Reports Of Torsades De Pointes Research Articles

Linezolid and the risk of QT interval prolongation: A pharmacovigilance study of the Food and Drug Administration Adverse Event Reporting System.

Few studies have investigated linezolid (LZD)-associated cardiotoxicity. This study explored the potential association between LZD and QT interval prolongation. Adverse event reports of QT interval prolongation associated with LZD from the Food and Drug Administration Adverse Event Reporting System from January 2013 to December 2021 were analysed and the reporting odds ratio (ROR) with 95% confidence intervals were calculated. A total of 6738 adverse event reports of LZD as the primary and secondary suspected drug were obtained from the database, including 192 reports with electrocardiogram QT prolonged (QTp), and the ROR value was 26.1 (95% CI = 22.6-30.2). There were 8 reports of long QT syndrome, ROR 14.2 (95% CI =7.1-28.5); 5 reports of torsade de pointes, ROR 3.2 (95% CI =1.3-7.6); and 5 reports of ventricular tachycardia, ROR 1.9 (95% CI =0.8-4.5). Subgroup analysis revealed that patients with tuberculosis treated with LZD had a higher reporting rate among all QTp reports, exhibiting an odds ratio of 330.0 (95% CI = 223.1-488.1). The odds ratios of QTp associated with LZD treatments in patients with and without tuberculosis were 4.2 (95% CI =3.4-5.3) and 1.2 (95% CI =0.8-1.6), respectively. The study showed an association between LZD and QT interval prolongation. In the report on patients with tuberculosis, the incidence of QTp was higher when treated with LZD.

Summary of Torsades de Pointes (TdP) Reports Associated with Intravenous Drug Formulations Containing the Preservative Chlorobutanol.

Drug-induced torsades de pointes (TdP) is a potentially lethal ventricular arrhythmia that is associated with drugs that prolong the QT interval on the electrocardiogram (ECG) due to their interference with the cardiac potassium current, IKR. Intravenous (IV) formulations of methadone have been associated with TdP and contain the preservative chlorobutanol, which, like methadone, blocks IKR. The combinations of chlorobutanol with methadone or terfenadine, another IKR blocker, produce synergistic IKR block. The aim of this study was to examine and summarize the evidence available to address the question: what other IV drug formulations contain chlorobutanol and are they associated with TdP? IV drug products containing the preservative chlorobutanol were identified by searching the websites DailyMed ( https://dailymed.nlm.nih.gov/dailymed/index.cfm ) and Drugs@FDA ( https://www.accessdata.fda.gov/scripts/cder/daf/ ). For each drug identified, PubMed and the FDA's Adverse Event Reporting System (FAERS) were searched for reports of TdP and/or QT prolongation and FAERS data were analyzed for disproportionality of reports. The search found nine drugs (methadone, epinephrine, papaverine, oxytocin, vasopressin, testosterone, estradiol, isoniazid, and desmopressin) that contain chlorobutanol 2.5 (n=1) or 5.0mg/mL. All nine drugs had reports of QT prolongation or TdP reported in FAERS and all but estradiol, testosterone, desmopressin, and isoniazid had reports of QT prolongation or TdP in PubMed. Two of the nine drugs (epinephrine and methadone) had positive signals (by disproportionality analysis) for TdP in FAERS (EB05 2.88 and 23.81, respectively) and four (methadone, epinephrine, papaverine, and vasopressin) were reported in published articles as the suspect drugs in cases of TdP. The pharmacologic profile of chlorobutanol (synergistic IKR block) and its association with reports of TdP and QT prolongation suggest the need for a full evaluation of its cardiac safety when used as a preservative in IV drug and vitamin formulations.

