitivity analyses: one restricted to cases and non-cases reported by physicians, and one including the reports of "cerebrovascular accident" among the cases. Results: Out of 2 733 224 ADR reports colligated in VigiBase®during the study period, 4714 were included in the study. TPO-RA indication was ITP in 96.6% of the reports. We found 598 cases of thrombosis: 203 arterial thromboses (94 IS and 110 MI) and 324 venous thrombosis. Among the 324 venous thromboses, 131 (40.4%) were pulmonary embolisms, 45 (13.9%) portal thromboses, and 17 (5.2%) cerebral venous thromboses were found. In multivariate analyses, there was an increased risk of thrombosis (ROR=1.46; 95% CI [1.18-1.82]) and venous thrombosis (ROR=1.46; 95% CI [1.10-1.94]) with eltrombopag. There was no statistically significant difference between the two TPO-RAs regarding arterial thrombosis (ROR=1.29; 95% CI [0.89-1.87]), IS (ROR=1.28; 95% CI [0.79-2.05]) and MI (ROR=1.53; 95% CI [0.96-2.43]). Age was independently associated with the risk of thrombosis. Female gender was a risk factor for venous thrombosis (ROR=1.55; 95% CI [1.16-2.06]); in contrast, it was a protective factor for arterial thrombosis (ROR=0.65; 95% CI [0.44-0.94]) and MI (ROR=0.55; 95% CI [0.34-0.90]). Exposure to oral contraceptive was also an independent risk factor for venous thrombosis (ROR=3.45; 95% CI [1.20-9.90]). Exposure to IVIg was associated with MI (ROR=2.13; 95% CI [1.23-3.68]). When we restricted to ADRs reported by physicians, all ROR measures were slightly increased (overall thrombosis: ROR=2.07; 95% CI [1.60-2.69]; venous thrombosis: ROR=2.02; 95% CI [1.44-2.83]), reaching significance for arterial thrombosis (ROR=1.58; 95% CI [1.01-2.48]) and IS (ROR=2.00; 95% CI [1.16-3.44]). Inclusion of the 45 reports of "cerebrovascular accident" did not influence the results (data not shown). Conclusions: This study suggests a signal for an increased risk of thrombosis with eltrombopag compared to romiplostim, that must be confirmed by population-based pharmacoepidemiological studies. Disclosures No relevant conflicts of interest to declare.

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Clinical Aspects of Unpredictable Adverse Drug Reaction and Assessment of Drug Casuality

Journal of Korean Society of Health-System Pharmacists ◽

10.32429/jkshp.2018.35.3.007 ◽

2018 ◽

Vol 35 (3) ◽

pp. 331-339

Author(s):

김광준 ◽

권용은 ◽

최인

Keyword(s):

Adverse Drug Reaction ◽

Drug Reaction ◽

Clinical Aspects

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Difficulties in the detection of the culprit drug for an adverse drug reaction in a complicated case

Orvosi Hetilap ◽

10.1556/oh.2008.28285 ◽

2008 ◽

Vol 149 (19) ◽

pp. 883-887 ◽

Cited By ~ 2

Author(s):

Henriette Kopcsányi ◽

Julianna Feldmann ◽

Zsófia Péch ◽

Ágnes Jurcsik

Keyword(s):

Adverse Drug Reaction ◽

Drug Reaction ◽

Complicated Case ◽

Erythema Exsudativum Multiforme ◽

Culprit Drug

Az adverz gyógyszerreakciók különféle klinikai megjelenési formái alapján a kiváltó gyógyszerre nehéz következtetni. A gyanúba vett gyógyszerek elhagyása után fellépő javulás vagy az empirikus tapasztalat, esetleg irodalmi adatok alapján lehet a felelős gyógyszert feltételezni. A gyógyszerérzékenység bizonyítása bonyolult, jól átgondolt orvosi tevékenység útján lehetséges, és azokban az esetekben szükséges, amikor a gyanús gyógyszer más vegyületcsoportba tartozó szerrel nem helyettesíthető, és a betegnek feltétlenül szükséges szednie. A jelen közlemény célja egy eset kapcsán körvonalazni azokat a lehetőségeket és veszélyeket, melyek a kivizsgálás során alkalmazhatók, illetve megjelenhetnek. A kivizsgálás során használt módszerek a gyanúba vett gyógyszerekkel – lamotrigin, risperidon, sertralin – zopiclonum, atorvastatin elvégzett epicutan teszt során egyedül a sertralin adott a multiform tünetekkel azonos pozitív reakciót. A pozitív bőrteszt területéről készült hisztológiai vizsgálat eredménye visszautalt az eredetileg észlelt klinikai formára (erythema exsudativum multiforme Stevens–Johnson-szindróma). A beteg bipoláris affektív zavara miatt a negatív bőrtesztet adó készítményekkel per os provokáció történt, ez azonban a beteg számára kockázatos, de az egyetlen megbízható és biztos módszer. Az elvégzett per os expozíció során a törzsön a lamotrigintől már tört adag bevételét követően három órán belül diffúz erythema, 12 órán belül az alkalmazott szteroid- és antihisztamin-kezelés ellenére scarlatiniform exanthema jelent meg. Az eset érdekessége, hogy a gyanúba vett gyógyszerek során epicutan teszttel egy gyógyszer érzékenysége igazolódott, azonban a másik gyanúba vett készítménnyel végzett pozitív per os expozíciós próba is váratlanul tünetet provokált (scarlatiniform, azonnali reakciót). Megállapítható, hogy csupán egy bizonyos módszer még a klinikai képpel való egyező eredmény alapján sem elegendő adverz gyógyszerreakció provokáló tényezőjének bizonyítására.

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