Proarrhythmic Potential of Dronedarone: Emerging Evidence from Spontaneous Adverse Event Reporting

To characterize the frequency and type of cardiac events, including torsade de pointes, associated with dronedarone and its structural analog, amiodarone, outside of the clinical trial setting. Retrospective analysis. Spontaneous reports in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database generated between July 1, 2009, and June 30, 2011. All reports of adverse events during the study period were reviewed to identify cardiac events associated with any approved drug in the United States. The type and number of cardiac events associated with dronedarone and amiodarone were determined. Active ingredients were identified using the Drugs@FDA database, and the Medical Dictionary for Regulatory Activities (MedDRA) was used to aggregate related adverse events. To avoid redundant reporting, all statistics were generated in reference to unique case identifiers. Dronedarone was associated with more adverse cardiovascular event reports than amiodarone (810 vs 493 reports) during the study period. Dronedarone was also associated with the most reports of torsade de pointes of any approved drug in the United States (37 reports), followed by amiodarone (29 reports). Reports of ventricular arrhythmias and cardiac arrest (138 vs 113 reports) as well as heart failure (179 vs 126 reports) were more common with dronedarone than amiodarone. Dronedarone was associated with reports of ventricular arrhythmia, cardiac arrest, and torsade de pointes in clinical practice. Whether this observation accounts for the increased risk of fatal arrhythmia observed in a recent prospective trial requires further investigation.

G018 Evaluation of IKr blocking properties of different molecules with or without torsadogenic properties

Currently, industrials and regulatory authorities are worried by Torsades de Pointes (TdP), a type of ventricular tachycardia, which can lead to sudden death. The most recent guidelines from the International Committee of Harmonization, recommend to assess properly the risk of TdP, by different approaches, among others an in vitro method. This method consists on studying the blockade of a voltage-dependant potassium channel, called hERG. Indeed, hERG channel, responsible for the IKr current, seems to be blocked by the majority of the torsadogenic molecules and, is thus considered as an important marker of pro arrhythmic risk. CERB developed a bio-computerized database named TdPScreen® to predict the risk of TdP. Known molecules are classified according to their pro arrhythmic potential, from group A to C. The group A corresponds to drugs with numerous or several reports of TdP, the group B to compounds causing QT prolongation with TdP at very low frequency; and in group C to drugs with no report of TdP or QT prolongation. This database suggests that other factors than a single blockade of IKr could be involved in the genesis of druginduced TdP. We performed experiments in patch-clamp using HEK cells expressing stably the hERG channel. Different compounds from the different groups, above mentioned, were evaluated for their IKr blocking potency and compared to the TdPScreen® database. Results show some torsadogenic drugs might exhibit very low IKr blocking properties (e.g. D-sotalol), whereas other non-torsadogenic drugs are potent IKr inhibitors (e.g. verapamil, diltiazem…). These results, and others, indicate that drugs can block hERG current without any influence on TdP appearance. We conclude that assessing pro arrhythmic potential of compounds, only on the blocking effects of IKr, in vitro, can lead to the eviction of interesting molecules.

First Do No Harm … Reduction?

An expert panel convened to discuss how to incorporate methadone's possible effect on the QT interval into clinical practice. The findings and recommendations of some of the panel members appear in...

The Black Box Warning for Droperidol

Mayo Clinic College of Medicine, Rochester, Minnesota. nuttall.gregory@mayo.eduI thank Doctor Sosis for his thoughtful comments and the journal Anesthesiology for the opportunity to respond. As noted in our article,1the black box warning on droperidol was based solely on case reports of torsade de pointes associated with droperidol use and the known pharmacologic effect of droperidol to prolong the QT interval. Our manuscript was an attempt to determine, through a retrospective study, the true incidence of torsade de pointes associated with droperidol administration in patients who received low-dose droperidol for prophylaxis and/or treatment of nausea and vomiting associated with anesthesia and surgery. We found the incidence of torsade de pointes to be extremely low. This, combined with the fact that droperidol is one of the few very effective rescue therapies for patients who develop nausea and vomiting postoperatively, led to our conclusion that “the Food and Drug Administration black box warning for low-dose droperidol is excessive and unnecessary.”Dr. Sosis was “surprised” that according to our study, the use of droperidol completely disappeared after insertion of the black box warning. We were not, because this is consistent with what we have observed in our colleagues’ behavior throughout many institutions and expressed at many national meetings. From Dr. Sosis’ comments, I can only assume that he and his institution have continued to use droperidol for their patients despite the black box warning. However, given the last paragraph of his letter, I suspect that this is not true and that he and his institution have also stopped using droperidol. Dr. Sosis is correct that there are black box warnings on midazolam (respiratory depression and arrest), succinylcholine (acute rhabdomyolysis with hyperkalemia), and ketamine (emergence phenomena), and yet anesthesiologists still use these drugs. Most of these black box warning complications are situations that anesthesiologists are comfortable preventing or treating or avoiding via patient selection.In contrast, the black box warning on droperidol mandates that a 12-lead electrocardiogram be performed before administration of droperidol. If the QTc is greater than 440 ms for males and 450 ms for females (QTc values seen in at least 10% of all adults), droperidol is not to be administered. Further, the patient must have electrocardiographic monitoring for 2–3 h after droperidol administration. Functionally, logistically, and practically, many anesthesiologists do not want to deal with these hassles. They also fear the litigation costs should they use droperidol without following the black box–required electrocardiographic monitoring and should the patient have an adverse outcome.The withdrawal of rofecoxib (Vioxx) and other medications demonstrates the importance of postmarketing or phase IV safety studies. The goal of our study was to perform a phase IV trial of droperidol. As such, we found droperidol to be a safe, effective, and inexpensive antiemetic.Mayo Clinic College of Medicine, Rochester, Minnesota. nuttall.gregory@mayo.edu

Torsade de pointes induced by psychotropic drugs and the prevalence of its risk factors

To investigate all published case reports of torsade de pointes (TdP) induced by psychotropic drugs (PDs) in order to examine the prevalence of risk factors for TdP prior to the drug initiation. We found 45 reports on 70 patients with TdP induced by PDs. Each report was analyzed for the presence of risk factors for TdP: female gender, heart disease, hypokalemia, high doses of offending agent, concomitant use of a QT interval prolonging agent, and a history of long-QT syndrome. Female gender was the most common risk factor for TdP (71.4%). The other studied risk factors were also frequently present (34.2-14.2%). Nearly all patients had at least one and 51 (73%) patients had >2 risk factors for TdP prior to PD initiation. We wish to raise the level of awareness of risk factors for TdP in the psychiatric community.

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres

Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres. Of them, 22 are clearly associated and/or labelled with a risk of TdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The 10 remaining drugs are without reports of TdP and QT prolongation. The relevance of different indicators such as APD(90) increase, reverse use dependency, action potential triangulation or effect on V(max) was evaluated by comparison with available clinical data. Finally, a complex algorithm called TDPscreen and based on two subalgorithms corresponding to particular electrophysiological patterns was defined. This latter algorithm enabled a clear separation of drugs into three groups: (A) drugs with numerous or several reports (>2 cases) of TdP, (B) drugs causing QT prolongation and/or TdP only, the latter at a very low frequency (< or =2 cases), (C) drugs without reports of TdP or QT prolongation. The use of such an algorithm combined with a database accrued from reference compounds with available clinical data is suggested as a basis for testing new candidate drugs in the early stages of development for proarrhythmic risk prediction.

Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.

To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System.

In this case series, we examined concomitant risk factors mentioned in reports of torsades de pointes, a rare ventricular arrhythmia, that occurred in association with administration of macrolide antimicrobials (e.g., azithromycin, clarithromycin, dirithromycin, and erythromycin). Increasing age, female sex, and concomitant diseases and drug administration believed to increase risks for torsades de pointes were commonly reported.

Effects of Cisapride on QT Interval in Children † 119

Background. Cisapride is widely used in children with gastroesophageal reflux. Recent reports of torsade de pointes and heart block associated with prolonged QT interval in children using cisapride raise concern about its safety.